Treatment of multiorgan failure with autologous pluripotent stem cell derived therapies

Abstract

Methods and compositions of matter for the treatment of multiple organ dysfunction syndrome using products derived from autologous pluripotent derived stem cells. Autologous pluripotent stem cells can be induced to differentiate into therapeutic cell populations including mesenchymal stem cell and regulatory T cell populations in the presence of a decellularized matrix. Said cells can be transfected with therapeutic genes to enhance function and activity upon administration to a subject. Combinations of autologous cell types can be utilized. In such combinations, the cell populations are conditioned to regulate disease and modulate immune responses for the treatment of multiorgan failure.

Description

TREATMENT OF MULTIORGAN FAILURE WITH AUTOLOGOUS PLURIPOTENT STEM CELL DERIVED THERAPIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims benefit of U.S. Provisional Patent Application Serial No. 63 / 604,870, filed on November 30, 2023, entitled "TREATMENT OF MULTIORGAN FAILURE WITH AUTOLOGOUS PLURIPOTENT STEM CELL DERIVED THERAPIES", the contents of which are incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] The invention pertains to the fields of regenerative medicine and multiorgan failure. Specifically, the invention relates treatment of multiorgan failure with cellular therapies and regenerative medicine approaches. More specifically, the invention pertains to utilization of autologous pluripotent stem cell derived cells to generate cells with immune modulatory properties and their use to treat conditions such as sepsis and their related multi-organ complications.BACKGROU ND OF THE INVENTION

[0003] It is accepted that one of the most common causes of death for patients admitted to the intensive care unit (ICU) is a conditioned known by multiple names such as multiple organ dysfunction syndrome (MODS), multi-organ failure, multiple systems organ failure, or through some of its more prominent manifestations, as the acute respiratory distress syndrome (ARDS) or disseminated intravascular coagulation (DIC).

[0004] Although the syndrome involves the dysfunction of many organs, it also affects physiologic systems not classically thought of as organs, including the hematologic system, immune system, or the endocrine system. Finally, although it is described as a syndrome, its clinical course and causes are highly variable, and there is only the most general form of consensus regarding the organs whose dysfunction comprises the syndrome, or the criteria that should be used to describe this dysfunction. Multiple Organ Dysfunction Syndrome (MODS) can be defined as the development of potentially reversible physiologic derangement involving twoor more organ systems not involved in the disorder that resulted in intensive care unit (ICU) admission and arising in the wake of a potentially life-threatening physiologic insult.

[0005] The observation that critically ill patients die, not as a result of the progression of the disorder that precipitated ICU admission, but of a complex series of physiologic derangements that develop following resuscitation and management in the ICU was first made in the 1960's. It was later discovered that the concomitant failure of multiple interdependent organ systems was the unsolved problem in critical care. Subsequent reports highlighted the important role of occult, uncontrolled infection in the pathogenesis of MODS, although control of infection did not necessarily result in reversal of the physiologic derangements, nor was infection universally present in patients with the syndrome.

[0006] MODS is characterized by the lung possessing reduced ability to provide normal gas exchange. This is associated with arterial hypoxemia. Causes of the impaired gas exchange include the following: 1) atelectasis (the collapse of part or all of a lung, is caused by a blockage of the air passages (bronchus or bronchioles) or by pressure on the lung); 2) intravascular thrombosis or altered regional flow contribute to ventilation / perfusion mismatch; and 3) increased capillary permeability leads to alveolar flooding and an increased diffusion distance for oxygen. Additionally, local lung injury resulting from infection or trauma contributes to compromised lung function. With the institution of ventilatory support, lung injury can be aggravated through what has been termed volutrauma and barotrauma, leading to further atelectasis in dependent lung zones, and cyst formation in the anti-dependent zones. Another adverse event is that during the process of tissue repair, initiated with the influx of inflammatory cells into the injured lung, results in fibrosis and hyaline membrane formation, the cardinal pathologic features of late ARDS.

[0007] Renal dysfunction in MODS is reflected in impairment of normal selective excretory function, initially in oliguria despite adequate intravascular volume, but later in a rising creatinine level, and fluid and electrolyte derangements of sufficient magnitude that dialysis is required. Its causes are both pre-renal and renal. Reduced renal blood flow secondary to systemic hypotension, altered regional perfusion, or increased intra-abdominal pressure is an early risk factor; evolution of the disorder is compounded by pre-existing physiologic deficit and the effects of nephrotoxic drugs. Obstructive causes must be considered and ruled out. As is the case for lung injury, ICU interventions contribute to the evolution of the syndrome: vasopressor agents cause further reductions in renal blood flow, while potentially nephrotoxic drugs are a key part of the anti-infective arsenal used in the ICU.

[0008] These cardiac pathology associated with MODS consist of: 1) generalized reduction in peripheral vascular tone, mediated largely through the local vasodilatory activity of nitric oxide; 2) systemic increase in capillary permeability producing diffuse capillary leak and edema, and contributing to further dysfunction in other organ systems; 3) microvascular plugging and stasis, resulting from occlusion of the microvasculature by abnormally rigid erythrocytes and leukocytes, and resulting in arteriovenous shunting that contributes to a high mixed venous saturation and 4) myocardial depression, affecting the right side of the heart in particular.

[0009] MODS is known to cause gastrointestinal dysfunction. In critical illness this likely results from the interacting effects of reduced regional blood flow, impaired motility, and alterations in the normal microbial flora. In the past, upper gastrointestinal bleeding or stress ulceration was the most common manifestation of gut dysfunction; this complication has become uncommon with improvements in hemodynamic support, earlier diagnosis of infection, and the appropriate use of effective prophylaxis. Intolerance of enteral feeding, reflected in bloating and diarrhea is another manifestation of gut dysfunction. However, in contrast to other organ systems, simple clinical measures of gut dysfunction are not readily available.

[0010] The other system effective is the hepatic system. In MODS is reflected in hyperbilirubinemia and cholestasis, rather than in biochemical evidence of hepatocellular injury or synthetic dysfunction. A stereotypical pattern of altered hepatic protein synthesis - the acute phase response - typically accompanies MODS as a non-specific manifestation of systemic inflammation. Serum levels of C reactive protein and alpha-1 anti-trypsin are elevated as part of the acute phase response, whereas levels of albumin, a negative acute phase reactant, are depressed.

[0011] Neurologically speaking, patients with MODS have an altered level of consciousness, reflected in a reduction in the Glasgow Coma Score, is the most readily recognizable manifestation of the neurologic dysfunction of MODS. Its causes are multiple, including the iatrogenic effects of sedatives and analgesics, metabolic alterations, subclinical cerebral edema and reduced cerebral perfusion pressure, and, perhaps, micro-abscesses in the brain. A peripheral neuropathy - the so-called 'critical illness polyneuropathy' - is commonly present, though harder to measure.

[0012] From a hematological perspective, leucocytosis is an adaptive response to a variety of acute stresses and therefore commonly present, although not truly a manifestation of organ dysfunction. Similarly, a mild anemia resulting from both bone marrow suppression and iatrogenic blood-taking is common. However, the most widely cited manifestation of dysfunction of the hematologic system in MODS is thrombocytopenia, in its most extreme formresulting in disseminated intravascular coagulation (DIC). Like other manifestations of MODS, the causes of thrombocytopenia in critical illness are many - heparin-induced thrombocytopenia, intravascular consumption, and reduced production to name a few.

[0013] Multiple abnormalities of non-specific and specific immune function are described in the critically ill patient, including impaired delayed type hypersensitivity responsiveness, altered production of antibodies, and a complex spectrum of abnormalities in the regulation of lymphocyte responses. The most readily evident and clinically relevant manifestation of altered immunity in MODS is the development of nosocomial ICU-acquired infection, caused by relatively avirulent organisms. The characteristic flora of ICU-acquired infection in MODS includes coagulase-negative Staphylococci, Enterococci, Candida, and Pseudomonas.

[0014] Multiple metabolic and endocrine abnormalities are evident during MODS, although they are less well-characterized, Hyperglycemia and relative insulin resistance is both common and readily detected. Less accessible abnormalities include the euthyroid sick syndrome, and relative adrenal insufficiency. The latter has recently gained prominence as a promising therapeutic target for the patient with prolonged inflammation and organ dysfunction.SUMMARY OF THE INVENTION

[0015] A summary is provided below based on numbered aspects of the invention.

[0016] 1. A method for treatment of multiorgan failure comprising: a) obtaining an autologous cellular population; b) generating a pluripotent cellular population from said autologous cellular population; c) differentiating said cellular population into cells useful for treatment of multiorgan failure; d) optionally priming said cells capable of treating multiorgan failure; e) preserving said cells for use; and f) administering said cells in a patient in need of treatment.

[0017] 2. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma C reactive protein of more than 50 percent as compared to an age matched control.

[0018] 3. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma interleukin-1 beta of more than 150 percent as compared to an age matched control.

[0019] 4. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma interleukin-6 of more than 100 percent as compared to an age matched control.

[0020] 5. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma interleukin-8 of more than 100 percent as compared to an age matched control.

[0021] 6. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma interleukin-11 of more than 50 percent as compared to an age matched control.

[0022] 7. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma interleukin-12 of more than 300 percent as compared to an age matched control.

[0023] 8. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma interleukin-15 of more than 150 percent as compared to an age matched control.

[0024] 9. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma interleukin-18 of more than 200 percent as compared to an age matched control.

[0025] 10. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma interleukin-17 of more than 100 percent as compared to an age matched control.

[0026] 11. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma interleukin-23 of more than 100 percent as compared to an age matched control.

[0027] 12. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma interleukin-27 of more than 100 percent as compared to an age matched control.

[0028] 13. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma interleukin-33 of more than 100 percent as compared to an age matched control.

[0029] 14. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma TNF-alpha of more than 50 percent as compared to an age matched control.

[0030] 15. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma HMGBl of more than 50 percent as compared to an age matched control.

[0031] 16. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma d-dimer of more than 50 percent as compared to an age matched control.

[0032] 17. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma lymphotoxin of more than 50 percent as compared to an age matched control.

[0033] 18. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma TRAIL of more than 50 percent as compared to an age matched control.

[0034] 19. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma TRANCE of more than 400 percent as compared to an age matched control.

[0035] 20. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma RANK ligand of more than 200 percent as compared to an age matched control.

[0036] 21. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma fibrinogen of more than 100 percent as compared to an age matched control.

[0037] 22. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma circular DNA of more than 50 percent as compared to an age matched control.

[0038] 23. The method of aspect 1, wherein said multiorgan failure is associated with an elevation of plasma free DNA of more than 25 percent as compared to an age matched control.

[0039] 24. The method of aspect 1, wherein said multiorgan failure is associated with vascular leakage.

[0040] 25. The method of aspect 1, wherein said multiorgan failure is associated with disseminated intravascular coagulation.

[0041] 26. The method of aspect 1, wherein said multiorgan failure is associated systemic endothelial activation.

[0042] 27. The method of aspect 26, wherein said systemic endothelial activation is associated with augmented levels of tissue factor on said endothelial surface as compared to an age matched control.

[0043] 28. The method of aspect 27, wherein said levels of tissue factor are 10 percent higher than an age matched control.

[0044] 29. The method of aspect 27, wherein said levels of tissue factor are 25 percent higher than an age matched control.

[0045] 30. The method of aspect 27, wherein said levels of tissue factor are 100 percent higher than an age matched control.

[0046] 31. The method of aspect 1, wherein said autologous cells are mesenchymal stem cells generated from said pluripotent stem cells are capable of programming macrophages to secrete enhanced levels of prostaglandin E2.

[0047] 32. The method of aspect 1, wherein said mesenchymal stem cells generated from said pluripotent stem cells are capable of programming macrophages to secrete enhanced levels of IL-10.

[0048] 33. The method of aspect 1, wherein said mesenchymal stem cells generated from said pluripotent stem cells are capable of programming macrophages to secrete enhanced levels of IL-35.

[0049] 34. The method of aspect 1, wherein said mesenchymal stem cells generated from said pluripotent stem cells are capable of programming macrophages to secrete enhanced levels of IL-22.

[0050] 35. The method of aspect 1, wherein said mesenchymal stem cells generated from said pluripotent stem cells are capable of programming macrophages to secrete enhanced levels of EGF.

[0051] 36. The method of aspect 1, wherein said mesenchymal stem cells generated from said pluripotent stem cells are capable of programming macrophages to secrete enhanced levels of CNTF.

[0052] 37. The method of aspect 1, wherein said mesenchymal stem cells generated from said pluripotent stem cells are capable of programming macrophages to secrete enhanced levels of soluble TNF alpha receptor p55.

[0053] 38. The method of aspect 1, wherein said mesenchymal stem cells generated from said pluripotent stem cells are capable of programming macrophages to secrete enhanced levels of soluble TNF alpha receptor p55.

[0054] 39. The method of aspect 1, wherein said mesenchymal stem cells are capable of suppressing a mixed lymphocyte reaction.

[0055] 40. The method of aspect 1, wherein said mesenchymal stem cells are capable of suppressing interferon gamma production in a mixed lymphocyte reaction.

[0056] 41. The method of aspect 1, wherein said mesenchymal stem cells are capable of suppressing TNF-alpha production in a mixed lymphocyte reaction.

[0057] 42. The method of aspect 1, wherein said mesenchymal stem cells are capable of suppressing IL-17 production in a mixed lymphocyte reaction.

[0058] 43. The method of aspect 1, wherein said mesenchymal stem cells are capable of suppressing calreticulin production in a mixed lymphocyte reaction.

[0059] 44. The method of aspect 1, wherein said mesenchymal stem cells are capable of enhancing alpha 1 antitrypsin production in a mixed lymphocyte reaction.

[0060] 45. The method of aspect 1, wherein said mesenchymal stem cells are capable of enhancing IL-10 production in a mixed lymphocyte reaction.

[0061] 46. The method of aspect 1, wherein said mesenchymal stem cells are capable of enhancing IL-4 production in a mixed lymphocyte reaction.

[0062] 47. The method of aspect 1, wherein said mesenchymal stem cells are capable of enhancing IL-13 production in a mixed lymphocyte reaction.

[0063] 48. The method of aspect 1, wherein said mesenchymal stem cells are capable of enhancing IL-20 production in a mixed lymphocyte reaction.

[0064] 49. The method of aspect 1, wherein said mesenchymal stem cells are capable of enhancing IL-22 production in a mixed lymphocyte reaction.

[0065] 50. The method of aspect 1, wherein said mesenchymal stem cells are capable of enhancing GDNF production in a mixed lymphocyte reaction.

[0066] 51. The method of aspect 1, wherein said mesenchymal stem cells express CXCR4.

[0067] 52. The method of aspect 1, wherein said mesenchymal stem cells express CD90.

[0068] 53. The method of aspect 1, wherein said mesenchymal stem cells express CD105.

[0069] 54. The method of aspect 1, wherein said mesenchymal stem cells express somatostatin receptor 1.

[0070] 55. The method of aspect 1, wherein said mesenchymal stem cells express thromboplastin.

[0071] 56. The method of aspect 1, wherein said mesenchymal stem cells expressTNFSF4.

[0072] 57. The method of aspect 1, wherein said mesenchymal stem cells express FoxL2.

[0073] 58. The method of aspect 1, wherein said mesenchymal stem cells express SPON2.

[0074] 59. The method of aspect 1, wherein said mesenchymal stem cells express VAT1L.

[0075] 60. The method of aspect 1, wherein said mesenchymal stem cells expressALDH1A1.

[0076] 61. The method of aspect 60, wherein said mesenchymal stem cells express enhanced ALDH1A1 when treated with valproic acid.

[0077] 62. The method of aspect 60, wherein said mesenchymal stem cells express enhanced ALDH1A1 when treated with phenylbutyrate.

[0078] 63. The method of aspect 60, wherein said mesenchymal stem cells express enhanced ALDH1A1 when treated with trichostatin A.

[0079] 64. The method of aspect 60, wherein said mesenchymal stem cells express enhanced ALDH1A1 when treated with interleukin-3.

[0080] 65. The method of aspect 60, wherein said mesenchymal stem cells express enhanced ALDH1A1 when treated with angiopoietin.

[0081] 66. The method of aspect 60, wherein said mesenchymal stem cells express enhanced ALDH1A1 when treated with trichostatin A.

[0082] 67. The method of aspect 1, wherein said mesenchymal stem cells express WT1.

[0083] 68. The method of aspect 1, wherein said mesenchymal stem cells express survivin.

[0084] 69. The method of aspect 1, wherein said mesenchymal stem cells express livin.

[0085] 70. The method of aspect 1, wherein said mesenchymal stem cells express PD-L1.

[0086] 71. The method of aspect 1, wherein said mesenchymal stem cells expressGPR126.

[0087] 72. The method of aspect 1, wherein said mesenchymal stem cells express IFIT2.

[0088] 73. The method of aspect 1, wherein said mesenchymal stem cells express CD49d.

[0089] 74. The method of aspect 1, wherein said mesenchymal stem cells express cathepsin C.

[0090] 75. The method of aspect 1, wherein said mesenchymal stem cells express PI M3.

[0091] 76. The method of aspect 1, wherein said mesenchymal stem cells express anoctamin 4.

[0092] 77. The method of aspect 1, wherein said mesenchymal stem cells express c-met.

[0093] 78. The method of aspect 1, wherein said cells useful for treatment of multiorgan failure are T cells.

[0094] 79. The method of aspect 78, wherein said T cells are capable of suppressing macrophage activation.

[0095] 80. The method of aspect 79, wherein said macrophage activation is production of nitric oxide.

[0096] 81. The method of aspect 79, wherein said macrophage activation is production of procoagulant microvesicles.

[0097] 82. The method of aspect 79, wherein said macrophage activation is characterized by release of vasodilatory factors.

[0098] 83. The method of aspect 82, wherein said vasodilatory factor is a prostaglandin.

[0099] 84. The method of aspect 83, wherein said prostaglandin is prostaglandin E2.

[0100] 85. The method of aspect 83, wherein said prostaglandin is prostaglandin El.

[0101] 86. The method of aspect 82, wherein said vasodilatory factor is a leukotriene.

[0102] 87. The method of aspect 82, wherein said vasodilatory factor is a mitogen activated protein kinase activator.

[0103] 88. The method of aspect 82, wherein said vasodilatory factor causes translocation of NF-kappa B.

[0104] 89. The method of aspect 82, wherein said vasodilatory factor causes degradation of iKB.

[0105] 90. The method of aspect 82, wherein said vasodilatory factor causes endothelial leakage.

[0106] 91. The method of aspect 82, wherein said vasodilatory factor is TNF-alpha.

[0107] 92. The method of aspect 82, wherein said vasodilatory factor is a prostacyclin.

[0108] 93. The method of aspect 82, wherein said vasodilatory factor is a bradykinin.

[0109] 94. The method of aspect 82, wherein said vasodilatory factor is lymphotoxin.

[0110] 95. The method of aspect 82, wherein said vasodilatory factor is complement component C3.

[0111] 96. The method of aspect 82, wherein said vasodilatory factor is complement component C3a.

[0112] 97. The method of aspect 82, wherein said vasodilatory factor is complement component C5.

[0113] 98. The method of aspect 82, wherein said vasodilatory factor is complement component C5a.

[0114] 99. The method of aspect 82, wherein said vasodilatory factor is complement component C3b.

[0115] 100. The method of aspect 82, wherein said vasodilatory factor is histamine.

[0116] 101. The method of aspect 82, wherein said vasodilatory factor is IL-2.

[0117] 102. The method of aspect 79, wherein said T cell is capable of producing moreTGF-beta as compared to interferon gamma upon crosslinking of CD3 and CD28.

[0118] 103. The method of aspect 79, wherein said T cell is capable of producing moreTGF-beta as compared to interferon gamma upon crosslinking of CD3 and CD45.

[0119] 104. The method of aspect 79, wherein said T cell is capable of producing moreTGF-beta as compared to interferon gamma upon crosslinking of CD3 and ICOS.

[0120] 105. The method of aspect 79, wherein said T cell is capable of producing moreTGF-beta as compared to interferon gamma upon crosslinking of CD3 and activation of protein kinase C.

[0121] 106. The method of aspect 79, wherein said T cell is capable of producing moreTGF-beta as compared to interferon gamma when treated with a calcium ionophore.

[0122] 107. The method of aspect 79, wherein said T cell is capable of producing moreTGF-beta as compared to interferon gamma upon crosslinking of CD3 and CD25.

[0123] 108. The method of aspect 79, wherein said T cell is capable of producing moreTGF-beta as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-2.

[0124] 109. The method of aspect 79, wherein said T cell is capable of producing moreTGF-beta as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-7.

[0125] 110. The method of aspect 79, wherein said T cell is capable of producing moreTGF-beta as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-15.

[0126] 111. The method of aspect 79, wherein said T cell is capable of producing more interleukin-10 as compared to interferon gamma upon crosslinking of CD3 and CD28.

[0127] 112. The method of aspect 79, wherein said T cell is capable of producing more interleukin-10 as compared to interferon gamma upon crosslinking of CD3 and CD45.

[0128] 113. The method of aspect 79, wherein said T cell is capable of producing more interleukin-10 as compared to interferon gamma upon crosslinking of CD3 and ICOS.

[0129] 114. The method of aspect 79, wherein said T cell is capable of producing more interleukin-10 as compared to interferon gamma upon crosslinking of CD3 and activation of protein kinase C.

[0130] 115. The method of aspect 79, wherein said T cell is capable of producing more interleukin-10 as compared to interferon gamma when treated with a calcium ionophore.

[0131] 116. The method of aspect 79, wherein said T cell is capable of producing more interleukin-10 as compared to interferon gamma upon crosslinking of CD3 and CD25.

[0132] 117. The method of aspect 79, wherein said T cell is capable of producing more interleukin-10 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-2.

[0133] 118. The method of aspect 79, wherein said T cell is capable of producing more interleukin-10 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-7.

[0134] 119. The method of aspect 79, wherein said T cell is capable of producing more interleukin-10 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-15.

[0135] 120. The method of aspect 79, wherein said T cell is capable of producing more interleukin-10 as compared to interferon gamma upon crosslinking of CD3 and addition of allogeneic antigen presenting cells.

[0136] 121. The method of aspect 79, wherein said T cell is capable of producing more interleukin-20 as compared to interferon gamma upon crosslinking of CD3 and CD28.

[0137] 122. The method of aspect 79, wherein said T cell is capable of producing more interleukin-20 as compared to interferon gamma upon crosslinking of CD3 and CD45.

[0138] 123. The method of aspect 79, wherein said T cell is capable of producing more interleukin-20 as compared to interferon gamma upon crosslinking of CD3 and ICOS.

[0139] 124. The method of aspect 79, wherein said T cell is capable of producing more interleukin-20 as compared to interferon gamma upon crosslinking of CD3 and activation of protein kinase C.

[0140] 125. The method of aspect 79, wherein said T cell is capable of producing more interleukin-20 as compared to interferon gamma when treated with a calcium ionophore.

[0141] 126. The method of aspect 79, wherein said T cell is capable of producing more interleukin-10 as compared to interferon gamma upon crosslinking of CD3 and CD25.

[0142] 127. The method of aspect 79, wherein said T cell is capable of producing more interleukin-20 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-2.

[0143] 128. The method of aspect 79, wherein said T cell is capable of producing more interleukin-20 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-7.

[0144] 129. The method of aspect 79, wherein said T cell is capable of producing more interleukin-20 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-15.

[0145] 130. The method of aspect 79, wherein said T cell is capable of producing more interleukin-20 as compared to interferon gamma upon crosslinking of CD3 and addition of allogeneic antigen presenting cells.

[0146] 131. The method of aspect 79, wherein said T cell is capable of producing more interleukin-35 as compared to interferon gamma upon crosslinking of CD3 and CD28.

[0147] 132. The method of aspect 79, wherein said T cell is capable of producing more interleukin-35 as compared to interferon gamma upon crosslinking of CD3 and CD45.

[0148] 133. The method of aspect 79, wherein said T cell is capable of producing more interleukin-35 as compared to interferon gamma upon crosslinking of CD3 and ICOS.

[0149] 134. The method of aspect 79, wherein said T cell is capable of producing more interleukin-35 as compared to interferon gamma upon crosslinking of CD3 and activation of protein kinase C.

[0150] 135. The method of aspect 79, wherein said T cell is capable of producing more interleukin-35 as compared to interferon gamma when treated with a calcium ionophore.

[0151] 136. The method of aspect 79, wherein said T cell is capable of producing more interleukin-35 as compared to interferon gamma upon crosslinking of CD3 and CD25.

[0152] 137. The method of aspect 79, wherein said T cell is capable of producing more interleukin-35 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-2.

[0153] 138. The method of aspect 79, wherein said T cell is capable of producing more interleukin-35 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-7.

[0154] 139. The method of aspect 79, wherein said T cell is capable of producing more interleukin-35 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-15.

[0155] 140. The method of aspect 79, wherein said T cell is capable of producing more interleukin-35 as compared to interferon gamma upon crosslinking of CD3 and addition of allogeneic antigen presenting cells.

[0156] 141. The method of aspect 79, wherein said T cell is capable of producing more soluble HLA-G as compared to interferon gamma upon crosslinking of CD3 and CD28.

[0157] 142. The method of aspect 79, wherein said T cell is capable of producing more soluble HLA-G as compared to interferon gamma upon crosslinking of CD3 and CD45.

[0158] 143. The method of aspect 79, wherein said T cell is capable of producing more soluble HLA-G as compared to interferon gamma upon crosslinking of CD3 and ICOS.

[0159] 144. The method of aspect 79, wherein said T cell is capable of producing more soluble HLA-G as compared to interferon gamma upon crosslinking of CD3 and activation of protein kinase C.

[0160] 145. The method of aspect 79, wherein said T cell is capable of producing more soluble HLA-G as compared to interferon gamma when treated with a calcium ionophore.

[0161] 146. The method of aspect 79, wherein said T cell is capable of producing more soluble HLA-G as compared to interferon gamma upon crosslinking of CD3 and CD25.

[0162] 147. The method of aspect 79, wherein said T cell is capable of producing more soluble HLA-G as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-2.

[0163] 148. The method of aspect 79, wherein said T cell is capable of producing more soluble HLA-G as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-7.

[0164] 149. The method of aspect 79, wherein said T cell is capable of producing more soluble HLA-G as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-15.

[0165] 150. The method of aspect 79, wherein said T cell is capable of producing more hepatocyte growth factor as compared to interferon gamma upon crosslinking of CD3 and addition of allogeneic antigen presenting cells.

[0166] 151. The method of aspect 79, wherein said T cell is capable of producing more hepatocyte growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and CD28.

[0167] 152. The method of aspect 79, wherein said T cell is capable of producing more hepatocyte growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and CD45.

[0168] 153. The method of aspect 79, wherein said T cell is capable of producing more hepatocyte growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and ICOS.

[0169] 154. The method of aspect 79, wherein said T cell is capable of producing more hepatocyte growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and activation of protein kinase C.

[0170] 155. The method of aspect 79, wherein said T cell is capable of producing more hepatocyte growth factor-1 as compared to interferon gamma when treated with a calcium ionophore.

[0171] 156. The method of aspect 79, wherein said T cell is capable of producing more hepatocyte growth factor-1 as compared to interferon gamma upon crosslinking of CD3 andCD25.

[0172] 157. The method of aspect 79, wherein said T cell is capable of producing more hepatocyte growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-2.

[0173] 158. The method of aspect 79, wherein said T cell is capable of producing more hepatocyte growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-7.

[0174] 159. The method of aspect 79, wherein said T cell is capable of producing more hepatocyte growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-15.

[0175] 160. The method of aspect 79, wherein said T cell is capable of producing more hepatocyte growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and addition of allogeneic antigen presenting cells.

[0176] 161. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and CD28.

[0177] 162. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and CD45.

[0178] 163. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and ICOS.

[0179] 164. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and activation of protein kinase C.

[0180] 165. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-1 as compared to interferon gamma when treated with a calcium ionophore.

[0181] 166. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and CD25.

[0182] 167. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-2.

[0183] 168. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-7.

[0184] 169. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-15.

[0185] 170. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-1 as compared to interferon gamma upon crosslinking of CD3 and addition of allogeneic antigen presenting cells.

[0186] 171. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-2 as compared to interferon gamma upon crosslinking of CD3 and CD28.

[0187] 172. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-2 as compared to interferon gamma upon crosslinking of CD3 and CD45.

[0188] 173. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-2 as compared to interferon gamma upon crosslinking of CD3 and ICOS.

[0189] 174. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-2 as compared to interferon gamma upon crosslinking of CD3 and activation of protein kinase C.

[0190] 175. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-2 as compared to interferon gamma when treated with a calcium ionophore.

[0191] 176. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-2 as compared to interferon gamma upon crosslinking of CD3 and CD25.

[0192] 177. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-2 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-2.

[0193] 178. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-2 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-7.

[0194] 179. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-2 as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-15.

[0195] 180. The method of aspect 79, wherein said T cell is capable of producing more fibroblast growth factor-2 as compared to interferon gamma upon crosslinking of CD3 and addition of allogeneic antigen presenting cells.

[0196] 181. The method of aspect 79, wherein said T cell is capable of producing more leukemia inhibitory factor as compared to interferon gamma upon crosslinking of CD3 and CD28.

[0197] 182. The method of aspect 79, wherein said T cell is capable of producing more leukemia inhibitory factor as compared to interferon gamma upon crosslinking of CD3 and CD45.

[0198] 183. The method of aspect 79, wherein said T cell is capable of producing more leukemia inhibitory factor as compared to interferon gamma upon crosslinking of CD3 and ICOS.

[0199] 184. The method of aspect 79, wherein said T cell is capable of producing more leukemia inhibitory factor as compared to interferon gamma upon crosslinking of CD3 and activation of protein kinase C.

[0200] 185. The method of aspect 79, wherein said T cell is capable of producing more leukemia inhibitory factor as compared to interferon gamma when treated with a calcium ionophore.

[0201] 186. The method of aspect 79, wherein said T cell is capable of producing more leukemia inhibitory factor as compared to interferon gamma upon crosslinking of CD3 and CD25.

[0202] 187. The method of aspect 79, wherein said T cell is capable of producing more leukemia inhibitory factor as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-2.

[0203] 188. The method of aspect 79, wherein said T cell is capable of producing more leukemia inhibitory factor as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-7.

[0204] 189. The method of aspect 79, wherein said T cell is capable of producing more leukemia inhibitory factor as compared to interferon gamma upon crosslinking of CD3 and addition of interleukin-15.

[0205] 190. The method of aspect 79, wherein said T cell is capable of producing more leukemia inhibitory factor as compared to interferon gamma upon crosslinking of CD3 and addition of allogeneic antigen presenting cells.

[0206] 191. The method of aspect 78, wherein said T cell is a T regulatory cell.

[0207] 192. The method of aspect 78, wherein said T cell is a natural T regulatory cell.

[0208] 193. The method of aspect 78, wherein said T cell is an induced T regulatory cell.

[0209] 194. The method of aspect 78, wherein said T cell is a TRI T cell.

[0210] 195. The method of aspect 78, wherein said T cell is a NKT cell.

[0211] 196. The method of aspect 78, wherein said T cell is a gamma delta T cell.

[0212] 197. The method of aspect 78, wherein said T cell is a type 2 NKT cell.

[0213] 198. The method of aspect 78, wherein said T cell is a type 2 gamma delta T cell.

[0214] 199. The method of aspect 78, wherein said T cell is a innate lymphoid cell type 2.

[0215] 200. The method of aspect 78, wherein said T cell is a innate lymphoid cell type 3.

[0216] 201. The method of aspect 191, wherein said T regulatory cell expresses GITR.

[0217] 202. The method of aspect 191, wherein said T regulatory cell expresses Fas ligand.

[0218] 203. The method of aspect 191, wherein said T regulatory cell expresses TNFSR1.

[0219] 204. The method of aspect 191, wherein said T regulatory cell expresses CD25.

[0220] 205. The method of aspect 191, wherein said T regulatory cell expresses ICOS.

[0221] 206. The method of aspect 191, wherein said T regulatory cell expresses HLA-G.

[0222] 207. The method of aspect 191, wherein said T regulatory cell expresses CTLA4.

[0223] 208. The method of aspect 191, wherein said T regulatory cell expresses FoxP3.

[0224] 209. The method of aspect 191, wherein said T regulatory cell expresses AIRE,

[0225] 210. The method of aspect 191, wherein said T regulatory cell expresses membrane bound TGF-beta.

[0226] 211. The method of aspect 191, wherein said T regulatory cell expresses VEGF.

[0227] 212. The method of aspect 191, wherein said T regulatory cell expresses VEGF-C.

[0228] 213. The method of aspect 191, wherein said T regulatory cell possesses ability to suppress antigen presenting activities of a cell population.

[0229] 214. The method of aspect 213, wherein said cell population is a B cell population.

[0230] 215. The method of aspect 214, wherein said B cell population is a B-l population.

[0231] 216. The method of aspect 214, wherein said B cell population is a B-10 population.

[0232] 217. The method of aspect 214, wherein said B cell population preferentially produces interleukin-10 upon ligation of the B cell receptor.

[0233] 218. The method of aspect 214, wherein said B cell population preferentially produces interleukin-35 upon ligation of the B cell receptor.

[0234] 219. The method of aspect 214, wherein said B cell population preferentially produces TGF-beta upon ligation of the B cell receptor.

[0235] 220. The method of aspect 214, wherein said B cell population preferentially secretes soluble TNF-receptor p55 upon exposure to interleukin-6.

[0236] 221. The method of aspect 214, wherein said B cell population preferentially secretes soluble TNF-receptor p75 upon exposure to interleukin-6.

[0237] 222. The method of aspect 213, wherein said cell population is a monocytic cell population.

[0238] 223. The method of aspect 222, wherein said monocytic cell population is a myeloid suppressor cell.

[0239] 224. The method of aspect 223, wherein said myeloid suppressor cell producesReptimed upon stimulation with TNF-alpha.

[0240] 225. The method of aspect 223, wherein said myeloid suppressor cell upregulates expression of indolamine 2,3 dioxygenase upon stimulation with interferon gamma.

[0241] 226. The method of aspect 223, wherein said myeloid suppressor cell upregulates production of COX-2 upon stimulation with TNF-alpha.

[0242] 227. The method of aspect 223, wherein said myeloid suppressor cell inhibits proliferation of T cells.

[0243] 228. The method of aspect 227 , wherein said T cells inhibited by said myeloid suppressor cells are Thl cells.

[0244] 229. The method of aspect 228, wherein said Thl cells express GAT A3.

[0245]

[0246] 230. The method of aspect 228, wherein said Thl cells produce more interferon gamma as compared to interleukin-4 upon stimulation with ionomycin.

[0247] 231. The method of aspect 228, wherein said Thl cells produce more interferon gamma as compared to interleukin-4 upon stimulation with a calcium ionophore.

[0248] 232. The method of aspect 228, wherein said Thl cells produce more interferon gamma as compared to interleukin-4 upon stimulation with a calcineurin activator.

[0249] 233. The method of aspect 228, wherein said Thl cells produce more interferon gamma as compared to interleukin-4 upon stimulation with a mitogen.

[0250] 234. The method of aspect 233, wherein said mitogen is PHA.

[0251] 235. The method of aspect 233, wherein said mitogen is PWM.

[0252] 236. The method of aspect 233, wherein said mitogen is ConA.

[0253] 237. The method of aspect 233, wherein said mitogen is Cynavirin.

[0254] 238. The method of aspect 233, wherein said mitogen is lipopolysaccharide.

[0255] 239. The method of aspect 233, wherein said mitogen is BCG.

[0256] 249. The method of aspect 233, wherein said mitogen is PHA.

[0257] 250. The method of aspect 227 , wherein said T cells inhibited by said myeloid suppressor cells are Th9 cells.

[0258] 251. The method of aspect 227 , wherein said T cells inhibited by said myeloid suppressor cells are Thl7 cells.

[0259] 252. The method of aspect 227 , wherein said T cells inhibited by said myeloid suppressor cells are type 1 NKT cells.

[0260] 253. The method of aspect 7. 1 , wherein said T cells inhibited by said myeloid suppressor cells are type 1 gamma delta T cells.

[0261] 254. The method of aspect 213, wherein said cell population is a dendritic cell population.

[0262] 255. The method of aspect 254, wherein said dendritic cell population expressesCDllc.

[0263] 256. The method of aspect 254, wherein said dendritic cell population expressesCD83.

[0264] 257. The method of aspect 254, wherein said dendritic cell population expressesTIGIT.

[0265] 258. The method of aspect 254, wherein said dendritic cell population expressesTIM-3.

[0266] 259. The method of aspect 254, wherein said dendritic cell population expressesCDlla.

[0267] 260. The method of aspect 254, wherein said dendritic cell population expressesCDlb.

[0268] 261. The method of aspect 254, wherein said dendritic cell population expressesCD40.

[0269] 262. The method of aspect 254, wherein said dendritic cell population expressesCD80.

[0270] 263. The method of aspect 254, wherein said dendritic cell population expressesCD86.

[0271] 264. The method of aspect 254, wherein said dendritic cell population expressesPD-L1.

[0272] 265. The method of aspect 254, wherein said dendritic cell population expressesPD-L2.

[0273] 266. The method of aspect 254, wherein said dendritic cell population expressesILT3.

[0274] 267. The method of aspect 254, wherein said dendritic cell population expressesILT4.

[0275] 268. The method of aspect 254, wherein said dendritic cell population expressesMDA.

[0276] 269. The method of aspect 254, wherein said dendritic cell population expressesTAP-1.

[0277] 270. The method of aspect 254, wherein said dendritic cell population expresses ability to produce exosomes.

[0278] 271. The method of aspect 270, wherein said exosomes possess ability to induce antigen presentation to T cells.

[0279] Til. The method of aspect 271, wherein said exosomes possess HLA II.

[0280] 273. The method of aspect 271, wherein said exosomes possess antigens derived from said dendritic cells.

[0281] 274. The method of aspect 271, wherein said exosomes express tetraspanin.

[0282] 275. The method of aspect 271, wherein said exosomes possess miRNA 155.

[0283] 276. The method of aspect 271, wherein said exosomes express CD40.

[0284] Til . The method of aspect 271, wherein said exosomes express CD80.

[0285] 278. The method of aspect 271, wherein said exosomes express CD86.

[0286] 279. The method of aspect 271, wherein said exosomes express Rabi.

[0287] 280. The method of aspect 271, wherein said exosomes express cell surface vimentin.

[0288] 281. The method of aspect 271, wherein said exosomes express CD8.

[0289] 282. The method of aspect 271, wherein said exosomes express alpha synuclein.

[0290] 283. The method of aspect 271, wherein said exosomes express phosphatidylserine.

[0291] 284. The method of aspect 271, wherein said exosomes express calreticulin.

[0292] 285. The method of aspect 271, wherein said exosomes express L1CAM.

[0293] 286. The method of aspect 271, wherein said exosomes express galectin-9.

[0294] 287. The method of aspect 271, wherein said exosomes express galectin-3.

[0295] 288. The method of aspect 271, wherein said exosomes express CD9.

[0296] 289. The method of aspect 271, wherein said exosomes express CD63.

[0297] 290. The method of aspect 271, wherein said exosomes express CD81.

[0298] 291. The method of aspect 271, wherein said exosomes express CD82.

[0299] 292. The method of aspect 271, wherein said exosomes express TSG-101.

[0300] 293. The method of aspect 271, wherein said exosomes express Flottilin-1.

[0301] 294. The method of aspect 271, wherein said exosomes express hsp-60.

[0302] 295. The method of aspect 271, wherein said exosomes express hsp-70.

[0303] 296. The method of aspect 271, wherein said exosomes express hsp-90.

[0304] 297. The method of aspect 271, wherein said exosomes express hsc-70.

[0305] 298. The method of aspect 271, wherein said exosomes express CD147.

[0306] 299. The method of aspect 271, wherein said exosomes express EpCAM.

[0307] 300. The method of aspect 271, wherein said exosomes express CD37.

[0308] 301. The method of aspect 271, wherein said exosomes express NKG2D.

[0309] 302. The method of aspect 1, wherein mesenchymal stem cells are generated from pluripotent stem cells and said mesenchymal stem cells are used to collect exosomes, wherein said exosomes are administered into a patient suffering from sepsis.

[0310] 303. The method of aspect 302, wherein said exosomes are generated by use of affinity chromatography of mesenchymal stem cell conditioned media.

[0311] 304. The method of aspect 303, wherein said mesenchymal stem cells are pretreated with a cellular stress before collection of exosomes.

[0312] 305. The method of aspect 304, wherein said cellular stress is hypoxia.

[0313] 306. The method of aspect 304, wherein said cellular stress is hyperoxia.

[0314] 307. The method of aspect 304, wherein said cellular stress is hyperthermia.

[0315] 308. The method of aspect 304, wherein said cellular stress is hypothermia.

[0316] 309. The method of aspect 304, wherein said cellular stress is radiation exposure.

[0317] 310. The method of aspect 304, wherein said cellular stress is DNA strand breaks.

[0318] 311. The method of aspect 304, wherein said cellular stress is misfolded protein accumulation.

[0319] 312. The method of aspect 304, wherein said cellular stress is exposure of said cell to hypotonic conditions.

[0320] 313. The method of aspect 304, wherein said cellular stress is exposure of said cell to hypertonic conditions.

[0321] 314. The method of aspect 304, wherein said cellular stress is induced by an activator of NF-kappa B.

[0322] 315. The method of aspect 314, wherein said activator of NF-kappa B is a heat shock protein.

[0323] 316. The method of aspect 315, wherein said heat shock protein is HSPD.

[0324] 317. The method of aspect 315, wherein said heat shock protein is GRPE1.

[0325] 318. The method of aspect 315, wherein said heat shock protein is GRPE2.

[0326] 319. The method of aspect 315, wherein said heat shock protein is HSP27.

[0327] 320. The method of aspect 315, wherein said heat shock protein is HSPB5.

[0328] 321. The method of aspect 315, wherein said heat shock protein is DNAj.

[0329] 322. The method of aspect 315, wherein said heat shock protein is HSP60.

[0330] 323. The method of aspect 315, wherein said heat shock protein is DNAk.

[0331] 324. The method of aspect 315, wherein said heat shock protein is HSP71.

[0332] 325. The method of aspect 315, wherein said heat shock protein is HSP72.

[0333] 326. The method of aspect 315, wherein said heat shock protein is GRP78.

[0334] 327. The method of aspect 314, wherein said activator of NF-kappa B is flagellin.

[0335] 328. The method of aspect 314, wherein said activator of NF-kappa B is peptidoglycan.

[0336] 329. The method of aspect 314, wherein said activator of NF-kappa B is ionomycin.

[0337] 330. The method of aspect 314, wherein said activator of NF-kappa B is lipopolysaccharide.

[0338] 331. The method of aspect 314, wherein said activator of NF-kappa B is double stranded RNA.

[0339] 332. The method of aspect 314, wherein said activator of NF-kappa B is interleukin-33.

[0340] 333. The method of aspect 314, wherein said activator of NF-kappa B is gp96.

[0341] 334. The method of aspect 314, wherein said activator of NF-kappa B is phorbol myristate acetate.

[0342] 335. The method of aspect 314, wherein said activator of NF-kappa B is TNFSF3.

[0343] 336. The method of aspect 314, wherein said activator of NF-kappa B is TNFSF5.

[0344] 337. The method of aspect 314, wherein said activator of NF-kappa B is interleukin-1 beta.

[0345] 338. The method of aspect 314, wherein said activator of NF-kappa B is BAFF.

[0346] 339. The method of aspect 314, wherein said activator of NF-kappa B is osteopontin.

[0347] 340. The method of aspect 314, wherein said activator of NF-kappa B is RIG1.

[0348] 341. The method of aspect 314, wherein said activator of NF-kappa B is MDA5.

[0349] 342. The method of aspect 314, wherein said activator of NF-kappa B is CD40 ligation.

[0350] 343. The method of aspect 314, wherein said activator of NF-kappa B is CD28 ligation.

[0351] 344. The method of aspect 314, wherein said activator of NF-kappa B is CD80 ligation.

[0352] 345. The method of aspect 314, wherein said activator of NF-kappa B is TNFSF13B.

[0353] 346. The method of aspect 314, wherein said activator of NF-kappa B is TNFSF11.

[0354] 347. The method of aspect 314, wherein said activator of NF-kappa B is - defensin.

[0355] 348. The method of aspect 314, wherein said activator of NF-kappa B is low molecular weight hyaluronic acid.

[0356] 349. The method of aspect 314, wherein said activator of NF-kappa B is lipid A.

[0357] 350. The method of aspect 314, wherein said activator of NF-kappa B is culture with allogeneic T cells.

[0358] 351. The method of aspect 314, wherein said activator of NF-kappa B fibronectin.

[0359] 352. The method of aspect 314, wherein said activator of NF-kappa B is snapin.

[0360] 353. The method of aspect 314, wherein said activator of NF-kappa B is tenascin C.

[0361] 354. The method of aspect 314, wherein said activator of NF-kappa B is Poly IC.

[0362] 355. The method of aspect 314, wherein said activator of NF-kappa B is lipoteichoic acid.

[0363] 356. The method of aspect 314, wherein said activator of NF-kappa B is zymosan.

[0364] 357. The method of aspect 314, wherein said activator of NF-kappa B isPam3CSK4.

[0365] 358. The method of aspect 314, wherein said activator of NF-kappa B is uric acid.

[0366] 359. The method of aspect 314, wherein said activator of NF-kappa B is Poly G10.

[0367] 360. The method of aspect 314, wherein said activator of NF-kappa B is unmethylated CpG DNA.

[0368] 361. The method of aspect 302, wherein the amount of exosomes administered is dependent on the severity of the sepsis in said patient being treated.

[0369] 362. The method of aspect 361, wherein said severity of sepsis is assessed by the extent of organ failure.

[0370] 363. The method of aspect 361, wherein said severity of sepsis is assessed by the number of organs failing.

[0371] 364. The method of aspect 363, wherein said severity of sepsis is assessed by the concentration of inflammatory markers in systemic circulation.

[0372] 365. The method of aspect 363, wherein said severity of sepsis is assessed by the concentration of inflammatory markers in the lung.

[0373] 366. The method of aspect 363, wherein said severity of sepsis is assessed by the concentration of inflammatory markers in cerebral spinal fluid.

[0374] 367. The method of aspect 363, wherein said severity of sepsis is assessed by the concentration of inflammatory markers in saliva.

[0375] 368. The method of aspect 363, wherein said severity of sepsis is assessed by the concentration of inflammatory markers in urine.

[0376] 369. The method of aspect 364-368, wherein said inflammatory marker is apoptotic bodies.

[0377] 370. The method of aspect 364-368, wherein said inflammatory marker is concentration of neutrophil extracellular traps.

[0378] 371. The method of aspect 364-368, wherein said inflammatory marker is histoneDNA in circulation.

[0379] 372. The method of aspect 364-368, wherein said inflammatory marker is interleukin-1 beta.

[0380] 373. The method of aspect 364-368, wherein said inflammatory marker is coagulation promoting extracellular vesicles.

[0381] 374. The method of aspect 364-368, wherein said inflammatory marker is apoptotic bodies bound to circulating DNA.

[0382] 375. The method of aspect 364-368, wherein said inflammatory marker is interleukin-2.

[0383] 376. The method of aspect 364-368, wherein said inflammatory marker is interleukin-6.

[0384] 377. The method of aspect 364-368, wherein said inflammatory marker is interleukin-8.

[0385] 378. The method of aspect 364-368, wherein said inflammatory marker is interleukin-11.

[0386] 379. The method of aspect 364-368, wherein said inflammatory marker is interleukin-12.

[0387] 380. The method of aspect 364-368, wherein said inflammatory marker is interleukin-18.

[0388] 381. The method of aspect 364-368, wherein said inflammatory marker is interleukin-17.

[0389] 382. The method of aspect 364-368, wherein said inflammatory marker is interleukin-21.

[0390] 383. The method of aspect 364-368, wherein said inflammatory marker is interleukin-23.

[0391] 384. The method of aspect 364-368, wherein said inflammatory marker is interleukin-27.

[0392] 385. The method of aspect 364-368, wherein said inflammatory marker is HMGBl.

[0393] 386. The method of aspect 364-368, wherein said inflammatory marker is interleukin-1 receptor antagonist.

[0394] 387. The method of aspect 364-368, wherein said inflammatory marker is interleukin-33.

[0395] 388. The method of aspect 364-368, wherein said inflammatory marker is interferon gamma.

[0396] 389. The method of aspect 364-368, wherein said inflammatory marker is interleukin-6 receptor.

[0397] 390. The method of aspect 364-368, wherein said inflammatory marker is PGE2.

[0398] 391. The method of aspect 364-368, wherein said inflammatory marker is RANTES.

[0399] 392. The method of aspect 364-368, wherein said inflammatory marker is solubleGalectin-3.

[0400] 393. The method of aspect 364-368, wherein said inflammatory marker is C reactive protein.

[0401] 394. The method of aspect 364-368, wherein said inflammatory marker is circulating vimentin.

[0402] 395. The method of aspect 364-368, wherein said inflammatory marker is circulating super oxide dismutase.

[0403] 396. The method of aspect 364-368, wherein said inflammatory marker is circulating MMP-1.

[0404] 397. The method of aspect 364-368, wherein said inflammatory marker is circulating MMP-3.

[0405] 398. The method of aspect 364-368, wherein said inflammatory marker is circulating MMP-5.

[0406] 399. The method of aspect 364-368, wherein said inflammatory marker is circulating MMP-9.

[0407] 400. The method of aspect 364-368, wherein said inflammatory marker is d-dimer.

[0408] 401. The method of aspect 364-368, wherein said inflammatory marker is fibrinogen.

[0409] 402. A method of treating suppression of adaptive immunity associated with sepsis comprising administration of pluripotent stem cell derived mesenchymal stem cells.

[0410] 403. The method of aspect 402, wherein said pluripotent stem cells are generated by somatic cell nuclear transfer.

[0411] 404. The method of aspect 403, wherein said somatic cell nuclear transfer is augmented inefficacy by suppression of p53 in the recipient cell.

[0412] 405. The method of aspect 404, wherein said suppression of said p53 is accomplished by induction of RNA interference.

[0413] 406. The method of aspect 405, wherein said induction of RNA interference is accomplished by administration of short interfering RNA.

[0414] 407. The method of aspect 405, wherein said induction of RNA interference is accomplished by administration of short hairpin RNA.

[0415] 408. The method of aspect 405, wherein said induction of RNA interference is accomplished by administration of double stranded RNA..

[0416] 409. The method of aspect 404, wherein said suppression of said p53 is accomplished by administration of antisense oligonucleotides.

[0417] 410. The method of aspect 409, wherein said administration of said antisense oligonucleotides induces activation of RNAse H.

[0418] 411. The method of aspect 404, wherein said suppression of said p53 is accomplished by administration of a ribozyme.

[0419] 412. The method of aspect 404, wherein said suppression of said p53 is accomplished by administration of a morpholino.

[0420] 413. The method of aspect 404, wherein said suppression of said p53 is accomplished by administration of an aptamer.

[0421] 414. The method of aspect 402, wherein said pluripotent stem cells are generated by reprogramming of somatic cells.

[0422] 415. The method of aspect 414, wherein said reprogramming is accomplished by introducing genes encoding for one or more of the following proteins: a) PIMl; b) PIM3; c) sox-2; d) c-myc; e) k-ras; f) NF-kappa B; g) NANOG; h) KLF4; and i) OCT4.

[0423] 416. The method of aspect 415, wherein said factors are delivered by protein transduction.

[0424] 417. The method of aspect 416, wherein said protein transduction is accomplished by utilizing protein transduction domain containing proteins.

[0425] 418. The method of aspect 417, wherein said protein containing said protein transduction domain is a cell penetrating peptide.

[0426] 419. The method of aspect 418, wherein said factors of aspect 415 are delivered by coinjection of proteins with cell penetrating peptides.T1

[0427] 420. The method of aspect 418, wherein said factors of aspect 415 are delivered by coinjection of DNA with cell penetrating peptides.

[0428] 421. The method of aspect 418, wherein said factors of aspect 415 are delivered by coinjection of proteins with cell penetrating peptides.

[0429] 422. The method of aspect 418, wherein said factors of aspect 415 are delivered by fusion with cell penetrating peptides.

[0430] 423. The method of aspect 422, wherein said fusion with said cell penetrating peptides is performed in a manner not to inhibit activity of said factors of aspect 415.

[0431] 424. The method of aspect 422, wherein said fusion with said cell penetrating peptides is performed in a manner not to inhibit cell penetrating activity of cell penetrating peptides.

[0432] 425. The method of aspect 418, wherein said cell penetrating peptide is LL37.

[0433] 426. The method of aspect 418, wherein said cell penetrating peptide is TAT.

[0434] 427. The method of aspect 418, wherein said cell penetrating peptide is penetratin.

[0435] 428. The method of aspect 418, wherein said cell penetrating peptide is polyarginine.

[0436] 429. The method of aspect 418, wherein said cell penetrating peptide is PEP-1.

[0437] 430. The method of aspect 418, wherein said cell penetrating peptide is TAT-H2.

[0438] 431. The method of aspect 418, wherein said cell penetrating peptide is Hph-1.

[0439] 432. The method of aspect 418, wherein said cell penetrating peptide is HP4.

[0440] 433. The method of aspect 418, wherein said cell penetrating peptide is LAH4.

[0441] 434. The method of aspect 418, wherein said cell penetrating peptide is LAH4-L1.

[0442] 435. The method of aspect 418, wherein said cell penetrating peptide isVectofusin.

[0443] 436. The method of aspect 418, wherein said cell penetrating peptide is low molecular weight protamine.

[0444] 437. The method of aspect 418, wherein said cell penetrating peptide is VP22.

[0445] 438. The method of aspect 415, wherein RNA encoding said factors is administered as RNA nanoparticle selected from the group consisting of messenger RNA nanoparticles for expressing transcription factors which allow somatic cells or adult stem cells to be dedifferentiated into induced pluripotent stem cells, micro RNA nanoparticles facilitating the dedifferentiation, small interfering RNA nanoparticles facilitating the dedifferentiation, complex RNA nanoparticles which include micro RNA facilitating the dedifferentiation and smallinterfering RNA facilitating the dedifferentiation, complex RNA nanoparticles which include messenger RNA for expressing a transcription factor and micro RNA facilitating the dedifferentiation, complex RNA nanoparticles which include messenger RNA for expressing a transcription factor and small interfering RNA facilitating the dedifferentiation, and complexRNA nanoparticles which include messenger RNA for expressing a transcription factor, microRNA facilitating the dedifferentiation, and small interfering RNA facilitating the dedifferentiation is used as the RNA nanoparticles for cell transformation.

[0446] 439. The method of aspect 438, wherein one or more chemicals associated with dedifferentiation are added to augment the dedifferentiation process.

[0447] 440. The method of aspect 439, wherein said chemical is an inhibitor of histone deacetylase(s).

[0448] 441. The method of aspect 439, wherein said chemical is an inhibitor of DNA methyltransferase(s).

[0449] 442. The method of aspect 439, wherein said chemical is an inhibitor of GSK-3.

[0450] 443. The method of aspect 384, wherein the RNA nanoparticles for cell transformation include at least one RNA selected from the group consisting of messenger RNA for expressing transcription factors which allow somatic cells or adult stem cells to be dedifferentiated into induced pluripotent stem cells, micro RNA facilitating the dedifferentiation, and small interfering RNA.

[0451] 444. The method of aspect 443, wherein said transcription factor is Oct4.

[0452] 445. The method of aspect 443, wherein said transcription factor is Sox2.

[0453] 446. The method of aspect 443, wherein said transcription factor is PIMl.

[0454] 447. The method of aspect 443, wherein said transcription factor is PI M3.

[0455] 445. The method of aspect 443, wherein said transcription factor is c-MYC.

[0456] 446. The method of aspect 443, wherein said transcription factor is l-MYC.

[0457] 447. The method of aspect 443, wherein said transcription factor is c-MET.

[0458] 448. The method of aspect 443, wherein said transcription factor is KLF-4.

[0459] 449. The method of aspect 443, wherein said transcription factor is Lin28.

[0460] 450. The method of aspect 443, wherein at least one RNA nanoparticle selected from the group consisting of messenger RNA nanoparticles for expressing transcription factors and / or adjuvant genes associated with dedifferentiation which allow somatic cells or adult stem cells to be dedifferentiated into induced pluripotent stem cells,

[0461] 451. The method of aspect 384, wherein the RNA nanoparticles capable of inducing cellular dedifferentiation and / or reprograming comprise of a spherical shape and have a diameter of 50 to 200 nm.

[0462] 452. A method of treating sepsis comprising administration of a pluripotent stem cell derived mesenchymal stem cell that is transfected with one more therapeutic genes, wherein one type of therapeutic gene is a cytokine.

[0463] 453. The method of aspect 452, wherein said therapeutic gene is capable of suppressing activation of pathological cytokines associated with sepsis.

[0464] 454. The method of aspect 453, wherein said pathological cytokines contribute to platelet aggregation.

[0465] 455. The method of aspect 453, wherein said pathological cytokines contribute to platelet endothelial adhesion.

[0466] 456. The method of aspect 453, wherein said pathological cytokines contribute to neutrophil activation.

[0467] 457. The method of aspect 453, wherein said pathological cytokines contribute to neutrophil extracellular trap release.

[0468] 458. The method of aspect 453, wherein said pathological cytokines contribute to neutrophil free radical generation.

[0469] 459. The method of aspect 453, wherein said pathological cytokines contribute to neutrophil extravasation.

[0470] 460. The method of aspect 453, wherein said pathological cytokines contribute to neutrophil degranulation.

[0471] 461. The method of aspect 453, wherein said pathological cytokines contribute to neutrophil viability.

[0472] 462. The method of aspect 453, wherein said pathological cytokines contribute to monocyte activation.

[0473] 463. The method of aspect 453, wherein said pathological cytokines contribute to monocyte extracellular trap release.

[0474] 464. The method of aspect 453, wherein said pathological cytokines contribute to monocyte free radical generation.

[0475] 465. The method of aspect 453, wherein said pathological cytokines contribute to monocyte extravasation.

[0476] 466. The method of aspect 453, wherein said pathological cytokines contribute to monocyte maturation.

[0477] 467. The method of aspect 453, wherein said pathological cytokines contribute to monocyte viability.

[0478] 468. The method of aspect 452, wherein said therapeutic cytokine may be a protein.

[0479] 469. The method of aspect 452, wherein said therapeutic cytokine may be a chemokine.

[0480] 470. The method of aspect 452, wherein said therapeutic cytokine may be a soluble receptor.

[0481] 471. The method of aspect 452, wherein said therapeutic cytokine may be a receptor antagonist.

[0482] 472. The method of aspect 452, wherein said therapeutic cytokine is interleukin-1 receptor antagonist.

[0483] 473. The method of aspect 452, wherein said therapeutic cytokine is interleukin-2.

[0484] 474. The method of aspect 452, wherein said therapeutic cytokine is amphiregulin.

[0485] 475. The method of aspect 452, wherein said therapeutic cytokine is interleukin-3.

[0486] 476. The method of aspect 452, wherein said therapeutic cytokine is interleukin-4.

[0487] 477. The method of aspect 452, wherein said therapeutic cytokine is interleukin-6 receptor.

[0488] 478. The method of aspect 452, wherein said therapeutic cytokine is interleukin-7.

[0489] 479. The method of aspect 452, wherein said therapeutic cytokine is interleukin-10.

[0490] 480. The method of aspect 452, wherein said therapeutic cytokine is interleukin-13.

[0491] 481. The method of aspect 452, wherein said therapeutic cytokine is interleukin-14.

[0492] 482. Th37method of aspect 452, wherein said therapeutic cytokine is interleukin-20.

[0493] 483. The method of aspect 452, wherein said therapeutic cytokine is interleukin-12 p40 homodimer.

[0494] 484. The method of aspect 452, wherein said therapeutic cytokine is interleukin-10495] 485. The method of aspect 452, wherein said therapeutic cytokine is interleukin¬21.

[0496] 486. The method of aspect 452, wherein said therapeutic cytokine is interleukin-10497] 487. The method of aspect 452, wherein said therapeutic cytokine is interleukin-

[0498] 488. The method of aspect 452, wherein said therapeutic cytokine is interleukin-10499] 489. The method of aspect 452, wherein said therapeutic cytokine is interleukin-10500] 490. The method of aspect 452, wherein said therapeutic cytokine is TGF-beta.

[0501] 491. The method of aspect 452, wherein said therapeutic cytokine is endoglin.

[0502] 492. The method of aspect 452, wherein said therapeutic cytokine is VEGF.

[0503] 493. The method of aspect 452, wherein said therapeutic cytokine is VEGF-C.

[0504] 494. The method of aspect 452, wherein said therapeutic cytokine is EGF.

[0505] 495. The method of aspect 452, wherein said therapeutic cytokine is IGF.

[0506] 496. The method of aspect 452, wherein said therapeutic cytokine is HGF.

[0507] 497. The method of aspect 452, wherein said therapeutic cytokine is angiopoietin.

[0508] 498. The method of aspect 452, wherein said therapeutic cytokine is placental derived growth factor.

[0509] 499. The method of aspect 452, wherein said therapeutic cytokine is protein C.

[0510] 500. The method of aspect 452, wherein said therapeutic cytokine is FGF-1.

[0511] 501. The method of aspect 452, wherein said therapeutic cytokine is FGF-2.

[0512] 502. The method of aspect 452, wherein said therapeutic cytokine is FGF-5.

[0513] 503. The method of aspect 452, wherein said therapeutic gene is Gata4.

[0514] 504. The method of aspect 452, wherein said therapeutic gene is Mef2C.

[0515] 505. The method of aspect 452, wherein said therapeutic gene is Tbx5.

[0516] 506. The method of aspect 452, wherein said therapeutic gene is Sox5.

[0517] 507. The method of aspect 452, wherein said therapeutic gene is Sox9.

[0518] 508. The method of aspect 452, wherein said therapeutic gene is MMP3.

[0519] 509. The method of aspect 452, wherein said therapeutic gene is MMP5

[0520] 510. The method of aspect 452, wherein said therapeutic gene is MMP14.

[0521] 511. The method of aspect 452, wherein said therapeutic gene is CD10.

[0522] 512. The method of aspect 452, wherein said therapeutic gene is WNT11.

[0523] 513. The method of aspect 452, wherein said therapeutic gene is BAPX1.

[0524] 514. The method of aspect 452, wherein said therapeutic gene is IGFBP5.

[0525] 515. The method of aspect 452, wherein said therapeutic gene is MMP16.

[0526] 516. The method of aspect 452, wherein said therapeutic gene is BMP2.

[0527] 517. The method of aspect 452, wherein said therapeutic gene is BMP4.

[0528] 518. The method of aspect 452, wherein said therapeutic gene is BMP7.

[0529] 519. The method of aspect 452, wherein said therapeutic gene is ADAMTS5.

[0530] 520. The method of aspect 452, wherein said therapeutic gene is BCL10.

[0531] 521. The method of aspect 452, wherein said therapeutic gene is MCOLN2.

[0532] 522. The method of aspect 452, wherein said therapeutic gene is LRRC8C.

[0533] 523. The method of aspect 452, wherein said therapeutic gene is PTGFR.

[0534] 524. The method of aspect 452, wherein said therapeutic gene is RLF.

[0535] 525. The method of aspect 452, wherein said therapeutic gene is MATN1.

[0536] 526. The method of aspect 452, wherein said therapeutic gene is PDPN.

[0537] 527. The method of aspect 452, wherein said therapeutic gene is TNFRSF18.

[0538] 528. The method of aspect 452, wherein said therapeutic gene is ITGA10.

[0539] 529. The method of aspect 452, wherein said therapeutic gene is THBS3.

[0540] 530. The method of aspect 452, wherein said therapeutic gene is SCYL1BP1.

[0541] 531. The method of aspect 452, wherein said therapeutic gene is HSPC159.

[0542] 532. The method of aspect 452, wherein said therapeutic gene is RHOQ.

[0543] 533. The method of aspect 452, wherein said therapeutic gene is MATN3.

[0544] 534. The method of aspect 452, wherein said therapeutic gene is SULT1C2.

[0545] 535. The method of aspect 452, wherein said therapeutic gene is BCL2L11.

[0546] 536. The method of aspect 452, wherein said therapeutic gene is KLF7.

[0547] 537. The method of aspect 452, wherein said therapeutic gene is BCL-2.

[0548] 538. The method of aspect 452, wherein said therapeutic gene is survivin.

[0549] 539. The method of aspect 452, wherein said therapeutic gene is livin.

[0550] 540. The method of aspect 452, wherein said therapeutic gene is IAP-C.

[0551] 541. The method of aspect 452, wherein said therapeutic gene is bcl-XL.

[0552] 542. The method of aspect 452, wherein said therapeutic gene is NRP2.

[0553] 543. The method of aspect 452, wherein said therapeutic gene is heme oxygenase.

[0554] 544. The method of aspect 452, wherein said therapeutic gene is NRF2.

[0555] 545. The method of aspect 452, wherein said therapeutic gene is SERPINE2.

[0556] 546. The method of aspect 452, wherein said therapeutic gene is FN1.

[0557] 547. The method of aspect 452, wherein said therapeutic gene is B3GNT7.

[0558] 548. The method of aspect 452, wherein said therapeutic gene is ADAMTS9.

[0559] 549. The method of aspect 452, wherein said therapeutic gene is ANKRD28.

[0560] 550. The method of aspect 452, wherein said therapeutic gene is GALNTL2.

[0561] 551. The method of aspect 452, wherein said therapeutic gene is Galectin-3.

[0562] 552. The method of aspect 452, wherein said therapeutic gene is Galectin-9.

[0563] 553. The method of aspect 452, wherein said therapeutic gene is PD-L1.

[0564] 554. The method of aspect 452, wherein said therapeutic gene is PD-L2.

[0565] 555. The method of aspect 452, wherein said therapeutic gene is TIM-1.

[0566] 556. The method of aspect 452, wherein said therapeutic gene is TIM-3.

[0567] 557. The method of aspect 452, wherein said therapeutic gene is HLA-G.

[0568] 558. The method of aspect 452, wherein said therapeutic gene is IRAK2.

[0569] 559. The method of aspect 452, wherein said therapeutic gene is SETD5.

[0570] 560. The method of aspect 452, wherein said therapeutic gene is FNDC3B.

[0571] 561. The method of aspect 452, wherein said therapeutic gene is B3GNT5.

[0572] 562. The method of aspect 452, wherein said therapeutic gene is CYTL1.

[0573] 563. The method of aspect 452, wherein said therapeutic gene is C1Q.TNF3.

[0574] 564. The method of aspect 452, wherein said therapeutic gene is ZFYVE16.

[0575] 565. The method of aspect 452, wherein said therapeutic gene is MAST4.

[0576] 566. The method of aspect 452, wherein said therapeutic gene is EDIL3.

[0577] 567. The method of aspect 452, wherein said therapeutic gene is HAPLN1.

[0578] 568. The method of aspect 452, wherein said therapeutic gene is PDLIM4.

[0579] 569. The method of aspect 452, wherein said therapeutic gene is cr5q35.

[0580] 570. The method of aspect 452, wherein said therapeutic gene is SQSTM1.

[0581] 571. The method of aspect 452, wherein said therapeutic gene is SCUBE3.

[0582] 572. The method of aspect 452, wherein said therapeutic gene is 50X5.

[0583] 573. The method of aspect 452, wherein said therapeutic gene is RNF24.

[0584] 574. The method of aspect 452, wherein said therapeutic gene is NUPL1.

[0585] 575. The method of aspect 452, wherein said therapeutic gene is ULBP2.

[0586] 576. The method of aspect 452, wherein said therapeutic gene is SOD2.

[0587] 577. The method of aspect 452, wherein said therapeutic gene is KIAA0999.

[0588] 578. The method of aspect 452, wherein said therapeutic gene is LRP11.

[0589] 579. The method of aspect 452, wherein said therapeutic gene is SYNJ2.

[0590] 580. The method of aspect 452, wherein said therapeutic gene is WTAP.

[0591] 581. The method of aspect 452, wherein said therapeutic gene is HIG2.

[0592] 582. The method of aspect 452, wherein said therapeutic gene is FAM62B.

[0593] 583. The method of aspect 452, wherein said therapeutic gene is TNFRSF10D.

[0594] 584. The method of aspect 452, wherein said therapeutic gene is SLC25A37.

[0595] 585. The method of aspect 452, wherein said therapeutic gene is BDKRB1.

[0596] 586. The method of aspect 452, wherein said therapeutic gene is FZD10.

[0597] 587. The method of aspect 452, wherein said therapeutic gene is VASN.

[0598] 588. The method of aspect 452, wherein said therapeutic gene is inhibitor of kappa B.

[0599] 589. The method of aspect 452, wherein said therapeutic gene is RelB.

[0600] 590. The method of aspect 452, wherein said therapeutic gene is EIF2C2.

[0601] 591. The method of aspect 452, wherein said therapeutic gene is RUNX1.

[0602] 592. The method of aspect 452, wherein said therapeutic gene is RELB.

[0603] 593. The method of aspect 452, wherein said therapeutic gene is ATF1.

[0604] 594. The method of aspect 452, wherein said therapeutic gene is UFMl.

[0605] 595. The method of aspect 452, wherein said therapeutic gene is MATN4.

[0606] 596. The method of aspect 452, wherein said therapeutic gene is NOS2A.

[0607] 597. The method of aspect 452, wherein said therapeutic gene is RHOF.

[0608] 598. The method of aspect 452, wherein said therapeutic gene is ETNK1.

[0609] 599. The method of aspect 452, wherein said therapeutic gene is SFXN3.

[0610] 600. The method of aspect 452, wherein said therapeutic gene is L0XL4.

[0611] 601. The method of aspect 452, wherein said therapeutic gene is GLIS3.

[0612] 602. The method of aspect 452, wherein said therapeutic gene is RPS6.

[0613] 603. The method of aspect 452, wherein said therapeutic gene is WISP1.

[0614] 604. The method of aspect 452, wherein said therapeutic gene is RB1CC1.

[0615] 605. The method of aspect 452, wherein said therapeutic gene is PTK2.

[0616] 606. The method of aspect 452, wherein said therapeutic gene is SRGAP1.

[0617] 607. The method of aspect 452, wherein said therapeutic gene is USP12.

[0618] 608. The method of aspect 452, wherein said therapeutic gene is GITR.

[0619] 609. The method of aspect 452, wherein said therapeutic gene is ICOS.

[0620] 610. The method of aspect 452, wherein said therapeutic gene is PDGF-BB.

[0621] 611. The method of aspect 452, wherein said therapeutic gene is TLR5.

[0622] 612. The method of aspect 452, wherein said therapeutic gene is ChGn.

[0623] 613. The method of aspect 452, wherein said therapeutic gene is C8orf72.

[0624] 614. The method of aspect 452, wherein said therapeutic gene is HAS2.

[0625] 615. The method of aspect 452, wherein said therapeutic gene is TRPS1.

[0626] 616. The method of aspect 452, wherein said therapeutic gene is ZCCHC7.

[0627] 617. The method of aspect 452, wherein said therapeutic gene is SLC28A3.

[0628] 618. The method of aspect 452, wherein said therapeutic gene is EDG2.

[0629] 619. The method of aspect 452, wherein said therapeutic gene is ITGB1.

[0630] 620. The method of aspect 452, wherein said therapeutic gene is CD44.

[0631] 621. The method of aspect 452, wherein said therapeutic gene is C10orf49.

[0632] 622. The method of aspect 452, wherein said therapeutic gene is YME1L1.

[0633] 623. The method of aspect 452, wherein said therapeutic gene is AKR1C2.

[0634] 624. The method of aspect 452, wherein said therapeutic gene is CHST3.

[0635] 625. The method of aspect 452, wherein said therapeutic gene is F0SL1.

[0636] 626. The method of aspect 452, wherein said therapeutic gene is RELA.

[0637] 627. The method of aspect 452, wherein said therapeutic gene is ASAM.

[0638] 628. The method of aspect 452, wherein said therapeutic gene is CHST11.

[0639] 629. The method of aspect 452, wherein said therapeutic gene is DSPG3.

[0640] 630. The method of aspect 452, wherein said therapeutic gene is LOC338758.

[0641] 631. The method of aspect 452, wherein said therapeutic gene is LOC399959.

[0642] 632. The method of aspect 452, wherein said therapeutic gene is KIAA0701.

[0643] 633. The method of aspect 452, wherein said therapeutic gene is SLC41A2.

[0644] 634. The method of aspect 452, wherein said therapeutic gene is LECT1.

[0645] 635. The method of aspect 452, wherein said therapeutic gene is GPC6.

[0646] 636. The method of aspect 452, wherein said therapeutic gene is EROIL.

[0647] 637. The method of aspect 452, wherein said therapeutic gene is SEMA6D.

[0648] 638. The method of aspect 452, wherein said therapeutic gene is LACTB.

[0649] 639. The method of aspect 452, wherein said therapeutic gene is ARIH1.

[0650] 640. The method of aspect 452, wherein said therapeutic gene is CSPG4.

[0651] 641. The method of aspect 452, wherein said therapeutic gene is AGC1.

[0652] 642. The method of aspect 452, wherein said therapeutic gene is LOC283824.

[0653] 643. The method of aspect 452, wherein said therapeutic gene is WWP2.

[0654] 644. The method of aspect 452, wherein said therapeutic gene is LOC201181.

[0655] 645. The method of aspect 452, wherein said therapeutic gene is MSI2.

[0656] 646. The method of aspect 452, wherein said therapeutic gene is PITPNC1.

[0657] 647. The method of aspect 452, wherein said therapeutic gene is TGIF.

[0658] 648. The method of aspect 452, wherein said therapeutic gene is 1552288.

[0659] 649. The method of aspect 452, wherein said therapeutic gene is ZNF146.

[0660] 650. The method of aspect 452, wherein said therapeutic gene is MIA.

[0661] 651. The method of aspect 452, wherein said therapeutic gene is ZNF160.

[0662] 652. The method of aspect 452, wherein said therapeutic gene is SNX5.

[0663] 653. The method of aspect 452, wherein said therapeutic gene is HSUP1.

[0664] 654. The method of aspect 452, wherein said therapeutic gene is BIC.

[0665] 655. The method of aspect 452, wherein said therapeutic gene is LIF.

[0666] 656. A method of treating sepsis comprising generation of a T regulatory cell population from a pluripotent stem cell population, wherein said T regulatory cell population is autologous to a patient suffering from sepsis.

[0667] 657. The method of aspect 656, wherein said T regulatory cell is generated by exposure of embryoid bodies derived from pluripotent stem cells to a bone marrow microenvironment mimetic.

[0668] 658. The method of aspect 657, wherein said bone marrow microenvironment mimetic is decellularized bone marrow.

[0669] 659. The method of aspect 657, wherein said bone marrow microenvironment mimetic is decellularized placenta.

[0670] 660. The method of aspect 657, wherein said bone marrow microenvironment mimetic is decellularized umbilical cord.

[0671] 661. The method of aspect 657, wherein said embryoid body is disaggregated before seeing of said bone marrow microenvironment mimetic.

[0672] 662. The method of aspect 661, cells used to seed said bone marrow microenvironment mimetic are derived from common lymphoid progenitors.

[0673] 663. The method of aspect 662, wherein said common lymphoid progenitors express CD22.

[0674] 664. The method of aspect 662, wherein said common lymphoid progenitors express VCAM-1.

[0675] 665. The method of aspect 662, wherein said common lymphoid progenitors express CD20.

[0676] 665. The method of aspect 662, wherein said common lymphoid progenitors express CD16.

[0677] 667. The method of aspect 662, wherein said common lymphoid progenitors express CD16a.

[0678] 668. The method of aspect 662, wherein said common lymphoid progenitors express CD16b.

[0679] 669. The method of aspect 662, wherein said common lymphoid progenitors express CD16c.

[0680] 670. The method of aspect 662, wherein said common lymphoid progenitors express FLT3.

[0681] 671. The method of aspect 662, wherein said common lymphoid progenitors express CD127.

[0682] 672. The method of aspect 662, wherein said common lymphoid progenitors express NCAM-l.

[0683] 673. The method of aspect 662, wherein said common lymphoid progenitors express neprilysin.

[0684] 674. The method of aspect 662, wherein said common lymphoid progenitors express NCR1.

[0685] 675. The method of aspect 657, wherein interleukin-2 is added to said decellularized matrix.

[0686] 676. The method of aspect 675, wherein interleukin-2 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 10 percent.

[0687] 677. The method of aspect 675, wherein interleukin-2 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 25 percent.

[0688] 678. The method of aspect 675, wherein interleukin-2 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 50 percent.

[0689] 679. The method of aspect 675, wherein interleukin-2 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 100 percent.

[0690] 680. The method of aspect 657, wherein interleukin-10 is added to said decellularized matrix.

[0691] 681. The method of aspect 680, wherein interleukin-10 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 10 percent.

[0692] 682. The method of aspect 680, wherein interleukin-10 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 25 percent.

[0693] 683. The method of aspect 680, wherein interleukin-10 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 50 percent.

[0694] 684. The method of aspect 680, wherein interleukin-10 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 100 percent.

[0695] 685. The method of aspect 657, wherein interleukin-21 is added to said decellularized matrix.

[0696] 686. The method of aspect 685, wherein interleukin-21 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 10 percent.

[0697] 687. The method of aspect 685, wherein interleukin-21 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 25 percent.

[0698] 688. The method of aspect 685, wherein interleukin-21 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 50 percent.

[0699] 689. The method of aspect 685, wherein interleukin-21 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 100 percent.

[0700] 690. The method of aspect 657, wherein interleukin-33 is added to said decellularized matrix.

[0701] 691. The method of aspect 690, wherein interleukin-33 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 10 percent.

[0702] 692. The method of aspect 690, wherein interleukin-33 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 25 percent.

[0703] 693. The method of aspect 690, wherein interleukin-33 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 50 percent.

[0704] 694. The method of aspect 690, wherein interleukin-33 is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 100 percent.

[0705] 695. The method of aspect 657, wherein TGF-beta is added to said decellularized matrix.

[0706] 696. The method of aspect 695, wherein TGF-beta is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 10 percent.

[0707] 697. The method of aspect 695, wherein TGF-beta is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 25 percent.

[0708] 698. The method of aspect 695, wherein TGF-beta is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 50 percent.

[0709] 699. The method of aspect 695, wherein TGF-beta is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 100 percent.

[0710] 700. The method of aspect 657, wherein endoglin is added to said decellularized matrix.

[0711] 701. The method of aspect 700, wherein endoglin is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 10 percent.

[0712] 702. The method of aspect 700, wherein endoglin is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 25 percent.

[0713] 703. The method of aspect 700, wherein endoglin is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 50 percent.

[0714] 704. The method of aspect 700, wherein endoglin is added to said decellularized matrix at a concentration and duration to induce expression of FoxP3 by more than 100 percent.

[0715] 705. The method of aspect 656, wherein said T regulatory cells is administered into a patient suffering from multiple organ failure.

[0716] 706. The method of aspect 705, wherein said T regulatory cell is administered together with one or more agents capable of increasing T regulatory cell number in vivo.

[0717] 707. The method of aspect 705, wherein said T regulatory cell is administered together with one or more agents capable of increasing T regulatory cell activity in vivo.

[0718] 708. The method of aspect 707, wherein said T regulatory cell activity is production of TGF-beta.

[0719] 709. The method of aspect 707, wherein said T regulatory cell activity is production of latency associated protein.

[0720] 710. The method of aspect 707, wherein said T regulatory cell activity is suppression of T cell activity.

[0721] 711. The method of aspect 710, wherein said T cell activity is production of interferon gamma upon stimulation with anti-CD3 and anti-CD28 antibody.

[0722] 712. The method of aspect 710, wherein said T cell activity is production of interleukin-2 upon stimulation with anti-CD3 and anti-CD28 antibody.

[0723] 713. The method of aspect 710, wherein said T cell activity is production of interleukin-6 upon stimulation with anti-CD3 and anti-CD28 antibody.

[0724] 714. The method of aspect 710, wherein said T cell activity is production of interleukin-7 upon stimulation with anti-CD3 and anti-CD28 antibody.

[0725] 715. The method of aspect 710, wherein said T cell activity is production of interleukin-11 upon stimulation with anti-CD3 and anti-CD28 antibody.

[0726] 716. The method of aspect 710, wherein said T cell activity is production of interleukin-12 upon stimulation with anti-CD3 and anti-CD28 antibody.

[0727] 717. The method of aspect 710, wherein said T cell activity is production of interleukin-15 upon stimulation with anti-CD3 and anti-CD28 antibody.

[0728] 718. The method of aspect 710, wherein said T cell activity is production of interleukin-17 upon stimulation with anti-CD3 and anti-CD28 antibody.

[0729] 719. The method of aspect 710, wherein said T cell activity is production of interleukin-18 upon stimulation with anti-CD3 and anti-CD28 antibody.

[0730] 720. The method of aspect 710, wherein said T cell activity is production of interleukin-21 upon stimulation with anti-CD3 and anti-CD28 antibody.

[0731] 721. The method of aspect 710, wherein said T cell activity is production of interleukin-23 upon stimulation with anti-CD3 and anti-CD28 antibody.

[0732] 722. The method of aspect 710, wherein said T cell activity is production of interleukin-27 upon stimulation with anti-CD3 and anti-CD28 antibody.

[0733] 723. The method of aspect 710, wherein said T cell activity is production of TNF- alpha upon stimulation with anti-CD3 and anti-CD28 antibody.

[0734] 724. The method of aspect 710, wherein said T cell activity is production of lymphotoxin upon stimulation with anti-CD3 and anti-CD28 antibody.

[0735] 725. The method of aspect 710, wherein said T cell activity is production of LIGHT upon stimulation with anti-CD3 and anti-CD28 antibody.

[0736] 726. The method of aspect 710, wherein said T cell activity is production of BLyS upon stimulation with anti-CD3 and anti-CD28 antibody.

[0737] 1. The method of aspect 710, wherein said T cell activity is production of BAFF upon stimulation with anti-CD3 and anti-CD28 antibody.

[0738] 728. The method of aspect 710, wherein said T cell activity is production of LIGHT upon stimulation with anti-CD3 and anti-CD28 antibody.

[0739] 729. The method of aspect 710, wherein said T cell activity is production of granzyme B upon stimulation with anti-CD3 and anti-CD28 antibody.

[0740] 730. The method of aspect 710, wherein said T cell activity is production of perforin upon stimulation with anti-CD3 and anti-CD28 antibody.

[0741] 731. The method of aspect 707, wherein said T regulatory cell activity is production of HLA-G.

[0742] 732. The method of aspect 707, wherein said T regulatory cell activity is production of soluble HLA-G.

[0743] 733. The method of aspect 707, wherein said T regulatory cell activity is production of soluble TNF-alpha receptor.

[0744] 734. The method of aspect 707, wherein said T regulatory cell activity is ability to suppress maturation of dendritic cells.

[0745] 735. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced migration potential.

[0746] 736. The method of aspect 734, wherein said maturation of dendritic cells is associated with reduced phagocytic potential.

[0747] 737. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced antigen presenting activity.

[0748] 738. The method of aspect 737, wherein said antigen presenting activity is ability to induce TCR activation of a naive T cell.

[0749] 739. The method of aspect 737 , wherein said antigen presenting activity is ability to induce proliferation of a naive T cell.

[0750] 740. The method of aspect 737, wherein said antigen presenting activity is ability to induce cytokine production from a naive T cell.

[0751] 741. The method of aspect 740, wherein said cytokine is interferon gamma.

[0752] 742. The method of aspect 740, wherein said cytokine is interleukin-2.

[0753] 743. The method of aspect 740, wherein said cytokine is interleukin-4.

[0754] 744. The method of aspect 740, wherein said cytokine is interleukin-7.

[0755] 745. The method of aspect 740, wherein said cytokine is interleukin-9.

[0756] 746. The method of aspect 740, wherein said cytokine is interleukin-12.

[0757] 747. The method of aspect 740, wherein said cytokine is interleukin-15.

[0758] 748. The method of aspect 740, wherein said cytokine is interleukin-17.

[0759] 749. The method of aspect 740, wherein said cytokine is interleukin-18.

[0760] 750. The method of aspect 740, wherein said cytokine is interleukin-21.

[0761] 751. The method of aspect 740, wherein said cytokine is interleukin-23.

[0762] 752. The method of aspect 740, wherein said cytokine is interleukin-27.

[0763] 753. The method of aspect 737, wherein said antigen presenting activity is ability to endow cytotoxic activity to a naive T cell.

[0764] 754. The method of aspect 753, wherein said cytotoxic activity is associated with granzyme B production.

[0765] 755. The method of aspect 753, wherein said cytotoxic activity is associated with perform production.

[0766] 756. The method of aspect 753, wherein said cytotoxic activity is associated with surface expression of Fas ligand.

[0767] 757. The method of aspect 753, wherein said cytotoxic activity is associated with production of TRAIL.

[0768] 758. The method of aspect 753, wherein said cytotoxic activity is associated with production of TNF-alpha.

[0769] 759. The method of aspect 753, wherein said cytotoxic activity is associated with production of lymphotoxin.

[0770] 760. The method of aspect 753, wherein said cytotoxic activity is associated with production of TRANCE.

[0771] 761. The method of aspect 753, wherein said cytotoxic activity is associated with production of RANK ligand.

[0772] 762. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of membrane vimentin.

[0773] 763. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of calreticulin.

[0774] 764. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of hsp60.

[0775] 765. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of hsp65.

[0776] 766. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of TLR3.

[0777] 767. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of TLR4.

[0778] 768. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of TLR5.

[0779] 769. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of TLR7.

[0780] 770. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of TLR9.

[0781] 771. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of MDA-5.

[0782] 772. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of STING.

[0783] 773. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of LRP.

[0784] 774. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of CXCL9.

[0785] 775. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of CXCL10.

[0786] 776. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of CXCL11.

[0787] 777. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of CCL5.

[0788] 778. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of miR155.

[0789] 779. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of CD83.

[0790] 780. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of CCR7.

[0791] 781. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of CCL8.

[0792] 782. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of SOD2.

[0793] 783. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of MT2A.

[0794] 784. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of OASL.

[0795] 785. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of GBP1.

[0796] 786. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of HES4.

[0797] 787. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of MTIB.

[0798] 788. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of MTIE.

[0799] 789. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of MTIG.

[0800] 790. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of MTIH.

[0801] 791. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of GADD45A.

[0802] 792. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of LAMP3.

[0803] 793. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of CD80.

[0804] 794. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of CD40.

[0805] 795. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of CD86.

[0806] 796. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of interleukin-12.

[0807] 797. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of ICOS.

[0808] 798. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of CDllc.

[0809] 799. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of interleukin-15.

[0810] 800. The method of aspect 734, wherein said maturation of dendritic cells is associated with enhanced expression of interleukin-18.

[0811] 801. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of interleukin-2 at a concentration and frequency sufficient to increase T regulatory cell number by 10 percent.

[0812] 802. The method of aspect 801, wherein said T regulatory cells are quantified by expression of CD25.

[0813] 803. The method of aspect 801, wherein said T regulatory cells are quantified by expression of CTLA4.

[0814] 804. The method of aspect 801, wherein said T regulatory cells are quantified by expression of GITR.

[0815] 805. The method of aspect 801, wherein said T regulatory cells are quantified by expression of FoxP3.

[0816] 806. The method of aspect 801, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0817] 807. The method of aspect 801, wherein said T regulatory cells are quantified by expression of HLA-G.

[0818] 808. The method of aspect 801, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0819] 809. The method of aspect 801, wherein said T regulatory cells are quantified by expression of CD69.

[0820] 810. The method of aspect 801, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0821] 811. The method of aspect 801, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0822] 812. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of interleukin-2 at a concentration and frequency sufficient to increase T regulatory cell number by 25 percent.

[0823] 813. The method of aspect 812, wherein said T regulatory cells are quantified by expression of CD25.

[0824] 814. The method of aspect 812, wherein said T regulatory cells are quantified by expression of CTLA4.

[0825] 815. The method of aspect 812, wherein said T regulatory cells are quantified by expression of GITR.

[0826] 816. The method of aspect 812, wherein said T regulatory cells are quantified by expression of FoxP3.

[0827] 817. The method of aspect 812, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0828] 818. The method of aspect 812, wherein said T regulatory cells are quantified by expression of HLA-G.

[0829] 819. The method of aspect 812, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0830] 820. The method of aspect 812, wherein said T regulatory cells are quantified by expression of CD69.

[0831] 821. The method of aspect 812, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0832] 822. The method of aspect 812, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0833] 823. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of interleukin-2 at a concentration and frequency sufficient to increase T regulatory cell number by 50 percent.

[0834] 824. The method of aspect 823, wherein said T regulatory cells are quantified by expression of CD25.

[0835] 825. The method of aspect 823, wherein said T regulatory cells are quantified by expression of CTLA4.

[0836] 826. The method of aspect 823, wherein said T regulatory cells are quantified by expression of GITR.

[0837] 827. The method of aspect 823, wherein said T regulatory cells are quantified by expression of FoxP3.

[0838] 828. The method of aspect 823, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0839] 829. The method of aspect 823, wherein said T regulatory cells are quantified by expression of HLA-G.

[0840] 830. The method of aspect 823, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0841] 831. The method of aspect 823, wherein said T regulatory cells are quantified by expression of CD69.

[0842] 832. The method of aspect 823, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0843] 833. The method of aspect 823, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0844] 834. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of interleukin-2 at a concentration and frequency sufficient to increase T regulatory cell number by 100 percent.

[0845] 835. The method of aspect 834, wherein said T regulatory cells are quantified by expression of CD25.

[0846] 836. The method of aspect 834, wherein said T regulatory cells are quantified by expression of CTLA4.

[0847] 837. The method of aspect 834, wherein said T regulatory cells are quantified by expression of GITR.

[0848] 838. The method of aspect 834, wherein said T regulatory cells are quantified by expression of FoxP3.

[0849] 839. The method of aspect 834, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0850] 840. The method of aspect 834, wherein said T regulatory cells are quantified by expression of HLA-G.

[0851] 841. The method of aspect 834, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0852] 842. The method of aspect 834, wherein said T regulatory cells are quantified by expression of CD69.

[0853] 843. The method of aspect 834, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0854] 844. The method of aspect 834, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0855] 845. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of anti-CD45RB antibody at a concentration and frequency sufficient to increase T regulatory cell number by 10 percent.

[0856] 846. The method of aspect 845, wherein said T regulatory cells are quantified by expression of CD25.

[0857] 847. The method of aspect 845, wherein said T regulatory cells are quantified by expression of CTLA4.

[0858] 848. The method of aspect 845, wherein said T regulatory cells are quantified by expression of GITR.

[0859] 849. The method of aspect 845, wherein said T regulatory cells are quantified by expression of FoxP3.

[0860] 850. The method of aspect 845, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0861] 851. The method of aspect 845, wherein said T regulatory cells are quantified by expression of HLA-G.

[0862] 852. The method of aspect 845, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0863] 853. The method of aspect 845, wherein said T regulatory cells are quantified by expression of CD69.

[0864] 854. The method of aspect 845, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0865] 855. The method of aspect 845, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0866] 856. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of anti-CD45RB antibody at a concentration and frequency sufficient to increase T regulatory cell number by 25 percent.

[0867] 857. The method of aspect 856, wherein said T regulatory cells are quantified by expression of granzyme B.

[0868] 858. The method of aspect 856, wherein said T regulatory cells are quantified by expression of CD25.

[0869] 859. The method of aspect 856, wherein said T regulatory cells are quantified by expression of CTLA4.

[0870] 860. The method of aspect 856, wherein said T regulatory cells are quantified by expression of GITR.

[0871] 861. The method of aspect 856, wherein said T regulatory cells are quantified by expression of FoxP3.

[0872] 862. The method of aspect 856, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0873] 863. The method of aspect 856, wherein said T regulatory cells are quantified by expression of HLA-G.

[0874] 864. The method of aspect 856, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0875] 865. The method of aspect 856, wherein said T regulatory cells are quantified by expression of CD69.

[0876] 866. The method of aspect 856, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0877] 867. The method of aspect 856, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0878] 868. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of anti-CD45RB antibody at a concentration and frequency sufficient to increase T regulatory cell number by 50 percent.

[0879] 869. The method of aspect 868, wherein said T regulatory cells are quantified by expression of granzyme B.

[0880] 870. The method of aspect 868, wherein said T regulatory cells are quantified by expression of CD25.

[0881] 871. The method of aspect 868, wherein said T regulatory cells are quantified by expression of CTLA4.

[0882] 872. The method of aspect 868, wherein said T regulatory cells are quantified by expression of GITR.

[0883] 873. The method of aspect 868, wherein said T regulatory cells are quantified by expression of FoxP3.

[0884] 874. The method of aspect 868, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0885] 875. The method of aspect 868, wherein said T regulatory cells are quantified by expression of HLA-G.

[0886] 876. The method of aspect 868, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0887] 877. The method of aspect 868, wherein said T regulatory cells are quantified by expression of CD69.

[0888] 878. The method of aspect 868, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0889] 879. The method of aspect 868, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0890] 880. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of anti-CD45RB antibody at a concentration and frequency sufficient to increase T regulatory cell number by 100 percent.

[0891] 881. The method of aspect 880, wherein said T regulatory cells are quantified by expression of granzyme B.

[0892] 882. The method of aspect 880, wherein said T regulatory cells are quantified by expression of CD25.

[0893] 883. The method of aspect 880, wherein said T regulatory cells are quantified by expression of CTLA4.

[0894] 884. The method of aspect 880, wherein said T regulatory cells are quantified by expression of GITR.

[0895] 885. The method of aspect 880, wherein said T regulatory cells are quantified by expression of FoxP3.

[0896] 886. The method of aspect 880, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0897] 887. The method of aspect 880, wherein said T regulatory cells are quantified by expression of HLA-G.

[0898] 888. The method of aspect 880, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0899] 889. The method of aspect 880, wherein said T regulatory cells are quantified by expression of CD69.

[0900] 890. The method of aspect 880, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0901] 891. The method of aspect 880, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0902] 892. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of human chorionic gonadotropin at a concentration and frequency sufficient to increase T regulatory cell number by 10 percent.

[0903] 893. The method of aspect 892, wherein said T regulatory cells are quantified by expression of granzyme B.

[0904] 894. The method of aspect 892, wherein said T regulatory cells are quantified by expression of CD25.

[0905] 895. The method of aspect 892, wherein said T regulatory cells are quantified by expression of CTLA4.

[0906] 896. The method of aspect 892, wherein said T regulatory cells are quantified by expression of GITR.

[0907] 897. The method of aspect 892, wherein said T regulatory cells are quantified by expression of FoxP3.

[0908] 898. The method of aspect 892, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0909] 899. The method of aspect 892, wherein said T regulatory cells are quantified by expression of HLA-G.

[0910] 900. The method of aspect 892, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0911] 901. The method of aspect 892, wherein said T regulatory cells are quantified by expression of CD69.

[0912] 902. The method of aspect 892, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0913] 903. The method of aspect 892, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0914] 904. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of human chorionic gonadotropin at a concentration and frequency sufficient to increase T regulatory cell number by 25 percent.

[0915] 905. The method of aspect 904, wherein said T regulatory cells are quantified by expression of granzyme B.

[0916] 906. The method of aspect 904, wherein said T regulatory cells are quantified by expression of CD25.

[0917] 907. The method of aspect 904, wherein said T regulatory cells are quantified by expression of CTLA4.

[0918] 908. The method of aspect 904, wherein said T regulatory cells are quantified by expression of GITR.

[0919] 909. The method of aspect 904, wherein said T regulatory cells are quantified by expression of FoxP3.

[0920] 910. The method of aspect 904, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0921] 911. The method of aspect 904, wherein said T regulatory cells are quantified by expression of HLA-G.

[0922] 912. The method of aspect 904, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0923] 913. The method of aspect 904, wherein said T regulatory cells are quantified by expression of CD69.

[0924] 914. The method of aspect 904, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0925] 915. The method of aspect 904, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0926] 916. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of human chorionic gonadotropin at a concentration and frequency sufficient to increase T regulatory cell number by 50 percent.

[0927] 917. The method of aspect 916, wherein said T regulatory cells are quantified by expression of granzyme B.

[0928] 918. The method of aspect 916, wherein said T regulatory cells are quantified by expression of CD25.

[0929] 919. The method of aspect 916, wherein said T regulatory cells are quantified by expression of CTLA4.

[0930] 920. The method of aspect 916, wherein said T regulatory cells are quantified by expression of GITR.

[0931] 921. The method of aspect 916, wherein said T regulatory cells are quantified by expression of FoxP3.

[0932] 922. The method of aspect 916, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0933] 923. The method of aspect 916, wherein said T regulatory cells are quantified by expression of HLA-G.

[0934] 924. The method of aspect 916, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0935] 925. The method of aspect 916, wherein said T regulatory cells are quantified by expression of CD69.

[0936] 926. The method of aspect 916, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0937] 927. The method of aspect 916, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0938] 928. The method of aspect 706 wherein said number of T regulatory cells is increased by administration of human chorionic gonadotropin at a concentration and frequency sufficient to increase T regulatory cell number by 100 percent.

[0939] 929. The method of aspect 928, wherein said T regulatory cells are quantified by expression of granzyme B.

[0940] 930. The method of aspect 928, wherein said T regulatory cells are quantified by expression of CD25.

[0941] 931. The method of aspect 928, wherein said T regulatory cells are quantified by expression of CTLA4.

[0942] 932. The method of aspect 928, wherein said T regulatory cells are quantified by expression of GITR.

[0943] 933. The method of aspect 928, wherein said T regulatory cells are quantified by expression of FoxP3.

[0944] 934. The method of aspect 928, wherein said T regulatory cells are quantified by expression of membrane bound TGF-beta.

[0945] 935. The method of aspect 928, wherein said T regulatory cells are quantified by expression of HLA-G.

[0946] 936. The method of aspect 928, wherein said T regulatory cells are quantified by expression of IL-10 receptor.

[0947] 937. The method of aspect 928, wherein said T regulatory cells are quantified by expression of CD69.

[0948] 938. The method of aspect 928, wherein said T regulatory cells are quantified by expression of VEGF receptor.

[0949] 939. The method of aspect 928, wherein said T regulatory cells are quantified by expression of TGF-beta receptor.

[0950] 928. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of interleukin-2 at a concentration and frequency sufficient to increase T regulatory cell activity by 10%.

[0951] 929. The method of aspect 928, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[0952] 930. The method of aspect 928, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[0953] 931. The method of aspect 928, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[0954] 932. The method of aspect 928, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[0955] 933. The method of aspect 928, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[0956] 934. The method of aspect 928, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[0957] 935. The method of aspect 928, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[0958] 936. The method of aspect 928, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[0959] 937. The method of aspect 928, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[0960] 938. The method of aspect 928, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[0961] 939. The method of aspect 928, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[0962] 940. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of interleukin-2 at a concentration and frequency sufficient to increase T regulatory cell activity by 25%.

[0963] 941. The method of aspect 940, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[0964] 942. The method of aspect 940, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[0965] 943. The method of aspect 940, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[0966] 944. The method of aspect 940, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[0967] 945. The method of aspect 940, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[0968] 946. The method of aspect 940, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[0969] 947. The method of aspect 940, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[0970] 948. The method of aspect 940, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[0971] 949. The method of aspect 940, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[0972] 950. The method of aspect 940, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[0973] 951. The method of aspect 940, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[0974] 952. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of interleukin-2 at a concentration and frequency sufficient to increase T regulatory cell activity by 50%

[0975] 953. The method of aspect 952, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[0976] 954. The method of aspect 952, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[0977] 955. The method of aspect 952, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[0978] 956. The method of aspect 952, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[0979] 957. The method of aspect 952, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[0980] 958. The method of aspect 952, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[0981] 959. The method of aspect 952, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[0982] 960. The method of aspect 952, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[0983] 961. The method of aspect 952, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[0984] 962. The method of aspect 952, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[0985] 963. The method of aspect 952, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[0986] 964. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of interleukin-2 at a concentration and frequency sufficient to increase T regulatory cell activity by 100%.

[0987] 965. The method of aspect 964, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[0988] 966. The method of aspect 964, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[0989] 967. The method of aspect 964, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[0990] 968. The method of aspect 964, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[0991] 969. The method of aspect 964, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[0992] 970. The method of aspect 964, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[0993] 971. The method of aspect 964, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[0994] 972. The method of aspect 964, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[0995] 973. The method of aspect 964, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[0996] 974. The method of aspect 964, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[0997] 975. The method of aspect 964, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[0998] 976. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of anti-CD45RB at a concentration and frequency sufficient to increase T regulatory cell activity by 10%.

[0999] 977. The method of aspect 976, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[1000] 978. The method of aspect 976, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[1001] 979. The method of aspect 976, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[1002] 980. The method of aspect 976, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[1003] 981. The method of aspect 976, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[1004] 982. The method of aspect 976, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[1005] 983. The method of aspect 976, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[1006] 984. The method of aspect 976, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[1007] 985. The method of aspect 976, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[1008] 986. The method of aspect 976, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[1009] 987. The method of aspect 976, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[1010] 988. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of anti-CD45RB at a concentration and frequency sufficient to increase T regulatory cell activity by 25%.

[1011] 989. The method of aspect 988, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[1012] 990. The method of aspect 988, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[1013] 991. The method of aspect 988, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[1014] 992. The method of aspect 988, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[1015] 993. The method of aspect 988, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[1016] 994. The method of aspect 988, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[1017] 995. The method of aspect 988, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[1018] 996. The method of aspect 988, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[1019] 997. The method of aspect 988, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[1020] 998. The method of aspect 988, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[1021] 999. The method of aspect 988, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[1022] 1000. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of anti-CD45RB at a concentration and frequency sufficient to increase T regulatory cell activity by 50%.

[1023] 1001. The method of aspect 1000, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[1024] 1002. The method of aspect 1000, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[1025] 1003. The method of aspect 1000, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[1026] 1004. The method of aspect 1000, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[1027] 1005. The method of aspect 1000, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[1028] 1006. The method of aspect 1000, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[1029] 1007. The method of aspect 1000, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[1030] 1008. The method of aspect 1000, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[1031] 1009. The method of aspect 1000, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[1032] 1010. The method of aspect 1000, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[1033] 1011. The method of aspect 1000, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[1034] 1012. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of anti-CD45RB at a concentration and frequency sufficient to increase T regulatory cell activity by 100%.

[1035] 1013. The method of aspect 1012, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[1036] 1014. The method of aspect 1012, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[1037] 1015. The method of aspect 1012, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[1038] 1016. The method of aspect 1012, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[1039] 1017. The method of aspect 1012, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[1040] 1018. The method of aspect 1012, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[1041] 1019. The method of aspect 1012, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[1042] 1020. The method of aspect 1012, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[1043] 1021. The method of aspect 1012, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[1044] 1022. The method of aspect 1012, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[1045] 1023. The method of aspect 1012, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[1046] 1012. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of anti-CD45RB at a concentration and frequency sufficient to increase T regulatory cell activity by 100%.

[1047] 1013. The method of aspect 1012, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[1048] 1014. The method of aspect 1012, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[1049] 1015. The method of aspect 1012, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[1050] 1016. The method of aspect 1012, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[1051] 1017. The method of aspect 1012, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[1052] 1018. The method of aspect 1012, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[1053] 1019. The method of aspect 1012, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[1054] 1020. The method of aspect 1012, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[1055] 1021. The method of aspect 1012, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[1056] 1022. The method of aspect 1012, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[1057]

[1058] 1023. The method of aspect 1012, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[1059] 1024. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of human chorionic gonadotropin at a concentration and frequency sufficient to increase T regulatory cell activity by 10%.

[1060] 1025. The method of aspect 1024, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[1061] 1026. The method of aspect 1024, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[1062] 1027. The method of aspect 1024, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[1063] 1028. The method of aspect 1024, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[1064] 1029. The method of aspect 1024, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[1065] 1030. The method of aspect 1024, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[1066] 1031. The method of aspect 1024, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[1067] 1032. The method of aspect 1024, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[1068] 1033. The method of aspect 1024, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[1069] 1034. The method of aspect 1024, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[1070] 1035. The method of aspect 1024, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[1071] 1036. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of human chorionic gonadotropin at a concentration and frequency sufficient to increase T regulatory cell activity by 25%.

[1072] 1037. The method of aspect 1036, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[1073] 1038. The method of aspect 1036, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[1074] 1039. The method of aspect 1036, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[1075] 1040. The method of aspect 1036, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[1076] 1041. The method of aspect 1036, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[1077] 1042. The method of aspect 1036, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[1078] 1043. The method of aspect 1036, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[1079] 1044. The method of aspect 1036, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[1080] 1045. The method of aspect 1036, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[1081] 1046. The method of aspect 1036, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[1082] 1047. The method of aspect 1036, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[1083] 1048. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of human chorionic gonadotropin at a concentration and frequency sufficient to increase T regulatory cell activity by 50%.

[1084] 1049. The method of aspect 1048, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[1085] 1050. The method of aspect 1048, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[1086] 1051. The method of aspect 1048, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[1087] 1052. The method of aspect 1048, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[1088] 1053. The method of aspect 1048, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[1089] 1054. The method of aspect 1048, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[1090] 1055. The method of aspect 1048, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[1091] 1056. The method of aspect 1048, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[1092] 1057. The method of aspect 1048, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[1093] 1058. The method of aspect 1048, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[1094] 1059. The method of aspect 1048, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.

[1095] 1060. The method of aspect 707 wherein said activity of T regulatory cells is increased by administration of human chorionic gonadotropin at a concentration and frequency sufficient to increase T regulatory cell activity by 50%.

[1096] 1061. The method of aspect 1060, wherein said T regulatory cells activity is suppression of conventional T cell proliferation.

[1097] 1062. The method of aspect 1060, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with concanavalin A.

[1098] 1063. The method of aspect 1060, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with PHA.

[1099] 1064. The method of aspect 1060, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with interleukin-2.

[1100] 1065. The method of aspect 1060, wherein said T regulatory cells activity is suppression of conventional T production of interferon gamma after stimulation with anti-CD3 and anti-CD28.

[1101] 1066. The method of aspect 1060, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with Poly IC.

[1102] 1067. The method of aspect 1060, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with lipopolysaccharide.

[1103] 1068. The method of aspect 1060, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with BCG.

[1104] 1069. The method of aspect 1060, wherein said T regulatory cells activity is suppression of dendritic cell maturation after stimulation with CpG DNA.

[1105] 1070. The method of aspect 1060, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interleukin-2.

[1106] 1071. The method of aspect 1060, wherein said T regulatory cells activity is suppression of NK activity after stimulation with interferon gamma.BRIEF DESCRIPTION OF DRAWINGS

[1107] Figure 1 is a bar graph showing survival rates in murine models of sepsis based on treatment of control, umbilical cord derived MSCs (UC-MSC), bone marrow derived MSCs (BM- MSC), and MSCs generated from pluripotent stem cells (PMSC).DETAILED DESCRIPTION OF THE INVENTION

[1108] The detailed description set forth below is intended as a description of various configurations of the subject technology and is not intended to represent the only configurations in which the subject technology may be practiced. The detailed description includes specific details for the purpose of providing an understanding of the subject technology. It will beapparent to those skilled in the art that the subject technology may be practiced without these specific details.

[1109] The invention provides methods, and compositions of matter for the treatment of sepsis / multiorgan dysfunction syndrome (MODS), multiple organ failure (MOF) and conditions emerging from such a state. The invention provides the use of various cellular therapies derived from pluripotent stem cells that are capable of: a) suppressing development of such syndromes; b) accelerated resolution of such syndromes; and c) resolving pathological consequences of such syndromes such as fibrosis.

[1110] Unless defined otherwise, the technical terms used herein have the same meaning as is commonly understood by one of skill in the art.

[1111] As used herein, the terms "subject" or "patient" refers to a human or an animal.

[1112] As used herein, "CD," "cluster of differentiation" or "common determinant" as used herein refers to cell surface molecules recognized by antibodies. Expression of some CDs (e.g., CD4, CD8, CD25, CD127) is specific for cells of a particular lineage or maturational pathway, and the expression of others varies according to the state of activation, position, or differentiation of the same cells. Preferably, in some embodiments, the CD determinants are human when the isolated cells are to be administered to a human or a human immune response is being studied.

[1113] As used herein, "CD4" refers to a cell-surface glycoprotein typically found on mature helper T cells and immature thymocytes, as well as on monocytes and macrophages. On T cells, CD4 is the co-receptor for the T cell receptor (TCR) and recruits the tyrosine kinase lek. With its Dl-portion, CD4 can attach to the P2-domain of MHC class II molecules. CD4+ (positive) refers to cells which stain brightly when contacted with labeled anti-CD4 antibody, and CD4- (negative) refers to cells of a type which stain the least brightly, dull, or not at all, when contacted with a fluorescently labeled CD4 antibody. Generally, the cells are distinguished according to their CD4 expression levels based upon a readily discernible differences in staining intensity as the CD4 staining is clearly bimodal. In some embodiments, the frequency distribution of the CD4 staining is obtained for all the cells and the population curve fit to a higher staining and lower staining population, and cells assigned to the population to which they most statistically are likely to belong in view of a statistical analysis of the respective population distributions.

[1114] As used herein, the term "CD25" refers to the alpha subunit of interleukin-2 receptor, a single-chain glycoprotein with a molecular weight of 55 kD. Following the activation of T cells with antigen or mitogen in the presence of the monokine interleukin-1, interleukin 2(IL-2) is rapidly synthesized and secreted. In response to this, a subpopulation of T cells expresses high affinity receptors for IL-2. These cells proliferate, expanding the T cell population which is capable of mediating helper, suppressor, and cytotoxic functions. IL-2 receptor is not uniquely found on T cells. CD25hi refers to cells which stain brightly when contacted with labeled anti-CD25 antibody, CD25+ refers to cells which stain less brightly when contacted with labeled anti-CD25 antibody, and CD25lo / - refers to cells which are of a type which stains the least brightly dull or null when contacted with a labeled CD25 antibody. Generally, the cells are distinguished according to their CD25 expression levels based upon differences in staining intensity as is known to one of ordinary skill in the art. In some embodiments, the cut off for designating a cell as a CD25 expression category hi, +, Io, or — cell can be set in terms of the fluorescent intensity distribution observed for all the cells. Generally, cells in the top 2, 3, 4, or 5% of staining intensity are designated "hi", with those falling in the top half of the population categorized as being "+".

[1115] As used herein, "inhibitors," "activators," and "modulators" of expression or of activity are used to refer to inhibiting, activating, or modulating cells, respectively, and are identified using in vitro and in vivo assays for expression or activity. The term "modulator" includes inhibitors and activators. A modulator can be an antibody or a soluble ligand which binds a protein of interest. Inhibitors are agents that, e.g., inhibit expression of a polypeptide or polynucleotide of the invention or bind to, partially or totally block stimulation or enzymatic activity, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity of a polypeptide or polynucleotide of the invention, e.g., antagonists. Preferred modulators according to the invention, inhibit or suppress immune responses to an antigen or alloantigen. Assays to identify inhibitors and activators include, e.g., applying putative modulators to immune cells and then determining the functional effects of the cell on the immune response (e.g., MLR). Inhibitors or modulators are compared to control samples without the inhibitor or modulator to examine the extent of effect. Control samples (untreated with modulators) are assigned a relative activity value of 100%. Inhibition is achieved when the activity value of a polypeptide or polynucleotide of the invention relative to the control sample is about 80%, optionally 50% or 25 to 1%, or less. Activation is achieved when the activity value of a polypeptide or polynucleotide of the invention relative to the control sample is 110%, optionally 150%, optionally 200-500%, or 1000-3000%, or higher.

[1116] As used herein, the term "isolated" when used with regard to a population of cells as used herein refers to a cell population which either has no naturally occurring counterpart or has been separated or purified from other components, including other cell types, whichnaturally accompany it, e.g., in normal or diseased tissues such as lung, kidney, or placenta, tumor tissue such as colon cancer tissue, or body fluids such as blood, serum, or urine. Typically, an isolated cell population is at least two-fold, four-fold, or eight-fold enriched for a specified cell type when compared to the natural source from which the population was obtained.

[1117] In some embodiments T regulatory (Treg) cells are utilized to treat MODS. In one embodiment Tregs are generated from pluripotent sources. In other embodiments Tregs are generated in vitro by culture of T cells with mesenchymal stem cells derived from pluripotent stem cells. In other embodiments Tregs are generated in vivo after administration of mesenchymal stem cells derived from pluripotent stem cell source.

[1118] Treg cells make express CD4, and / or CD8 or may lack expression of both markers.

[1119] As used herein, a population or subpopulation of cells which is "substantially" of a specified cell type is one which has a count of the specified cell type which is at least 50%, 75%, 80%, 90%, 95% or, most preferably, 98% or 99% of the total cell count of the population or subpopulation or one which is at least two-fold, four-fold, eight-fold, ten-fold or 20-fold enriched for a specified cell type as compared to a source population of the specified cell type.

[1120] An "anti-X antibody" or "X antibody" according to the invention is an antibody which can specifically bind to X. For instance, the anti-CD127 antibody or CD127 antibody is capable of binding CD127. The antibodies for use according to the invention include, but are not limited to, recombinant antibodies, polyclonal antibodies, monoclonal antibodies, chimeric antibodies, human monoclonal antibodies, humanized or primatized monoclonal antibodies, and antibody fragments. Many lymphocyte biomarker specific antibodies are commercially available. These include anti-CD127, anti-CD4, and anti-CD25 antibodies.

[1121] As used herein, "antibody" refers to a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. Typically, the antigen-binding region of an antibody will be most critical in specificity and affinity of binding. An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25 kD) and one "heavy" chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variableheavy chain (VH) refer to these light and heavy chains respectively. Antibodies exist, e.g., as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. Thus, for example, pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond. The F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)'2 dimer into an Fab' monomer. The Fab' monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554 (1990)). In some embodiments, a high affinity ligand of a target may be used in place of the antibody.

[1122] As used herein, the term "specifically (or selectively) binds" to an antibody or "specifically (or selectively) immunoreactive with," when referring to a protein or peptide, refers to a binding reaction that is determinative of the presence of the protein, often in a heterogeneous population of proteins and other biologies. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only those polyclonal antibodies that are specifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules.

[1123] Preferably a "label" or a "detectable moiety" is covalently or noncovalently attached to the antibody. A label may be detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. Particularly useful labels are fluorescent dyes. Methods of attaching labels to antibodies are well known to those of ordinary skill in the art. Particularly preferred labels are those which are attached to the antibody by a linker which can be readily cleaved or separated or subject to hydrolysis by contact with a predetermined enzyme under physiological conditions. The antibody may also be conjugated with a magnetic particle, such as a paramagnetic microbead. An activated T cell bound by a magnetically labeled antibody may be isolated using techniques including, but not limited to, magnetic cell sorting. Suitably labeled antibodies to CD127, CD4 and CD25, as well as many other CDs, are commercially available and known to one of ordinary skill in the art. The antibody maybe labeled before or after contact with the sample or before or after contact with the CD. The CD antibody may be labeled by contacting with a labeled antibody which binds to the CD- antibody.

[1124] As used herein, "induced pluripotent stem cell" (iPSC) refers to a type of pluripotent stem cell that can be reprogrammed from adult somatic cells (e.g., from skin or blood cells, or from another tissue source). This technology was pioneered by the introduction of four specific genes encoding transcription factors Oct3 / 4, Sox2, c-Myc and Klf4 into mouse adult fibroblasts under embyronic stem (ES) cell culture conditions.

[1125] As used herein, "mesenchymal stem cell" (MSC) refers to cells that are (1) adherent to plastic, (2) express CD73, CD90, and CD105 antigens, while being CD14, CD34, CD45, and HLA-DR negative, and (3) possess ability to differentiate to osteogenic, chondrogenic and adipogenic lineage. As used herein, "mesenchymal stromal cell" or "MSC" can be derived from any tissue including, but not limited to, bone marrow, adipose tissue, amniotic fluid, endometrium, trophoblast-derived tissues, cord blood, Wharton jelly, placenta, amniotic tissue, derived from pluripotent stem cells, and tooth. As used herein, "mesenchymal stromal cell" or "MSC" includes cells that are CD34 positive upon initial isolation from tissue but are similar to cells described about phenotypically and functionally. As used herein, "MSC" includes cells that are isolated from tissues using cell surface markers selected from the list comprised of NGF-R, PDGF-R, EGF-R, IGF-R, CD29, CD49a, CD56, CD63, CD73, CD105, CD106, CD140b, CD146, CD271, MSCA-1, SSEA4, STRO-1 and STRO-3 or any combination thereof and satisfy the ISCT criteria either before or after expansion. As used herein, "mesenchymal stromal cell" or "MSC" includes cells described in the literature as bone marrow stromal stem cells (BMSSC), marrow-isolated adult multipotent inducible cells (MIAMI) cells, multipotent adult progenitor cells (MAPC), mesenchymal adult stem cells (MASCS), MultiStem®, Prochymal®, remestemcel-L, Mesenchymal Precursor Cells (MPCs), Dental Pulp Stem Cells (DPSCs), PLX cells, PLX-PAD, AlloStem®, Astrostem®, Ixmyelocel-T, MSC-NTF, NurOwn™, Stemedyne™-MSC, Stempeucel®, StempeucelCLI, StempeucelOA, HiQCell, Hearticellgram-AMI, Revascor®, Cardiorel®, Cartistem®, Pneumostem®, Promostem®, Homeo-GH, AC607, PDA001, SB623, CX601, AC607, Endometrial Regenerative Cells (ERC), adipose-derived stem and regenerative cells (ADRCs).

[1126] As used herein, "decellularized matrix" refers to isolated extracellular matrix that has been separated from its inhabiting cells, which may, for example, be performed using tissue engineering techniques such as by mechanical and / or chemical methods. In certain embodiments, a decellularized matrix is provided to pluripotent stem cells as a bone marrow microenvironment mimetic. In certain embodiments, a decellularized matrix provides asubstrate for cell culture and / or as a source of factors for promoting certain features of cultured cells.

[1127] In one embodiment iPSC derived mesenchymal stem cells are generated in a current Good Manufacturing Practices (cGMP) manner. A key component in the cGMP grade cell therapy-compliant culture system is the choice of reagents and supplements utilized during the manufacturing process. The use of animal-derived reagents and tissue culture supplements represents a critical issue in the manufacture of cGMP products designated for clinical use. Transplantation of human cells exposed to animal-derived products can potentially transfer immunogenic sugars such as N-glycolylneuraminic acid (Neu5Gc) into the human body, may trigger chronic inflammation and immune reaction, and may introduce undesirable and potentially harmful adventitious contaminants. In certain embodiments, a novel xenogeneic protein-free manufacturing process for the production of a cells for use in treatment of sepsis, or MODS is provided. The cGMP Facility quality program includes an active vendor qualification program, administered by the QA unit. The program includes qualification and approval of all vendors from which reagents, supplies, equipment, and testing services are purchased. There is a system in place which establishes various reagents and supplies as critical vs. non-critical. Vendors that supply critical materials (such as reagents and reagent kits utilized during product manufacture, and for qualification of the final product according to the pre-established lotrelease criteria) are audited by the QA Unit as part of the vendor qualification process. These procedures are established to assure that vendors meet the current cGMP Quality System standards. A material specification program is also in place for supplies, materials and reagents used during manufacture, storage, and testing of cellular products. Reagents are qualified on the basis of relevant information supplied in MSDS, the Certificate of Analysis (CoA), Manufacturer's Insert, and as a result of validation / testing activities. All the information is carefully reviewed to determine the suitability of each reagent, supply, and material purchased. In case of reagents that are not designated for clinical use or not FDA approved, the need for additional testing is determined on case-to-case basis. All custom-made reagents that are not FDA approved are quarantined upon receipt into the cGMP Facility. This is until all the appropriate paperwork is reviewed, and the results of testing performed at receipt are reviewed and deemed acceptable. The cGMP quality program has a mechanism in place for recall notification, for FDA- approved and USP grade materials.

[1128] In certain embodiments, a cell manufacturing approach comprises of 3 culture and expansion cell passages, in T-225 cm2 tissue culture flasks, and 5-layer CellSTACK tissue culture chambers (Cornig, Corning, NY). In some embodiments, cells are seeded at 4,000 ± 500cells / cm2 at each cell passage. Briefly, 1-2 vials of iPSC derived, or pluripotent derived mesenchymal stem cells are thawed and washed in DMEM LG complete media (DMEM, LG without Phenol Red, Gibco Life Technologies, Carlsbad, CA), supplemented with 5% PLTGold (Mill Creek, Rochester, MN), lx GlutaMAX (Gibco Life Technologies, Carlsbad, CA), and lx MEM- NEAA (Gibco Life Technologies, Carlsbad, CA). Cells are counted to determine total viable cells and cell viability and plated onto 5-10 (n=5-10) T-225 cm2 tissue culture flasks and cultured in 5% CO2 tissue culture incubators, at 37°C, in DMEM LG complete media (DMEM GL CM), with media changes every 2-3 days, to 75-80% confluence. Cells are harvested with TrypLE Select Enzyme Gibco Life Technologies, Carlsbad, CA) for 3- 6 minutes at 37°C, washed and resuspended in complete DMEM LG CM. Samples are collected to assess total viable cells and cell viability. Cells are cultured in 7-10 of 5-layer CellSTACK tissues culture chambers for P2 and up to 25-35 of 5-layer CellSTACK tissue culture chambers for P3 and expanded to 75-80% confluence at each passage. At the time of each harvest, cells are counted, viability is assessed by Trypan Blue dye exclusion and sterility samples are collected. During last harvest, in addition to the assessment of total viable cells and cell viability by Trypan Blue, samples are collected to assess Mycoplasma by PCR (cells in spent media). Resulting cell pellet is re-suspended in Cryostor® CS10 solution (Biolife Solutions (Bothell, WA) at a concentration of 10x106 cells / ml and cells are cryopreserved using a controlled rate freezer. One lot or batch comprises of pluripotent stem cell derived Final Batch Product (batch, cryopreserved) manufactured. The cells are cryopreserved and tested and released for administration. The Final Batch Product (batch, cryopreserved) is tested for cell dose / storage container (cryo-bag), and must be >80% viable, of >90% purity by FLOW Cytometric analysis.

[1129] In one embodiment, pluripotent stem cell derived MSC are administered to a subject a dose of 100±20 xl0(6) cells. The cell dose is dependent on numerous factors including patient characteristics, and disease characteristics. The proposed dose is based on previous reports with clinical protocols involving systemic (i.e., IV) administration of UC-MSC products, including patients with ARDS. The infusion comprises (1) 50 ml of either Plasma-Lyte (USP, pH 7.4, Injection) supplemented with 10% HSA (USP) and 5,000 U unfractionated Heparin (USP, Injection) and containing a dose of 100±20 x 10(6). For cellular administration according to the invention, the cells are demonstrated to be negative for Endotoxin (<1.65 EU / ml) and Mycoplasma, and free of any contaminating organisms, as assessed by USP <71> sterility testing.

[1130] Once the pluripotent stem cell derived Final Batch Product (batch, cryopreserved) is tested and released for administration, sufficient numbers of cells (batch, cryopreserved) are issued and shipped to each of the participating clinical sites, with the rest of the Final BatchProduct (batch, cryopreserved) remaining in storage, in cGMP Facility. The iPSC derived MSC Final Batch Product (batch, cryopreserved) designated for distribution to participating hospitals are handled by an approved vendor experienced in logistics of cold technology transfer, and shipped in validated dry shippers, with continuous temperature monitoring and GPS location capabilities during shipment. Upon arrival at the participating site the product will be transferred to ultra-low temperature storage or vapor phase of LN2 fitted with continuous temperature monitoring device. Upon receipt of the Request for Transplant / infusion at the research pharmacy or Cell Therapy Laboratory, a sufficient amount of Final Batch Product (batch, cryopreserved) will be thawed and prepared for infusion, as described in Product Preparation Manual, provided by the cGMP Facility, at each participating clinical site. Cell (Final Infusion Product / iPSC-MSC Thawed / Diluted) are infused in subjects that have been screened and consented to participate in the clinical trial, described in this application. Briefly, when Request for Transplant (Tx / infusion) is received by the cGMP Facility, sufficient amount of iPSC-MSC Final Batch Product (batch, cryopreserved) to satisfy the required dose is then removed from ultralow temperature storage, rapidly thawed, and slowly diluted in 50 ml of PLASMA-LYTE A (USP, pH 7.4, Injection), supplemented with 10% HSA (USP) and 5,000 U unfractionated Heparin (USP). Cells are released for administration based on cell dose, cell viability, and Gram stain results. Testing samples for IP release testing will be collected from the final container (CryoStore 50 ml bag from OriGen Biomedical, Austin TX, or 300 ml transfer bag from Fenwal, Lake Zurich, IL), following dilution with PLASMA-LYTE A supplemented with 10% HSA and 5,000 U unfractionated Heparin. IP will be placed in a validated transport container fitted with the continuous temperature monitoring device. Detailed SOPs are implemented for product preparation for administration and transport to the clinical cite (intensive care unit, ICU). At the time of study initiation, study staff from participating clinical sites will be trained on how to receive the product at the clinical site, records requirements and return of the transport container, temperature monitoring device and required documentation back to the cGMP Facility. As with any cellular product iPSC-MSC is assessed for various safety parameters. For bacterial testing a sample (a single drop) is fixed on a slide (two slides will be submitted), stained and examined for bacterial growth, cell morphology and characteristics. Gram stain results must be negative. This test is utilized as a post-batch release criterion, to provide additional information as to the aseptic technique utilized by personnel during preparation of Thawed Product for infusion. Results of sterility sample and this Gram stain test will be utilized for the infusion of the Thawed Product. Automated cell count is performed using Cellometer Auto 2000 Cell Counter that employs bright field imaging to quickly and accurately identify and count individual cells. Cellconcentrations, diameters and % viability are automatically calculated and reported. Twenty (20) pl of cell suspension diluted to an appropriate concentration will be loaded onto a disposable slide specific for the instrument. Cellometer acquires cell images from 4 different fields may be analyzed to determine cell count, concentration, cell size and cell viability using Trypan Blue using the bright filed cell counter feature. Image of each field counted is stored and can be retrieved, if necessary. The count may be repeated twice to obtain an accurate result. Cell counts are performed in-process (before and during culture and expansion), at the time of batch release, and immediately before the infusion of the cells of the invention. In some embodiments, cell dose of 100±20 xl0(6) ± 20 cells / infusion is required. Cell viability of >80% serves as a Final Product and IP release criterion.

[1131] Embodiments of the invention disclose steps for providing an iPSC population that is suitable for differentiation into therapeutic cells, and the methods for subsequent generation of therapeutic cells for treating multiorgan failure. Embodiments of the invention provide iPSCs that are generated from somatic cells of a subject that are subsequently differentiated into autologous therapeutic cell types for treatment of the subject.

[1132] In one embodiment, somatic cell nuclear transfer is performed, wherein the somatic cell nuclear transfer is augmented by suppression of the p53 in the iPSCs by RNA interference, and wherein RNA interference comprises treating the cells with short interfering RNA, short hairpin RNA, double stranded RNA, antisense oligonucleotides, a ribozyme, morpholino oligonucleotides or an aptamer to silence the gene.

[1133] In one embodiment, generation of iPSCs is performed by reprogramming somatic cells, wherein reprogramming of somatic cells is performed by introducing genes encoding for one or a plurality of the following factors: PIMl, PIM3, sox-2, c-myc, k-ras, NF-kappa B, NANOG, KLF4, and OCT4.

[1134] In one embodiment, the factors are delivered to somatic cells by protein transduction using protein transduction domain containing proteins such as cell penetrating peptides. In one embodiment, cell penetrating peptides are delivered by co-injection of DNA or protein, and wherein a cell penetrating peptide may comprise one or a plurality of the following: LL37, TAT, penetratin, polyarginine, PEP-1, TAT-H2, Hph-1, HP4, LAH4, LAH4-L1, vectofusin, low molecular weight protamine, and VP22.

[1135] In one embodiment, RNA nanoparticles comprising RNA encoding one or a plurality of the factors capable of inducing cellular dedifferentiation and / or reprogramming are introduced to the somatic cells to induce cellular dedifferentiation and / or reprogramming, wherein the RNA nanoparticles are selected from the group consisting of messenger RNAnanoparticles for expressing transcription factors which allow somatic cells or adult stem cells to be dedifferentiated into induced pluripotent stem cells, micro RNA nanoparticles facilitating the dedifferentiation, small interfering RNA nanoparticles facilitating the dedifferentiation, complex RNA nanoparticles which include micro RNA facilitating the dedifferentiation and small interfering RNA facilitating the dedifferentiation, complex RNA nanoparticles which include messenger RNA for expressing a transcription factor and micro RNA facilitating the dedifferentiation, complex RNA nanoparticles which include messenger RNA for expressing a transcription factor and small interfering RNA facilitating the dedifferentiation, and complex RNA nanoparticles which include messenger RNA for expressing a transcription factor, micro RNA facilitating the dedifferentiation, and small interfering RNA facilitating the dedifferentiation is used as the RNA nanoparticles for cell transformation.

[1136] In one embodiment, the RNA nanoparticles for cell transformation include at least one RNA selected from the group consisting of messenger RNA for expressing transcription factors which allow somatic cells or adult stem cells to be dedifferentiated into induced pluripotent stem cells, microRNA facilitating the dedifferentiation, and small interfering RNA, and wherein the transcription factor comprises one or a plurality of the following: Oct4, Sox2, PIM1, PIM3, c-MYC, l-MYC, c-MET, KLF-4, and Lin28.

[1137] In one embodiment, at least one RNA nanoparticle is selected from the group consisting of messenger RNA nanoparticles for expressing transcription factors and / or adjuvant genes associated with dedifferentiation which allow somatic cells or adult stem cells to be dedifferentiated into induced pluripotent stem cells. In one embodiment, the RNA nanoparticles capable of inducing cellular dedifferentiation and / or reprograming comprise of a spherical shape and have a diameter of 50 to 200 nm.

[1138] In one embodiment, one or a plurality of chemicals associated with dedifferentiation are added to cultures of iPSCs to augment the dedifferentiation process of somatic cells, and wherein the one or plurality of chemicals are selected from the following group: an inhibitor of histone deacetylase(s), an inhibitor of DNA methyltransferase(s), and an inhibitor of glycogen synthase kinase 3 (GSK-3).

[1139] In certain embodiments, iPSCs generated using these methods are cultured and allowed to form embryoid bodies under the appropriate culture conditions. In certain embodiments, an iPSC-derived differentiated cell type is generated by exposure of embryoid bodies derived from iPSCs to a decellularized matrix. In some embodiments, embryoid bodies are disaggregated prior to being subjected to the cellular differentiation protocols of theinvention. In some embodiments, embryoid bodies are disaggregated prior to addition or seeding of a decellularized matrix in the cell culture system.

[1140] The invention provides cellular compositions and methods for modulating an immune response in a subject who is afflicted with multiorgan dysfunction and sepsis. Methods for generating one or a plurality of therapeutic cell population to provide various aspects of immune modulation are disclosed.

[1141] In one embodiment, methods are provided to prevent, treat, or lessen the severity of complications associated with multiple organ dysfunction or to promote regeneration of cells and tissues within the affected organ(s). In one embodiment, multiple organ dysfunction syndrome in a subject is associated with one or a plurality of the following complications: vascular leakage, disseminated intravascular coagulation, and systemic endothelial activation.

[1142] In one embodiment, multiple organ dysfunction syndrome in a subject is associated with sepsis.

[1143] In one embodiment, sepsis is associated with one or a plurality of the following pathological cellular activities and mechanisms: platelet aggregation, platelet endothelial adhesion, neutrophil activation, neutrophil extravasation, neutrophil degranulation, monocyte activation, monocyte extracellular trap release into circulation, free radical generation, monocyte extravasation, and monocyte maturation. In one embodiment, one or a plurality of the pathological mechanisms associated with sepsis are reduced, eliminated, or prevented by administration of differentiated cell type(s) of the invention to the subject.

[1144] In one embodiment, multiple organ dysfunction is associated with expression or upregulation of one or a plurality of the following molecules in plasma or serum of a subject: C reactive protein, IL-lbeta, IL-6, IL8-, IL-11, IL-12, IL-15, IL-18, IL-17, IL-23, IL-27, IL-33, TNF-alpha, HMGB1, d-dimer, lymphotoxin, TRAIL, TRANCE, RANK ligand, circular DNA, and free DNA.Reagents and assay kits for measuring these molecules in plasma or serum are widely available and known to one of ordinary skill in the art, allowing for measurements to be performed using plasma specimens obtained prior to and at various time points following administration of a treatment to a subject. In one embodiment, one or a plurality of these molecules are reduced or eliminated in terms of their expression levels by administration of differentiated cell type(s) of the invention to the subject. In another embodiment, the upregulation of one or a plurality of these molecules is prevented by administration of differentiated cell type(s) derived from iPSCs.

[1145] In one embodiment, the severity of sepsis is assessed based on the concentrations of one or a plurality of inflammatory molecules or entities present in a tissue or a body fluid, wherein the tissue may comprise blood, lung, cerebrospinal fluid, saliva, urine or combinationsthereof, and wherein the inflammatory molecule or entity comprises one or a plurality of the following: exosomes, apoptotic bodies, neutrophil extracellular traps, histone DNA, IL-lbeta, extracellular vesicles, apoptotic bodies bound to circulating DNA, IL-2, IL-6, IL-8, IL-11, IL-12, IL- 18, IL-17, IL-21, IL-23, IL-27, high mobility group box 1 (HMGBl), IL-1 receptor antagonist, IL-33, IFN-gamma, IL-6 receptor, prostaglandin E2 (PGE2), RANTES, galectin 3, C reactive protein, vimentin, superoxide dismutase, MMP-1, MMP-3, MMP-5, MMP-9 d-dimer, and fibrinogen. In one embodiment, one or a plurality of the molecules or entities are reduced, eliminated, or prevented in terms of concentrations or expression levels by administration of differentiated cell type(s) of the invention to the subject.

[1146] Embodiments of the invention provide methods of treating a subject with multiple organ dysfunction and sepsis by administering one or a plurality of iPSC-derived therapeutic cells disclosed herein. In one embodiment, a therapeutic cell comprises one of following cell types: a T cell, a regulatory T cell, a type 1 regulatory T cell (TRI) cell, an NK cell, an NK T cell, a neutrophil (e.g., a regulatory neutrophil), a gamma-delta T cell, a type 2 NK T cell, a type 2 gamma-delta T cell, a type 2 innate lymphoid cell, a type 3 innate lymphoid cell, a macrophage, a type 2 macrophage (an M2-type or alternatively-activated macrophage), a myeloid suppressor cell, or a dendritic cell. In certain embodiments, a plurality of therapeutic cell types is administered for treating a subject.

[1147] Certain embodiments of the invention provide iPSC-derived cells having immune suppressive or anti-inflammatory phenotypes and functions. In certain embodiments, the iPSC- derived cell products of the invention possess one or a plurality of the following cytokine profiles upon stimulation by crosslinking the appropriate cellular receptor in vitro: higher TGF-beta levels as compared IFN-gamma levels, higher IL-10 levels as compared to IFN-gamma levels, higher IL- 20 levels as compared to IFN-gamma levels, higher IL-35 levels as compared to IFN-gamma levels, higher soluble HLA-G levels as compared to IFN-gamma levels, higher hepatocyte growth factor levels as compared to IFN-gamma levels, higher fibroblast growth factor-1 levels as compared to IFN-gamma levels, higher fibroblast growth factor-2 levels as compared to IFN- gamma levels, and higher leukemia inhibitory factor levels as compared to IFN-gamma levels. One of ordinary skill in the art understands that specific reagents or molecules are useful for stimulating a particular cell type (e.g., a T cell, a regulatory T cell, or a B cell, or others) to induce cellular activation and cytokine expression. In some embodiments, receptor crosslinking to induce cytokine production by a cell is performed using one of the following combinations of reagents / stimulators in vitro: anti-CD3 plus anti-CD28 antibodies, anti-CD3 plus anti-CD45 antibodies, anti-CD3 plus anti-ICOS antibodies, anti-3 antibody and a protein kinase C activator, acalcium ionophore, anti-CD3 plus anti-CD25 antibodies, anti-CD3 antibody plus IL-2, anti-CD3 antibody plus IL-7, anti-CD3 antibody plus IL-15, anti-CD3 antibody plus allogeneic antigen presenting cells.

[1148] In one embodiment, a method for treating a subject with multiple organ dysfunction syndrome using an autologous cell population differentiated from iPSCs is provided, the method comprising: a) identifying a subject with multiple organ dysfunction syndrome; b) generating an induced pluripotent stem cell (iPSC) population from the subject; c) establishing a cell culture system comprising iPSCs, wherein the cell culture system also comprises a decellularized matrix which provides cell differentiation factors, wherein exposure of the iPSCs to the decellularized matrix induces differentiation into a cell type, and wherein the differentiated cell type comprises one or a plurality of the following: a T cell, a regulatory T cell, a type 1 regulatory T cell (TRI) cell, an NKT cell, a gamma-delta T cell, a type 2 NK T cell, a type 2 gamma-delta T cell, a type 2 innate lymphoid cell, a type 3 innate lymphoid cell, a macrophage, a type 2 macrophage, a myeloid suppressor cell, or a dendritic cell; d) optionally, transfecting the one or plurality of differentiated cell types with one or a plurality of therapeutic genes; e) optionally, treating the one or plurality of differentiated cell types with one or a plurality of cytokines and / or growth factors, and f) administering a therapeutically effective amount of the autologous differentiated cell type(s) to the subject.

[1149] In certain embodiments, a decellularized matrix in a cell culture system of the invention is derived from bone marrow, placenta, or umbilical cord. In one embodiment, the decellularized matrix is added to a cell culture system comprising embryoid bodies that have been disaggregated or dissociated. In one embodiment, cells are applied to seed the decellularized matrix, which, in some embodiments comprise common lymphoid progenitors. In certain embodiments, a common lymphoid progenitor is identified or selected on the basis of expression of one or more of the following molecules: CD22, VCAM-l CD20, CD16, CD16a, CD16b, CD16c, FLT3, CD127, NCAM-1, neprilysin, and NCR1.

[1150] In one embodiment, therapeutic cell type(s) derived from iPSCs by the methods of the invention are modified by introduction of a therapeutic gene prior to administration to a subject. The therapeutic gene selected for introduction into a particular therapeutic cell type is based on the cell lineage as well as the desired immune modulatory features of the cell product. In one embodiment, a therapeutic gene comprises a gene encoding an immune modulatory factor. In one embodiment, the immune modulatory factor comprises one or a plurality of the following: a chemokine, a soluble receptor, a receptor antagonist, IL-1 receptor antagonist, IL-2, amphiregulin, IL-3, IL-4, IL-6 receptor, IL-7, IL-10, IL-13, IL-14, IL-20, IL-12 p40 homodimer, IL-22,IL-21, IL-33, IL-35, IL-37, IL-38, TGF-beta, endoglin, VEGF, VEGFC, EGF, IGF, HGF, angiopoietin, placental derived growth factor (PDGF), FGF-1, FGF-2, FGF-5, Gata4, Mef2C, Tbx5, Sox5, Sox9, MMP3, MMP5, MMP14, CD10, WNT11, BAPX1, IGFBP5, MMP16, BMP2, BMP4, BMP7, ADAMTS5, BLC1O, MCOLN2, LRRC8C, PTGFR, RLF, MATN1, PDPN, TNFRSF18, ITGA10, THBS3, SCYL1BP1, HSPC159, RHOQ, MATN3, SULT1C2, BCL2L11, KLF7, BLC-2, survivin, livin, IAP-C, bcl-XL, NRP2, heme oxygenase, NRF2, SERPINE2, FN1, B3GNT7, ADAMTS9, ANKRD28, GALNTL2, galectin-3, galectin-9, PD-L1, PD-L2, TIM-1, TIM-3, HLA-G, IRAK2, SETD5, FNDC3B, B3GNT5, CYTL1, C1Q.TNF3, ZFYVE16, MAST4, EDIL3, HAPLN1, PDLIM4, cr5q35, SQSTM1, SCUBE3, SOX5, RNF24, NUPL1, ULBP2, SOD2, KIAA0999, LRP11, SYNJ2, WTAP, HIG2 FAM62B, TNFRSF1OD, SLC25A37, BDKRB1, FZD1O, VASN, inhibitor of kappa B, RelB, EIF2C2, RUNX1 RELB, ATFI, UFM1, MATN4, NOS2A, RHOF, ETK1, SFXN3, LOXL4, GLIS3, RPS6, WISP1, RB1CC1, PTK2, SRGAP1, USP12, GITR, ICOS, PDGF-BB, TLR5, ChGn, C8orf72, HAS2, TRPS1, ZCCHC7, SLC8A3, EDG2, ITGB1, CD44, C10orf49, YME1L1, AKR1C2, CHST3, FOSL1 RELA, ASAM, CHST11, DSPG3, LOC338758, LOC399959, KIAA0701, SLC41A2, LECT1, GPC6, EROIL, SEMA6D, LACTB, ARIH1, CSPG4, AGC1, LOC283824, WWP2, LOC201181, MS12, PITPNC1, TGIF, 1552288, ZNF146, MIA, ZNF160, SNX5, HSUP1, BIC, and LIF.

[1151] In one embodiment, the differentiated cells in the cell culture system, such as regulatory T cells or mesenchymal stem cells derived from iPSCs, are used to collect exosomes. In certain embodiments, the differentiated cell type(s) are subjected to cellular stress prior to collection of exosomes, wherein the cellular stress comprises one or more of the following conditions or stimuli: hypoxia, hyperoxia, hyperthermia, hypothermia, radiation exposure, DNA strand breaks, misfolded protein accumulation, exposure to hypotonic conditions, exposure to hypertonic conditions, treatment with an activator of NF-kappaB, or exposure to a heat shock protein. In certain embodiments, a heat shock protein may comprise one or a plurality of the following: HSPD, GRPE1, GRPE2, HSP27, HSPB5, DNAj, HSP60, DNAk, HSP71, HSP72, and GRP78. In certain embodiments, an activator of NF-kappaB comprises one or a plurality of the following: flagellin, peptidoglycan, ionomycin, lipopolysaccharide, double stranded RNA, IL-33, gp96, phorbol myristate acetate, TNFSF3, TNFSF5, IL-lbeta, BAFF, osteopontin, RIG1, MDA5, CD40 ligation, CD28 ligation, CD80 ligation, TNFSF13B, TNFSF11, beta-defensin, low molecular weight hyaluronic acid, lipid A, culture with allogeneic T cells, fibronectin, snapin, tenascin C, poly(l:C), lipoteichoic acid, zymosan, Pam3CSK4, uric acid, poly GIO, and unmethylated CpG DNA. One or a plurality of agents that induce cellular stress are provided to a culture system enhance the secretion of exosomes from differentiated cells exposed to said agents. The exosomes can subsequently be collected and purified from the cell culture medium using methods known inthe art for use as a source of therapeutic exosomes that are administered to the subject alone or in conjunction with therapeutic cells. In certain embodiments, the exosomes express one or a plurality of the following molecules: HLA class II, tetraspanins, CD40, CD80, CD86, Rabi, vimentin, CD8, alpha synuclein, phosphatidylserine, calreticulin, L1CAM, galectin-9, galectin-3, CD9, CD63, CD81, TSG-101, Flotillin-1, hsp-60, hsp-70, hsp-90, hsc-70, CD147, EpCAM, CD37, and NKG2D. In some embodiments, these molecules may be identified on exosomes for enumeration or purification purposes. In some embodiments, the expression of one or a plurality of these molecules on / in exosomes may be modulated by exposure to a cellular stressor by the cells.

[1152] In certain embodiments, exosomes can be purified or selected from cell culture supernatants comprising a differentiated cell type derived from iPSCs. In certain embodiments, exosomes are isolated and counted, and prepared as therapeutic material for administration to the subject by the appropriate route of administration (e.g., intramuscularly, subcutaneously, intravenously, and the like). Embodiments of the invention provide a method for treating a subject with multiple organ dysfunction syndrome involving administration of biologic products derived from autologous pluripotent derived stem cells comprising therapeutic cells and exosomes. In certain embodiments, therapeutic cells and exosomes derived thereof are provided to a subject at the same time, on the same day, and / or as components of the same or different pharmaceutical formulations.

[1153] In one embodiment, a method for treating a subject with multiple organ dysfunction syndrome using autologous mesenchymal stem cells is provided, the method comprising: a) identifying a subject with multiple organ dysfunction syndrome; b) generating an induced pluripotent stem cell (iPSC) population from the subject; c) establishing a cell culture system comprising iPSCs, wherein the cell culture system also comprises a decellularized matrix, wherein the decellularized matrix is derived from bone marrow, placenta, or umbilical cord, and wherein exposure of the iPSCs to the decellularized matrix provides factors for inducing differentiation of iPSCs into mesenchymal stem cells; d) optionally, transfecting the differentiated mesenchymal stem cells with one or a plurality of therapeutic genes; and e) administering a therapeutically effective amount of the autologous differentiated mesenchymal stem cells to the subject.

[1154] Certain embodiments provide methods for generating mesenchymal stem cell populations from iPSCs with regenerative and immune modulatory properties that render these cells suitable for treating multiple organ failure. In one embodiment, the methods of the invention provide differentiated mesenchymal stem cells that express one or a plurality of thefollowing molecules: CXCR4, CD90, CD105, somatostatin receptor 1 (SSTR1), thromboplastin, tumor necrosis factor superfamily member 4 (TNFSF4), forkhead box L2 (FoxL2), spondin-2 (SPON2 / M-spondin), vesicle amine transport protein 1-1 ike (VAT1L), aldehyde dehydrogenase 1 family, member Al (ALDH1A1), WT1, survivin, livin, programmed cell death ligand-1 (PD-L1), G protein-coupled receptor 126 (GPR126), interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), CD49d, cathepsin C, PIM3, anoctamin-4, and c-met. In certain embodiments, differentiated mesenchymal stem cells are induced to further upregulate ALD1A1 upon treatment with one or a plurality of the following compounds in culture: valproic acid, phenylbutyrate, trichostatin A, angiopoietin, and IL-3. Methods known in the art such as flow cytometry, immunofluorescence microscopy, Western blotting, or other techniques may be used to ascertain the expression of molecules by therapeutic cell populations generated using the methods of the invention.

[1155] In one embodiment, the methods of the invention provide differentiated mesenchymal stem cells that are endowed with one or a plurality of the following functional capabilities: programming macrophages to secrete cytokines, suppressing cellular proliferation in a mixed lymphocyte reaction, and modulating cytokine production in a mixed lymphocyte reaction. These functional capabilities may be assessed by obtaining a population of differentiated mesenchymal stem cells and culturing them with the appropriate cell type (e.g., macrophages, T cells) in vitro. Methods and reagents that are known in the art can be used to assess these functional qualities of the mesenchymal stem cells in vitro using differentiated cells taken directly from a culture medium of the invention. In certain embodiments, the ability of differentiated mesenchymal stem cells to induce programming of macrophages is assessed by culturing the two cell types together in the appropriate culture medium and measuring cytokine production. Programming of macrophages by the cells of the invention can be deduced based on elevated concentrations or one or a plurality of the following cytokines in culture: PGE2, IL-10, IL-35, IL-22, EGF, CNTF, and soluble TNFalpha receptor p55. In certain embodiments, modulation of cytokine production in a mixed lymphocyte reaction by a differentiated mesenchymal stem cell comprises can be ascertained based on upregulation of one or a plurality of the following molecules: IFN-gamma, TNFalpha, IL-17, and calreticulin, and / or enhancing one or a plurality of the following molecules: alpha 1 antitrypsin, IL-10, IL-4, IL-13, IL-20, IL-22, and glial cell line- derived neurotrophic factor (GDNF).

[1156] In one embodiment, the mesenchymal stem cells derived from iPSCs by the methods of the invention are modified by introduction of a therapeutic gene prior to administration to a subject. In one embodiment, a therapeutic gene comprises a gene encodingan immune modulatory factor. In one embodiment, the immune modulatory factor comprises one or a plurality of the following: a chemokine, a soluble receptor, a receptor antagonist, IL-1 receptor antagonist, IL-2, amphiregulin, IL-3, IL-4, IL-6 receptor, IL-7, IL-10, IL-13, IL-14, IL-20, IL- 12 p40 homodimer, IL-22, IL-21, IL-33, IL-35, IL-37, IL-38, TGF-beta, endoglin, VEGF, VEGFC, EGF, IGF, HGF, angiopoietin, placental derived growth factor (PDGF), FGF-1, FGF-2, FGF-5, Gata4, Mef2C, Tbx5, Sox5, Sox9, MMP3, MMP5, MMP14, CD10, WNT11, BAPX1, IGFBP5, MMP16, BMP2, BMP4, BMP7, ADAMTS5, BLC1O, MCOLN2, LRRC8C, PTGFR, RLF, MATN1, PDPN, TNFRSF18, ITGA10, THBS3, SCYL1BP1, HSPC159, RHOQ, MATN3, SULT1C2, BCL2L11, KLF7, BLC-2, survivin, livin, IAP-C, bcl-XL, NRP2, heme oxygenase, NRF2, SERPINE2, FN1, B3GNT7, ADAMTS9, ANKRD28, GALNTL2, galectin-3, galectin-9, PD-L1, PD-L2, TIM-1, TIM-3, HLA-G, IRAK2, SETD5, FNDC3B, B3GNT5, CYTL1, C1Q.TNF3, ZFYVE16, MAST4, EDIL3, HAPLN1, PDLIM4, cr5q35, SQSTM1, SCUBE3, SOX5, RNF24, NUPL1, ULBP2, SOD2, KIAA0999, LRP11, SYNJ2, WTAP, HIG2 FAM62B, TNFRSF1OD, SLC25A37, BDKRB1, FZD10, VASN, inhibitor of kappa B, RelB, EIF2C2, RUNX1 RELB, ATFI, UFM1, MATN4, NOS2A, RHOF, ETK1, SFXN3, LOXL4, GLIS3, RPS6, WISP1, RB1CC1, PTK2, SRGAP1, USP12, GITR, ICOS, PDGF-BB, TLR5, ChGn, C8orf72, HAS2, TRPS1, ZCCHC7, SLC8A3, EDG2, ITGB1, CD44, C10orf49, YME1L1, AKR1C2, CHST3, FOSL1 RELA, ASAM, CHST11, DSPG3, LOC338758, LOC399959, KIAA0701, SLC41A2, LECT1, GPC6, EROIL, SEMA6D, LACTB, ARIH1, CSPG4, AGC1, LOC283824, WWP2, LOC201181, MS12, PITPNC1, TGIF, 1552288, ZNF146, MIA, ZNF160, SNX5, HSUP1, BIC, and LIF.

[1157] Certain embodiments provide methods for generating regulatory T cells from iPSCs, wherein the regulatory T cells exert functions that are associated with tissue repair and dampening the pathological immune responses that occur in conditions such as sepsis.

[1158] In one embodiment, a method for treating a subject with multiple organ dysfunction syndrome using autologous regulatory T cells is provided, the method comprising: a) identifying a subject with multiple organ dysfunction syndrome; b) generating an induced pluripotent stem cell (iPSC) population from the subject; c) establishing a cell culture system comprising iPSCs, wherein the cell culture system also comprises a decellularized matrix, wherein the decellularized matrix is derived from bone marrow, placenta, or umbilical cord, and wherein exposure of the iPSCs to the decellularized matrix provides factors for differentiation of iPSCs into regulatory T cells; d) optionally, transfecting the differentiated regulatory T cells with one or a plurality of therapeutic genes; and e) administering a therapeutically effective amount of the autologous differentiated mesenchymal stem cells to the subject.

[1159] In certain embodiments, the methods of the invention provide differentiated iPSC- derived regulatory T cells that express one or a plurality of the following molecules: GITR, fasligand, TNFSR1, CD25, ICOS, HLA-G, CTLA-4, FoxP3, autoimmune regulator (AIRE), membranebound TGF-beta, VEGF, and VEGF-C. One or a plurality of these molecules may be assayed to confirm the regulatory T cell phenotype of the differentiated cells in culture. One or a plurality of these molecules may be measured to ascertain the immune modulatory propensity of the cells, e.g., high expression of CTLA-4 is a crucial determinant of immune suppressive functions of regulatory T cells.

[1160] In certain embodiments, iPSC-derived regulatory T cells are administered to the subject in conjunction with one or a plurality of agents provided to increase the activity and / or the numbers of regulatory T cells in vivo. In certain embodiments, the one or plurality of agents that are administered to the subject with the differentiated regulatory ? cells comprise IL-2, anti- CD45RB antibody, and human chorionic gonadotropin. In certain embodiments, the one or plurality of agents are administered to the subject intravenously, intramuscularly, subcutaneously, or by another appropriate route of administration. Accordingly, methods of the invention are provided to monitor an increase in the quantities of regulatory T cells in a subject to whom iPSC-derived regulatory T cells and / or additional agent(s) were administered. In certain embodiments, a specimen such as blood is obtained from subject, cells including lymphocytes are isolated, and regulatory T cells are quantified based on expression of one or a plurality of the following molecules: CD25, CTLA-4, GITR, FoxP3, membrane bound TGF-beta, HLA-G, IL-10 receptor, CD69, VEGF receptor, and TGF-beta receptor. In certain embodiments, the concentration or numbers of regulatory T cells having a defined phenotype is increased by at least 10%, at least 25%, at least 50%, or at least 100% by administering of one or a plurality of agents to the subject along with iPSC-derived regulatory T cells. In other embodiments, the activity of regulatory T cells is monitored in a subject who received treatment with the methods of the invention. In one embodiment, the level of activity of regulatory T cells is measured in vitro based on one or a plurality of the following parameters: suppression of conventional T cell proliferation, suppression of conventional T cell interferon gamma production after stimulation with concanavalin A, PHA, interleukin-2, and / or anti-CD3 / anti-CD28 antibodies, suppression of dendritic cell maturation after stimulation with poly(l:C), lipopolysaccharide, BCG, and / or CpG DNA, and suppression of natural killer cell activity after stimulation with interleukin-2 and / or interferon gamma. In certain embodiments, the activity of regulatory T cells is increased by at least 10%, at least 25%, at least 50%, or at least 100% by administering of one or a plurality of agents to the subject along with iPSC-derived regulatory T cells, as determined in at least one of these parameters. Relative increases in regulatory ? cell activity may be ascertained based on comparisons to controls included in the in vitro assays. In some embodiments, cells are obtainedfrom a subject who received differentiated, iPSC-derived regulatory ? cells together with one or a plurality of agents and from a subject who received only the differentiated cells without an agent to enhance the numbers and / or activity of regulatory T cells.

[1161] In certain embodiments, a cell culture system for differentiation of therapeutic cells from iPSCs comprises a decellularized matrix and the addition of at least one cytokine. In certain embodiments, one or a plurality of the following cytokines are added to a culture system: IL-2, IL-10, IL-21, IL-33, TGF-beta, and endoglin. In certain embodiments, one or more cytokines are added to a decellularized matrix established for differentiation of regulatory T cells from iPSCs. In certain embodiments, addition of one or plurality of cytokines increases expression of FoxP3 by the regulatory T cells as compared to equivalent culture systems that are not supplement with the cytokine(s). In certain embodiments, the expression levels of FoxP3 by differentiated regulatory ? cells are increased by at least 10%, at least 25%, at least 50%, or at least 100% by adding one or a plurality of cytokines to the decellularized matrix.

[1162] In certain embodiments, the differentiated regulatory ? cells generated using the methods of the invention possess the ability to suppress the functions of antigen presenting cells, wherein the antigen presenting cells comprise B cells, B-l cells, B-20 cells, monocytes, myeloid suppressor cells, dendritic cells, or combinations thereof. In certain embodiments, an antigen presenting cell comprises a dendritic cell, wherein the dendritic cell expresses one or a plurality of the following molecules that serve as identifying features of phenotype and function: CDllc, CD83, ?IGI?, ?IM-3, CDlla, CDlb, CD40, CD80, CD86, PD-L1, PD-L2, IL?3, IL?4, MDA, and ?AP-1. In certain embodiments, an antigen presenting cell population produces exosomes, wherein the exosomes express one or a plurality of the following molecules: HLA class II, tetraspanins, CD40, CD80, CD86, Rabi, vimentin, CD8, alpha synuclein, phosphatidylserine, calreticulin, L1CAM, galectin-9, galectin-3, CD9, CD63, CD81, ?SG-101, Flotillin-1, hsp-60, hsp-70, hsp-90, hsc-70, CD147, EpCAM, CD37, and NKG2D. In certain embodiments, suppressing the functions of an antigen presenting cell by a therapeutic cell of the invention induces a corresponding decrease in exosome production and release by the cell population. In certain embodiments, suppression of antigen presenting cell function modulates the composition of one or a plurality of molecules found in / on exosomes. In one embodiment, the differentiated regulatory ? cells generated by methods of the invention suppress the functions of an antigen presenting cell-derived exosome in vitro. In some embodiments, an antigen presenting cell population comprises B cells that produce one or a plurality of factors upon stimulation through the B cell receptor or using cytokines (e.g., IL-6) including IL-10, IL-35, ?GF-beta, soluble ?NF receptor p55, and soluble ?NF receptor p75). In some embodiments, the production of one or aplurality of these factors by a B cell is modulated in vitro or in vivo by an iPSC-derived regulatory T cell. In other embodiments, a differentiated regulatory T cell generated using the methods of the invention modulates the activity of a myeloid suppressor cell. In a specific embodiment, a myeloid suppressor cell exhibits one or a plurality of the following molecular changes or functions: upregulation of indolamine 2,3 dioxygenase, upregulation of COX-2, and inhibition of T cell proliferation, wherein an inhibited T cell may comprise a Thl cell, Th9 cell, a Thl7 cell, a type 1 NKT cell, a type 1 gamma-delta T cell, or an IFN-gamma-producing T cell. In certain embodiments, an iPSC-derived therapeutic cell improves the ability of a myeloid suppressor cell to inhibit T cell activation which may be assessed in co-cultures of these cell types. In such experiments, an inhibited T cell produces reduced quantities or concentrations of IFN-gamma upon stimulation in vitro with one or a plurality of agents such as ionomycin, a calcium ionophore, or a mitogen (e.g., PHA, PWM, ConA, cynavirin, lipopolysaccharide, BCG, PHA or others). In such an assay, control experiments involving assessments of activated T cells that have not been influenced by differentiated cells generated using the methods of the invention are preferably included. In certain embodiments, suppression of antigen presenting cell activities leads to inhibition of T cell activation by the antigen presenting cells, wherein the T cells inhibited by antigen presenting cells may comprise Thl cells, Th9 cells, Thl7 cells, type 1 NKT cells, and type 1 gamma-delta T cells. These embodiments may also be practiced for assessing regulatory T cells isolated from a subject who has undergone treatment with a therapeutic cell of the invention. In this embodiment, a specimen comprising regulatory T cells is obtained from a subject (e.g., a blood specimen) to whom differentiated iPSC-derived cells of the invention have been administered, the regulatory T cells are purified and said regulatory T cells are applied to the aforementioned in vitro assays.

[1163] In certain embodiments, the activity of iPSC-derived regulatory T cells from culture or a regulatory T cell population isolated from a treated subject can be evaluated based on inhibition of T cell activation in vitro (e.g., by stimulating the conventional T cells using anti-CD3 and anti-CD28 antibody). In certain embodiments, the concentrations of one or a plurality of the following molecules can be measured: TGF-beta, latency associated protein, IFN-gamma, IL-2, IL- 6, IL-7, IL-11, IL-12, IL-15, IL-17, IL-18, IL-21, IL-23, IL-27, TNF-alpha, lymphotoxin, LIGHT, BLyS, BAFF, LIGHT, granzyme B, perforin, HLA-G, soluble HLA-G, and soluble TNF-alpha receptor. Methods of the invention provide regulatory T cells that modulate the expression levels of one or more of these molecules in vitro and in vivo.

[1164] In other embodiments, the methods of the invention involve evaluating the suppression of dendritic cell maturation by regulatory T cells in vitro, wherein maturation ofdendritic cells can be indicated by one or a plurality of the following dendritic cell functions: high migration potential, reduced phagocytic potential, high antigen presenting activity, ability to induce TCR activation of a naive T cell, ability to induce cytokine production from a naive T cell, and the ability to endow cytotoxic activity to a naive T cell. In certain embodiments, regulatory T cells are obtained (i.e., from cell culture or from a treated subject) and said regulatory ? cells are co-cultured with dendritic cells in vitro. In one embodiment, iPSC-derived regulatory T cells are provided that suppress dendritic cell maturation. In certain embodiments, maturation of dendritic cells is indicated by high expression of one or a plurality of the following factors: membrane vimentin, calreticulin, hsp60, hsp65, TLR3, TLR4, TLR5, TLR7, TLR9, MDA-5, STING, LRP, CXCL9, CXCL10, CXCL11, CCL5, miR155, CD83, CCR7, CCL8, SOD2, MT2A, OASL, GBP1, HES4, MTIB, MTIE, MTIG, MTIH, GADD45A, LAMP3, CD80, CD40, CD86, interleukin-12, ICOS, CDllc, interleukin-15, and interleukin-18. In this embodiment, the effects of iPSC-derived regulatory T cells of the invention may be compared against naive T cells (i.e., negative control cells) and human regulatory T cells isolated directly from a subject (i.e., positive control cells) for their in vitro effects on other cell types. In certain embodiments, iPSC-derived regulatory ? cells are utilized in an in vitro assay that comprises dendritic cells and T cells and / or T cell activation reagents (e.g., anti-CD3 and anti-CD28 antibodies), and dendritic cells are subsequently assessed. In certain embodiments, the ability of a dendritic cell of induce cytokine production from a naive T cell is monitored in vitro by measuring one or a plurality of the following cytokines: IFN-gamma, IL-2, IL-4, IL-7, IL-9, IL-12, IL-15, IL-17, IL-18, IL-21, IL-23, and IL-27. In exemplary embodiments, a method of the invention that provides potent regulatory ? cells is reflected by reduced production of one or a plurality of cytokines by T cells and / or by dendritic cells in vitro. In other embodiments, the ability of a dendritic cell to endow cytotoxic activity to a naive T cell in vitro is assessed by measuring the production or upregulation of one or a plurality of the following factors: granzyme B, perforin, fas ligand, TRAIL, TNF-alpha, lymphotoxin, TRANCE, and RANK in cell co-culture experiments using methods known in the art. In certain embodiments, a target cell is provided in the culture to monitor target cell death elicited by T cells, wherein naive T cells in cultures that have been exposed to iPSC-derived regulatory T cells can be compared to control, non-exposed naive T cells. Certain embodiments of the invention provide a population of iPSC-derived regulatory T cells that exert potent suppression of T cell cytotoxicity. Certain embodiments also provide methods of treating a subject with iPSC-derived regulatory T cells and, optionally, the administration of other agents, that establish a regulatory T cell population in vivo that is potently immune suppressive.

[1165] In other embodiments, the methods of the invention involve evaluating the suppression of macrophage activation by regulatory T cells, wherein macrophage activation comprises production of nitric oxide, production of procoagulant microvesicles or exosomes, and / or release of vasodilatory factors. In certain embodiments, the vasodilatory factors comprise one or more of the following: prostaglandin E2, prostaglandin El, a leukotriene, a mitogen activated protein kinase activator, TNF-alpha, a prostacyclin, a bradykinin, lymphotoxin, complement component C3, complement component C3a, complement component C5, complement component C5a, complement component C3b, histamine, and IL-2. In certain embodiments, methods are provided that generate iPSC-derived regulatory T cells that suppress macrophage activation. In certain embodiments, the methods of administering an iPSC-derived regulatory ? cell to a subject provide a regulatory ? cell population with macrophage suppressive activity upon assessment in the abovementioned assays.Example: Protection from Endotoxin Induced Lethality by Pluripotent Stem Cell Derived Mesenchymal Stem Cells

[1166] Induced pluripotent stem cells were purchased from A?CC and propagated according to the manufacturer instructions. Cells were seeded onto decellularized bone matrix and cultured in the presence of complete DMEM media together with BMP2 (5 ng / ml) and BMP4 (10 ng / ml). Cultured cells were maintained for 14 days after which expression of mesenchymal stem cell marker CD73 and CD105 were detected. Cells were isolated based on CD105 expression and administered to a murine model of endotoxin induced sepsis. Mice were treated with 1 mg of LPS intraperitoneally and survival was monitored. Mice received 1 million umbilical cord MSC, bone marrow MSC or MSC generated from pluripotent stem cells described above (PMSC). Results are shown in FIG. 1.

Claims

Claims1. A method for treating a subject with multiple organ dysfunction syndrome using autologous mesenchymal stem cells comprising: a) identifying a subject with multiple organ dysfunction syndrome; b) generating an induced pluripotent stem cell (iPSC) population from the subject; c) establishing a cell culture system comprising said iPSCs, wherein the cell culture system also comprises a decellularized matrix derived from the group consisting of: bone marrow, placenta, and umbilical cord, and wherein exposure of the iPSCs to the decellularized matrix induces differentiation of iPSCs into mesenchymal stem cells; and d) administering a therapeutically effective amount of the autologous differentiated mesenchymal stem cells to the subject.

2. The method of Claim 1, wherein the differentiated mesenchymal stem cells express one or a plurality of the following molecules: CXCR4, CD90, CD105, somatostatin receptor 1 (SSTR1), thromboplastin, tumor necrosis factor superfamily member 4 (TNFSF4), forkhead box L2 (FoxL2), spondin-2 (SPON2 / M-spondin), vesicle amine transport protein 1-1 ike (VAT1L), aldehyde dehydrogenase 1 family, member Al (ALDH1A1), WT1, survivin, livin, programmed cell death ligand-1 (PD-L1), G protein-coupled receptor 126 (GPR126), interferon- induced protein with tetratricopeptide repeats 2 (IFIT2), CD49d, cathepsin C, PIM3, anoctamin- 4, and c-met.

3. The method of Claim 1, wherein the differentiated mesenchymal stem cells are endowed with one or a plurality of the following functional capabilities: programming macrophages to secrete cytokines, suppressing cellular proliferation in a mixed lymphocyte reaction, and modulating cytokine production in a mixed lymphocyte reaction.

4. The method of Claim 3, wherein programming of macrophages to secrete cytokines by differentiated mesenchymal stem cells comprises enhancing the levels or concentrations of one or a plurality of the following cytokines: PGE2, IL-10, IL-35, IL-22, EGF, CNTF, and soluble TNFalpha receptor p55.

5. The method of Claim 3, wherein modulating cytokine production in a mixed lymphocyte reaction by a differentiated mesenchymal stem cell comprises one or a plurality of the following effects: suppressing one or a plurality of the following molecules: IFN-gamma, TNFalpha, IL-17, and calreticulin, and / or enhancing one or a plurality of the following molecules: alpha 1 antitrypsin, IL-10, IL-4, IL-13, IL-20, IL-22, and glial cell line-derived neurotrophic factor (GDNF).

6. The method of Claim 2, wherein the differentiated mesenchymal stem cells can be induced to further upregulate ALD1A1 (stem cell marker) upon treatment with one or a plurality of the following compounds: valproic acid, phenylbutyrate, trichostatin A, angiopoietin, and IL-3.

7. The method of Claim 1, further comprising transfecting the differentiated mesenchymal stem cells with one or more therapeutic genes encoding an immune modulatory factor prior to administration into the subject.

8. The method of Claim 7, wherein the immune modulatory factor comprises one or a plurality of the following: a chemokine, a soluble receptor, a receptor antagonist, IL-1 receptor antagonist, IL-2, amphiregulin, IL-3, IL-4, IL-6 receptor, IL-7, IL-10, IL-13, IL-14, IL-20, IL- 12 p40 homodimer, IL-22, IL-21, IL-33, IL-35, IL-37, IL-38, TGF-beta, endoglin, VEGF, VEGFC, EGF, IGF, HGF, angiopoietin, placental derived growth factor (PDGF), FGF-1, FGF-2, FGF-5, Gata4, Mef2C, Tbx5, Sox5, Sox9, MMP3, MMP5, MMP14, CD10, WNT11, BAPX1, IGFBP5, MMP16, BMP2, BMP4, BMP7, ADAMTS5, BLC1O, MCOLN2, LRRC8C, PTGFR, RLF, MATN1, PDPN, TNFRSF18, ITGA10, THBS3, SCYL1BP1, HSPC159, RHOQ, MATN3, SULT1C2, BCL2L11, KLF7, BLC- 2, survivin, livin, IAP-C, bcl-XL, NRP2, heme oxygenase, NRF2, SERPINE2, FN1, B3GNT7, ADAMTS9, ANKRD28, GALNTL2, galectin-3, galectin-9, PD-L1, PD-L2, TIM-1, TIM-3, HLA-G, IRAK2, SETD5, FNDC3B, B3GNT5, CYTL1, C1QTNF3, ZFYVE16, MAST4, EDIL3, HAPLN1, PDLIM4, cr5q35, SQSTM1, SCUBE3, SOX5, RNF24, NUPL1, ULBP2, SOD2, KIAA0999, LRP11, SYNJ2, WTAP, HIG2 FAM62B, TNFRSF10D, SLC25A37, BDKRB1, FZD10, VASN, inhibitor of kappa B, RelB, EIF2C2, RUNX1 RELB, ATFI, UFM1, MATN4, NOS2A, RHOF, ETK1, SFXN3, LOXL4, GLIS3, RPS6, WISP1, RB1CC1, PTK2, SRGAP1, USP12, GITR, ICOS, PDGF-BB, TLR5, ChGn, C8orf72, HAS2, TRPS1, ZCCHC7, SLC8A3, EDG2, ITGB1, CD44, C10orf49, YME1L1, AKR1C2, CHST3, FOSL1 RELA, ASAM, CHST11, DSPG3, LOC338758, LOC399959, KIAA0701, SLC41A2, LECT1, GPC6, EROIL, SEMA6D, LACTB, ARIH1, CSPG4, AGC1, LOC283824, WWP2, LOC201181, MS12, PITPNC1, TGIF, 1552288, ZNF146, MIA, ZNF160, SNX5, HSUP1, BIC, and LIF.

9. The method of Claim 1, wherein multiorgan failure is associated with elevation or upregulation of one or a plurality of the following molecules in plasma: C reactive protein, IL- lbeta, IL-6, IL8-, IL-11, IL-12, IL-15, IL-18, IL-17, IL-23, IL-27, IL-33, TNF-alpha, HMGB1, d-dimer, lymphotoxin, TRAIL, TRANCE, RANK ligand, circular DNA, and free DNA.

10. The method of Claim 1, wherein multiple organ dysfunction syndrome is associated with one or a plurality of the following complications in the subject: vascular leakage, disseminated intravascular coagulation, and systemic endothelial activation.

11. The method of Claim 1, wherein the multiple organ dysfunction syndrome in the subject is associated with sepsis.

12. The method of Claim 11, wherein sepsis associated with one or a plurality of the following pathological mechanisms: platelet aggregation, platelet endothelial adhesion, neutrophil activation, neutrophil extravasation, neutrophil degranulation, monocyte activation, monocyte extracellular trap release, free radical generation, monocyte extravasation, and monocyte maturation.

13. The method of Claim 12, wherein one or a plurality of the pathological mechanisms are reduced or eliminated by administration of differentiated mesenchymal stem cells to the subject.

14. The method of Claim 11, wherein the severity of sepsis in the subject is assessed based on the concentrations of one or a plurality of inflammatory molecules present in a tissue, wherein the tissue may comprise blood, lung, cerebrospinal fluid, saliva, urine or combinations thereof, and wherein the inflammatory marker may comprise one or a plurality of the following: apoptotic bodies, neutrophil extracellular traps, histone DNA, IL-lbeta, extracellular vesicles, apoptotic bodies bound to circulating DNA, IL-2, IL-6, IL-8, IL-11, IL-12, IL-18, IL-17, IL- 21, IL-23, IL-27, HMGBl, IL-1 receptor antagonist, IL-33, IFN-gamma, IL-6 receptor, PGE2, RANTES, galectin 3, C reactive protein, vimentin, superoxide dismutase, MMP-1, MMP-3, MMP- 5, MMP-9 d-dimer, and fibrinogen.

15. The method of Claim 1, wherein the differentiated mesenchymal stem cell is generated by exposure of embryoid bodies derived from iPSCs to the decellularized matrix.

16. The method of Claim 15, wherein the embryoid body is disaggregated before seeding the decellularized matrix.

17. The method of Claim 1, wherein the differentiated mesenchymal stem cells in the cell culture system are used to collect exosomes.

18. The method of Claim 17, wherein the exosomes are also administered to the subject.

19. The method of Claim 17, wherein the differentiated mesenchymal stem cells are subjected to cellular stress prior to collection of exosomes.

20. The method of Claim 19, wherein the cellular stress is induced by one or more of the following conditions or stimuli: hypoxia, hyperoxia, hyperthermia, hypothermia, radiation exposure, DNA strand breaks, misfolded protein accumulation, exposure to hypotonic conditions, exposure to hypertonic conditions, treatment with an activator of NF-kappaB, or exposure to a heat shock protein.

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