Compositions and methods for extending graft and receptor survival

Abstract

The invention discloses a method for coping with rejection reaction of a graft acceptor to a graft. Methods of extending graft survival in a transplant recipient, extending survival in a recipient, delaying and / or inhibiting a delay of implant function in a recipient, and / or reducing the amount of an immunosuppressive agent for transplantation. The disclosed methods include providing a graft with CHP or a pharmaceutically acceptable salt thereof. A method of preparing a pharmaceutical composition for treating a graft to modulate graft survival in a graft recipient is also provided.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 386,531, filed on December 8, 2022, the entire content of which is incorporated herein by reference. Technical field

[0003] The present invention relates to treating a graft in an animal recipient to extend the survival of the graft in the recipient. The present invention relates to extending the survival of an allograft in a recipient by administering CHP or a pharmaceutically acceptable salt thereof to the recipient. The present invention also relates to methods for preventing graft rejection and / or reducing the amount of immunosuppressive agents used at the time of transplantation and / or for maintenance after transplantation. Background art

[0004] For most patients with chronic organ failure, organ transplantation is the preferred treatment. Although transplantation of kidneys, livers, lungs, and hearts offers excellent opportunities for recovery for recipients, facilitating a return to a more normal lifestyle, it is limited by the medical / surgical suitability of potential recipients, the increasing shortage of donors, and the premature failure of transplanted organ function.

[0005] Despite significant improvements in the treatment of suppressing implant rejection (or graft rejection reaction), rejection remains the single greatest obstacle to successful organ transplantation. Rejection includes not only acute rejection but also chronic rejection. According to the OPTN / SRTR Annual Report, in 2022, 6.8% of adult kidney transplant recipients in 2018 - 2019 experienced acute rejection within 1 year, including 9.1% of recipients aged 18 - 34 and 5.9% of recipients aged 65 and older. Among patients receiving interleukin - 2 (IL - 2) - receptor antibody induction, 8.4% of patients had an acute rejection reaction after 1 year, compared with 6.6% of patients receiving T - cell depletion induction and 6.4% in a small subset of patients transplanted without induction. For the liver, the one - year survival rate of transplanted livers is approximately 90%, the five - year transplant survival rate is approximately 75%, and the 2018 - 2019 report shows that 11.5% of adult liver transplant recipients had at least one episode of acute rejection within 1 year. See OPTN / SRTR Annual Report, 2022.

[0006] To suppress harmful immune responses during transplantation and in the first few months after transplantation (induction phase) and over the long term after transplantation (maintenance phase), it is usually necessary to administer immunosuppressive drugs (such as cyclosporine A, tacrolimus, and corticosteroids) or antibody therapies (such as anti-T cell antibodies). Unfortunately, immunosuppression often has undesirable side effects. For example, cyclosporine can cause reduced renal function, hypertension, toxic side effects, and must be administered for life. Corticosteroids can lead to reduced resistance to infection, painful arthritis, osteoporosis, and cataracts. Anti-T cell antibodies can cause fever, hypertension, diarrhea, or aseptic meningitis and are quite expensive.

[0007] Therefore, there is a need to develop methods or therapies that induce unresponsiveness or tolerance to a graft in a host, and / or prolong the survival of the graft and / or the recipient of the implant, and / or prevent or delay implant failure and / or inhibit delayed implant function, and / or reduce the amount of immunosuppressive agents used during and / or after transplantation. SUMMARY OF THE INVENTION

[0008] According to one aspect of the invention, a method of suppressing an immune response comprises administering to an animal in need of such treatment an effective amount of cyclo histidine-proline (CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof. In this embodiment, the immune response can include acute rejection and / or chronic rejection of a graft by the animal recipient. According to another aspect, the method can further comprise administering an immunosuppressive agent. In one embodiment, the immune response can be graft rejection. CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof, optionally together with an immunosuppressive agent, can be administered during transplantation surgery and / or during the induction period and / or for a long time after transplantation surgery (maintenance phase). When used in combination, CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof and the immunosuppressive agent can be administered simultaneously or sequentially and can be formulated as a single preparation or different preparations.

[0009] In another embodiment, the present invention provides a method for suppressing an immune response to a transplanted organ, tissue or cell, which comprises administering an effective amount of CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof to a mammal in need thereof. In this embodiment, the transplanted organ, tissue or cell comprises an organ, tissue or cell of the lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc. In this embodiment, the immune response may include acute rejection and / or chronic rejection of the graft by the animal recipient. According to another aspect, the method may further comprise administering an immunosuppressant. CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof and the immunosuppressant may be administered during the transplantation surgery and / or during induction and / or chronically (maintenance period) after the transplantation surgery. When used in combination, CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof and the immunosuppressant may be administered simultaneously or sequentially, and may be formulated as a single preparation or different preparations.

[0010] Another aspect of the present invention provides a method for prolonging the survival period of an implant, delaying or preventing implant failure and / or suppressing delayed implant function in a recipient animal, which comprises treating the graft with a composition comprising CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof. In this embodiment, the graft comprises an organ, tissue or cell of the lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc. According to another aspect, the method may further comprise administering an immunosuppressant. When used in combination, CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof and optionally the immunosuppressant may be administered during the transplantation surgery and / or during induction and / or chronically (maintenance period) after the transplantation surgery. When used in combination, CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof and the immunosuppressant may be administered simultaneously or sequentially, and may be formulated as a single preparation or different preparations.

[0011] Another aspect of the present invention provides a method for prolonging the survival period of a graft animal recipient, which comprises administering to the animal recipient an effective amount of a composition comprising CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof. In this embodiment, the graft comprises an organ, tissue or cell of the lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc. According to another aspect, the method may further comprise administering an immunosuppressant. When used in combination, CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof may be administered during the transplantation surgery, and / or during the induction period, and / or chronically (maintenance period) after the transplantation surgery. When used in combination, CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof and the immunosuppressant may be administered simultaneously or sequentially, and may be formulated as a single preparation or different preparations.

[0012] Another aspect of the present invention provides a method for prolonging the survival period of an implant, delaying or preventing implant failure and / or inhibiting the delay of implant function in an animal recipient, which comprises administering to the animal recipient an effective amount of a composition comprising CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof. In this embodiment, the graft includes organs, tissues or cells such as lungs, liver, kidneys, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc. According to another aspect, the method may further comprise administering an immunosuppressant. When used in combination, CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof can be administered during the transplantation surgery, and / or during the induction period, and / or for a long time (maintenance period) after the transplantation surgery. When used in combination, CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof and the immunosuppressant can be administered simultaneously or sequentially, and can be formulated into a single preparation or different preparations.

[0013] One aspect of the present invention further includes a composition for inhibiting an immune response, which comprises CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof. The composition may further comprise an immunosuppressant, or may be administered in combination with an immunosuppressant. The composition optionally used in combination with an immunosuppressant can be administered during the transplantation surgery (induction period) and / or for a long time (maintenance period) after the transplantation surgery. When used in combination, the composition and the immunosuppressant can be administered simultaneously or sequentially, and can be formulated into a single preparation or different preparations.

[0014] One aspect of the present invention further includes a composition for prolonging the survival period of a graft in an animal recipient and / or prolonging the survival period of the graft animal recipient, which comprises CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a solvate thereof. In this embodiment, the graft includes organs, tissues or cells such as lungs, liver, kidneys, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc. The composition may further comprise an immunosuppressant, or may be administered in combination with an immunosuppressant. The composition optionally used in combination with an immunosuppressant can be administered during the transplantation surgery and / or during the induction period and / or for a long time (maintenance period) after the transplantation surgery. When used in combination, the composition and the immunosuppressant can be administered simultaneously or sequentially, and can be formulated into a single preparation or different preparations.

[0015] One aspect of the present invention further includes the use of CHP, its pharmaceutically acceptable salts, its stereoisomers or solvates in a method for inhibiting an immune response; or a method for prolonging the survival of a graft in an animal recipient and / or prolonging the survival of the graft animal recipient. According to this aspect, CHP, its pharmaceutically acceptable salts, its stereoisomers or solvates can be used in combination with an immunosuppressant. The composition optionally used in combination with an immunosuppressant can be administered during the transplantation surgery, and / or during the induction period, and / or for a long term (maintenance period) after the transplantation surgery. When used in combination, CHP, its pharmaceutically acceptable salts, its stereoisomers or solvates and the immunosuppressant can be administered simultaneously or sequentially, and can be formulated into a single preparation or different preparations.

[0016] One aspect of the present invention further includes the use of CHP, its pharmaceutically acceptable salts, its stereoisomers or solvates in the preparation of a medicament, wherein the medicament is administered to prolong the survival of a graft in an animal recipient, and / or, the medicament is administered to prolong the survival of the graft animal recipient. In this embodiment, the graft includes organs, tissues or cells such as lungs, liver, kidneys, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc. According to this aspect, CHP, its pharmaceutically acceptable salts, its stereoisomers or solvates can be used in combination with an immunosuppressant. When used in combination, CHP, its pharmaceutically acceptable salts, its stereoisomers or solvates and the immunosuppressant can be administered simultaneously or sequentially, and can be formulated into a single medicament or different medicaments. One or more medicaments can be administered during the transplantation process and / or during the induction period and / or for a long term (maintenance phase) after the transplantation surgery.

[0017] Another aspect of the present invention further includes a method for reducing the amount of an immunosuppressant administered to a subject during transplantation, and / or during the induction period, and / or during the maintenance period after transplantation, which comprises administering to the subject an effective amount of CHP, its pharmaceutically acceptable salts, its stereoisomers or solvates. In this embodiment, the graft to be transplanted into the subject includes organs, tissues or cells such as lungs, liver, kidneys, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc. CHP, its pharmaceutically acceptable salts, its stereoisomers or solvates and the immunosuppressant can be administered simultaneously or sequentially, and can be formulated into a single preparation or different preparations. The one or more preparations can be administered during the transplantation surgery (induction period) and / or for a long term (maintenance period) after the transplantation surgery.

[0018] According to certain aspects, the present invention includes the following non-limiting exemplary embodiments.

[0019] Embodiment 1. A method for prolonging the survival period of a recipient of an allogenic transplant and / or prolonging the survival period of the allogenic transplant in the recipient, comprising administering to the recipient an effective amount of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof.

[0020] Embodiment 2. The method according to Embodiment 1, further comprising providing the allogenic transplant, wherein the transplant is treated with cyclo-His-Pro (CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof before being transplanted into the recipient.

[0021] Embodiment 3. The method according to Embodiment 1, further comprising administering an immunosuppressant to the recipient.

[0022] Embodiment 4. The method according to Embodiment 1, wherein the administration of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof is initiated 0.5 - 18 hours or 18 - 36 hours before anesthesia for transplanting the allogenic transplant into the recipient.

[0023] Embodiment 5. The method according to Embodiment 1, wherein the administration of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof comprises administering an effective amount of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof as maintenance therapy after transplantation.

[0024] Embodiment 6. The method according to Embodiment 3, wherein the administration of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof and the administration of the immunosuppressant are carried out simultaneously, in parallel, or sequentially.

[0025] Embodiment 7. The method according to Embodiment 3, wherein the administration of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof is initiated 0.5 - 18 hours or 18 - 36 hours before anesthesia for transplanting the allogenic transplant into the recipient.

[0026] Embodiment 8. The method according to Embodiment 3, wherein the administration of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof comprises administering an effective amount of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof as maintenance therapy after transplantation.

[0027] Embodiment 9. The method according to Embodiment 1, wherein the allogenic transplant is tissue, an organ, or cells of the lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus, or penis.

[0028] Embodiment 10. The method according to Embodiment 3, wherein the heterologous graft is tissue, an organ or cells of the lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus or penis.

[0029] Embodiment 11. The method according to Embodiment 1, wherein administering cyclo-His-Pro (CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof inhibits the immune response of the receptor to the heterologous graft.

[0030] Embodiment 12. The method according to Embodiment 1, wherein the effective amount of the CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof is about 0.001 - 0.005 mg / kg, 0.005 - 0.01 mg / kg, 0.01 - 0.02 mg / kg, 0.02 - 0.04 mg / kg, 0.04 - 0.06 mg / kg, 0.06 - 0.08 mg / kg, 0.08 - 1 mg / kg, 1 - 5 mg / kg, 5 - 6 mg / kg, 6 - 7 mg / kg, 7 - 8 mg / kg, 8 - 10 mg / kg, 10 - 15 mg / kg, 15 - 20 mg / kg, 20 - 25 mg / kg, 25 - 30 mg / kg, 30 - 35 mg / kg, 35 - 40 mg / kg, 40 - 45 mg / kg, 45 - 50 mg / kg, 50 - 100 mg / kg, 100 - 150 mg / kg, 150 - 200 mg / kg, 200 - 300 mg / kg, 300 - 400 mg / kg, 400 - 500 mg / kg, 500 - 600 mg / kg, 600 - 700 mg / kg, 700 - 800 mg / kg, 800 - 900 mg / kg, 900 - 1000 mg / kg, 1000 - 1100 mg / kg, 1100 - 1200 mg / kg, 1200 - 1300 mg / kg, 1300 - 1400 mg / kg, 1400 - 1500 mg / kg, 1500 - 1600 mg / kg, 1600 - 1700 mg / kg, 1700 - 1800 mg / kg, 1800 - 1900 mg / kg, 1900 - 2000 mg / kg, 2000 - 2100 mg / kg, 2100 - 2200 mg / kg, 2200 - 2300 mg / kg, 2300 - 2400 mg / kg, 2400 - 2500 mg / kg, 2500 - 2600 mg / kg, 2600 - 2700 mg / kg, 2700 - 2800 mg / kg, 2800 - 2900 mg / kg or 2900 - 3000 mg / kg.

[0031] Embodiment 13. A method for suppressing or reducing the immune response of a recipient to a heterologous graft, for reducing the rejection reaction of the recipient to the heterologous graft, and / or for reducing the amount of an immunosuppressive agent administered to a recipient of a heterologous graft during and / or after transplantation of the heterologous graft, the method comprising administering to the recipient an effective amount of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt, stereoisomer or solvate thereof.

[0032] Embodiment 14. The method according to Embodiment 13, further comprising providing the heterologous graft, wherein the graft is treated with cyclo-His-Pro (CHP), a pharmaceutically acceptable salt, stereoisomer or solvate thereof before transplantation into the recipient.

[0033] Embodiment 15. The method according to Embodiment 13, wherein administration of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt, stereoisomer or solvate thereof is initiated 0.5 - 18 hours or 18 - 36 hours before anesthesia for transplantation of the heterologous graft into the recipient.

[0034] Embodiment 16. The method according to Embodiment 13, wherein administration of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt, stereoisomer or solvate thereof comprises administering an effective amount of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt, stereoisomer or solvate thereof as maintenance therapy after transplantation.

[0035] Embodiment 17. The method according to Embodiment 13, wherein administration of cyclo-His-Pro (CHP), a pharmaceutically acceptable salt, stereoisomer or solvate thereof and administration of the immunosuppressive agent are carried out simultaneously, in parallel or sequentially.

[0036] Embodiment 18. The method according to Embodiment 13, wherein the heterologous graft is tissue, an organ or cells of the lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus or penis.

[0037] Embodiment 19. The method according to Embodiment 13, wherein the effective amount of the CHP, its pharmaceutically acceptable salt, stereoisomer or solvate is about 0.001 - 0.005 mg / kg, 0.005 - 0.01 mg / kg, 0.01 - 0.02 mg / kg, 0.02 - 0.04 mg / kg, 0.04 - 0.06 mg / kg, 0.06 - 0.08 mg / kg, 0.08 - 1 mg / kg, 1 - 5 mg / kg, 5 - 6 mg / kg, 6 - 7 mg / kg, 7 - 8 mg / kg, 8 - 10 mg / kg, 10 - 15 mg / kg, 15 - 20 mg / kg, 20 - 25 mg / kg, 25 - 30 mg / kg, 30 - 35 mg / kg, 35 - 40 mg / kg, 40 - 45 mg / kg, 45 - 50 mg / kg, 50 - 100 mg / kg, 100 - 150 mg / kg, 150 - 200 mg / kg, 200 - 300 mg / kg, 300 - 400 mg / kg, 400 - 500 mg / kg, 500 - 600 mg / kg, 600 - 700 mg / kg, 700 - 800 mg / kg, 800 - 900 mg / kg, 900 - 1000 mg / kg, 1000 - 1100 mg / kg, 1100 - 1200 mg / kg, 1200 - 1300 mg / kg, 1300 - 1400 mg / kg, 1400 - 1500 mg / kg, 1500 - 1600 mg / kg, 1600 - 1700 mg / kg, 1700 - 1800 mg / kg, 1800 - 1900 mg / kg, 1900 - 2000 mg / kg, 2000 - 2100 mg / kg, 2100 - 2200 mg / kg, 2200 - 2300 mg / kg, 2300 - 2400 mg / kg, 2400 - 2500 mg / kg, 2500 - 2600 mg / kg, 2600 - 2700 mg / kg, 2700 - 2800 mg / kg, 2800 - 2900 mg / kg or 2900 - 3000 mg / kg.

[0038] Embodiment 20. A composition for prolonging the survival period of a xenotransplant recipient and / or prolonging the survival period of a xenograft in a recipient, which comprises an effective amount of cyclo - His - Pro (CHP), its pharmaceutically acceptable salt, stereoisomer or solvate as an active ingredient, and a pharmaceutically acceptable carrier.

[0039] Embodiment 21. The composition according to Embodiment 20, wherein the xenograft is treated with cyclo - His - Pro (CHP), its pharmaceutically acceptable salt, stereoisomer or solvate before transplantation into the recipient.

[0040] Embodiment 22. The composition according to Embodiment 20 is administered to the recipient in combination with an immunosuppressant.

[0041] Embodiment 23. The composition according to Embodiment 20, wherein the composition is administered to the recipient 0.5 - 18 hours or 18 - 36 hours before anesthesia for transplanting the heterologous graft into the recipient.

[0042] Embodiment 24. The composition according to Embodiment 20, wherein the composition is administered as maintenance therapy after being transplanted into the recipient.

[0043] Embodiment 25. The composition according to Embodiment 22, wherein the composition and the immunosuppressant are administered to the recipient simultaneously, concurrently or sequentially.

[0044] Embodiment 26. The composition according to Embodiment 22, wherein the composition is administered to the recipient 0.5 - 18 hours or 18 - 36 hours before anesthesia for transplanting the heterologous graft into the recipient.

[0045] Embodiment 27. The composition according to Embodiment 22, wherein the composition is administered as maintenance therapy after being transplanted into the recipient.

[0046] Embodiment 28. The composition according to Embodiment 20, wherein the heterologous graft is tissue, organ or cells of the lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus or penis.

[0047] Embodiment 29. The composition according to Embodiment 20, wherein the heterologous graft is tissue, organ or cells of the lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus or penis.

[0048] Embodiment 30. The composition according to Embodiment 20, wherein administration of the composition inhibits the immune response to the heterologous transplant in the recipient.

[0049] Embodiment 31. The composition according to Embodiment 20, wherein the effective amount of CHP, its pharmaceutically acceptable salt, stereoisomer or solvate is about 0.001 - 0.005 mg / kg, 0.005 - 0.01 mg / kg, 0.01 - 0.02 mg / kg, 0.02 - 0.04 mg / kg, 0.04 - 0.06 mg / kg, 0.06 - 0.08 mg / kg, 0.08 - 1 mg / kg, 1 - 5 mg / kg, 5 - 6 mg / kg, 6 - 7 mg / kg, 7 - 8 mg / kg, 8 - 10 mg / kg, 10 - 15 mg / kg, 15 - 20 mg / kg, 20 - 25 mg / kg, 25 - 30 mg / kg, 30 - 35 mg / kg, 35 - 40 mg / kg, 40 - 45 mg / kg, 45 - 50 mg / kg, 50 - 100 mg / kg, 100 - 150 mg / kg, 150 - 200 mg / kg, 200 - 300 mg / kg, 300 - 400 mg / kg, 400 - 500 mg / kg, 500 - 600 mg / kg, 600 - 700 mg / kg, 700 - 800 mg / kg, 800 - 900 mg / kg, 900 - 1000 mg / kg, 1000 - 1100 mg / kg, 1100 - 1200 mg / kg, 1200 - 1300 mg / kg, 1300 - 1400 mg / kg, 1400 - 1500 mg / kg, 1500 - 1600 mg / kg, 1600 - 1700 mg / kg, 1700 - 1800 mg / kg, 1800 - 1900 mg / kg, 1900 - 2000 mg / kg, 2000 - 2100 mg / kg, 2100 - 2200 mg / kg, 2200 - 2300 mg / kg, 2300 - 2400 mg / kg, 2400 - 2500 mg / kg, 2500 - 2600 mg / kg, 2600 - 2700 mg / kg, 2700 - 2800 mg / kg, 2800 - 2900 mg / kg or 2900 - 3000 mg / kg.

[0050] Embodiment 32. A composition for inhibiting or reducing the immune response of a recipient to a xenograft, for reducing the rejection of a xenograft by a recipient, and / or for reducing the amount of an immunosuppressant administered before and / or after transplantation of a xenograft into a recipient of the xenograft, the composition comprising an effective amount of cyclo-His-Pro (CHP), its pharmaceutically acceptable salt, stereoisomer or solvate as an active ingredient, and a pharmaceutically acceptable carrier.

[0051] Embodiment 33. The composition according to Embodiment 32, wherein the graft is treated with cyclo-His-Pro (CHP), a pharmaceutically acceptable salt, stereoisomer or solvate thereof before transplantation into a recipient.

[0052] Embodiment 34. The composition according to Embodiment 32, wherein the composition is administered to the recipient 0.5 - 18 hours or 18 - 36 hours before anesthesia for transplantation of the heterologous graft into the recipient.

[0053] Embodiment 35. The composition according to claim 32, wherein the composition is administered to the recipient as maintenance therapy after transplantation.

[0054] Embodiment 36. The composition according to Embodiment 32, wherein the composition and the immunosuppressant are administered simultaneously, in parallel or sequentially.

[0055] Embodiment 37. The composition according to Embodiment 32, wherein the heterologous graft is tissue, an organ or cells of the lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus or penis.

[0056] Embodiment 38. The composition according to Embodiment 32, wherein the effective amount of CHP, its pharmaceutically acceptable salt, stereoisomer or solvate is about 0.001 - 0.005 mg / kg, 0.005 - 0.01 mg / kg, 0.01 - 0.02 mg / kg, 0.02 - 0.04 mg / kg, 0.04 - 0.06 mg / kg, 0.06 - 0.08 mg / kg, 0.08 - 1 mg / kg, 1 - 5 mg / kg, 5 - 6 mg / kg, 6 - 7 mg / kg, 7 - 8 mg / kg, 8 - 10 mg / kg, 10 - 15 mg / kg, 15 - 20 mg / kg, 20 - 25 mg / kg, 25 - 30 mg / kg, 30 - 35 mg / kg, 35 - 40 mg / kg, 40 - 45 mg / kg, 45 - 50 mg / kg, 50 - 100 mg / kg, 100 - 150 mg / kg, 150 - 200 mg / kg, 200 - 300 mg / kg, 300 - 400 mg / kg, 400 - 500 mg / kg, 500 - 600 mg / kg, 600 - 700 mg / kg, 700 - 800 mg / kg, 800 - 900 mg / kg, 900 - 1000 mg / kg, 1000 - 1100 mg / kg, 1100 - 1200 mg / kg, 1200 - 1300 mg / kg, 1300 - 1400 mg / kg, 1400 - 1500 mg / kg, 1500 - 1600 mg / kg, 1600 - 1700 mg / kg, 1700 - 1800 mg / kg, 1800 - 1900 mg / kg, 1900 - 2000 mg / kg, 2000 - 2100 mg / kg, 2100 - 2200 mg / kg, 2200 - 2300 mg / kg, 2300 - 2400 mg / kg, 2400 - 2500 mg / kg, 2500 - 2600 mg / kg, 2600 - 2700 mg / kg, 2700 - 2800 mg / kg, 2800 - 2900 mg / kg or 2900 - 3000 mg / kg.

[0057] Embodiment 39. Use of cyclo - His - Pro (CHP), its pharmaceutically acceptable salt, stereoisomer, or solvate thereof in the preparation of a medicament for (i) prolonging the survival period of a xenograft recipient; (ii) prolonging the survival period of a xenograft in a recipient; (iii) inhibiting or reducing the immune response of a recipient to a xenograft; (iv) reducing the rejection reaction of a recipient to a xenograft; and / or (v) reducing the amount of immunosuppressive agent administered during and / or after transplantation of a xenograft into a recipient of the xenograft.

[0058] Other features and advantages of the present invention will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will be apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] The patent or application document contains at least one color drawing. Copies of this patent or patent application publication with color drawings will be provided by the official upon request and payment of the necessary fees.

[0060] Figure 1 is a photograph of a transplanted kidney after reperfusion. After reperfusion, blood flow is smooth and the kidney has a good color.

[0061] Figure 2 is a diagram showing an exemplary experimental procedure for heterotopic kidney transplantation in rats.

[0062] Figure 3A and Figure 3B show the survival rates of kidney transplants in the positive control group and the CHP-treated group during the first 80 days ( Figure 3A ) and 1 year ( Figure 3B ) after transplantation.

[0063] Figure 4 is an ultrasound image showing smooth blood flow in the transplanted body.

[0064] Figure 5 show histological images of transplanted kidneys in the positive control group (syngeneic TPL) and the CHP-treated group (TPL + CHP).

[0065] Figure 6A – Figure 6D show the changes in body weight (g), blood urea nitrogen (BUN) (mg / dL), creatinine (mg / dL), and Uproc / Crea ratio (mg / mg) during the 46 weeks after transplantation in the syngeneic transplantation (syngeneic) and CHP-treated transplantation groups (TPL + CHP), respectively.

[0066] Figure 7A and Figure 7B are diagrams showing the quantitative comparison of blood urea nitrogen (BUN) ( Figure 7A ) and serum creatinine levels ( Figure 7B ) in recipient rats five days after transplantation. Each data point represents the following groups: syngeneic transplantation recipients (syngeneic; n = 3), kidney transplantation recipients without CHP administration (TPL; n = 5), and CHP-treated transplantation recipients (TPL + CHP; n = 5).

[0067] Figure 8These are representative immunohistochemical images of PAS and Nrf2 staining, where the scale bar represents 100 μm (at a magnification of ×100). All animals were sacrificed five days after kidney transplantation. Detailed implementation

[0068] Definition

[0069] Unless otherwise defined, all terms and phrases used herein include the meanings that the terms and phrases have been determined to have in the art, unless the contrary is clearly stated or is apparent from the context in which the terms or phrases are used. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, specific methods and materials are now described.

[0070] Unless otherwise specified, a single numerical value is used as an approximation, as if there were the words "about" or "approximately" before these values. Similarly, unless otherwise clearly specified, the numerical values within the various ranges specified in the present invention are stated as approximations, as if there were the words "about" or "approximately" before both the minimum and maximum values within the stated ranges. In this way, variations above and below the stated ranges can be used to achieve substantially the same results as the values within the ranges. As used herein, the terms "about" or "approximately" should have the ordinary and common meaning of a person of ordinary skill in the art most closely related to the disclosed subject matter or a person of ordinary skill in the field related to the range or element being discussed. The amount of widening from the strict numerical boundaries depends on many factors. For example, some factors that can be considered include the criticality of the element and / or the impact of a given amount of variation on the performance of the claimed subject matter, as well as other considerations known to those skilled in the art. As used herein, using different numbers of significant figures for different numerical values does not mean restricting how the words "about" or "approximately" will be used to widen a particular numerical value or range. Thus, generally, "about" or "approximately" widens the numerical value. In addition, the disclosure of a range is intended to be a continuous range, including every value between the minimum and maximum values plus the widening of the range provided by using the terms "about" or "approximately". Therefore, the recitation of a numerical range in this document is merely intended as a shorthand method for separately referring to each individual value falling within that range, and each individual value is incorporated into the specification as if it were separately recited herein. In one aspect, as used in referring to a numerical value, the word "about" is intended to include a variance of 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from the numerical value(s).

[0071] The term "animal" as used herein includes all members of the animal kingdom, including humans. The term "mammal" includes humans and non-human mammals. Similarly, the term "subject" includes human and veterinary subjects.

[0072] As used herein, the terms "active agent", "active ingredient", "drug", "pharmaceutical agent", or "preparation" refer to any chemical that elicits a biochemical reaction when administered to a human or an animal. A drug can be a substrate or a product of a biochemical reaction, or a drug can interact with a cellular receptor and cause a physiological reaction, or a drug can bind to a receptor and block the receptor from causing a physiological reaction.

[0073] The phrase "consisting essentially of" as used herein with respect to a composition or preparation means that the composition or preparation contains the listed compounds as the only active ingredients and may additionally contain pharmaceutically acceptable inert additives, excipients, or carriers. These inert additives, excipients, or carriers are known in the art.

[0074] The terms "parenteral administration" and "administered parenterally" are well recognized in the art and refer to a mode of administration other than enteral and topical administration, typically by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection.

[0075] As used herein, the term "treatment" refers to a method for obtaining a beneficial or desired result, including a clinical result. Beneficial or desired clinical results can include, but are not limited to, alleviation or improvement of one or more symptoms or disorders, reduction of the severity of a disease, stabilization (i.e., not worsening) of a disease state, prevention of the spread of a disease, delay or slowing of disease progression, improvement or alleviation of a disease state, and remission (whether partial or total), whether detectable or not. "Treatment" can also refer to prolonging the survival of a recipient or a graft as compared to the expected survival in the absence of treatment.

[0076] The phrase "pharmaceutically acceptable" additives, excipients, or carriers as used herein includes those well known in the art. Generally, the nature of the carrier will depend on the particular mode of administration employed. For example, parenteral preparations generally contain injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, saline, balanced salt solutions, aqueous dextrose solutions, glycerol, etc. as vehicles. For solid compositions (e.g., in the form of powders, pills, tablets, or capsules), conventional non-toxic solid carriers can include, for example, pharmaceutical grade mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, the pharmaceutical composition to be administered can contain small amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents, such as sodium acetate or sorbitan monolaurate.

[0077] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are pharmaceutically useful in substances having cations and anions coupled by electrostatic attraction. Generally, it can include metal salts, salts of organic bases, salts of inorganic acids, salts of organic acids, salts of basic or acidic amino acids, etc. Examples of metal salts can include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, barium salt, etc.), aluminum salts, etc.; examples of salts formed with organic bases can include salts formed with triethylamine, pyridine, methylpyridine, 2,6-dimethylpyridine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.; examples of salts formed with inorganic acids can include salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; examples of salts formed with organic acids can include salts formed with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; examples of salts formed with basic amino acids can include salts formed with arginine, lysine, ornithine, etc.; examples of salts formed with acidic amino acids include salts formed with aspartic acid, glutamic acid, etc.

[0078] As used herein, the term "therapeutically effective amount" or "effective dose" is the amount of the active agent present in the compositions described herein that is required to provide an extended effect for the graft or the animal recipient of the graft. The precise amount depends on many factors such as the specific activity of the composition, the delivery device used, the physical characteristics of the composition, its intended use, and patient considerations such as the severity of the disease state, patient compliance, etc.

[0079] The terms "increased" or "increase" or "extended" are used herein to generally mean an increase or extension of a statically significant amount; in some embodiments, the terms "increased" or "increase" or "extended" mean an increase or extension of at least 10% compared to a reference level (e.g., without the treatment or administration described herein), such as an increase of at least about 10%, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase (or extension) or any increase (or extension) between 10 - 100%. Other examples of "increase" or "extension" include an increase or extension of at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold or more compared to the reference level.

[0080] The terms "inhibit" or "inhibited" are generally used herein to refer to a slowing or reduction in the progression of a disease or the development of symptoms compared to the absence of the intervention described herein.

[0081] The terms "reduced" or "reducing" or "decrease" are generally used herein to refer to a statistically significant decrease. In some embodiments, "reduced" or "reducing" means a decrease of at least 10% as compared to a reference level (e.g., no treatment or administration as described herein), such as a decrease of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g., no level or undetectable level as compared to the reference level), or any decrease between 10-100% as compared to the reference level. In the case of a marker or symptom, these terms refer to a statistically significant decrease in that level. The decrease can be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and preferably decreased to a level acceptable within the normal range for an individual without the given disease. In the context of a decrease in the amount of an immunosuppressant, the term means a statistically significant decrease in such a level. The decrease can be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and preferably decreased to a level acceptable within the normal range for an individual without the given disease.

[0082] As used herein, the term "induction period" can be the pre-operative, intra-operative (intubation, incision, transplantation, end of surgery) and / or post-operative period. The pre-operative period can cover 0-3 days before surgery, 1 day before surgery, 2 days before surgery, 3 days before surgery, 0 days before surgery, 24 hours before surgery, 18 hours before surgery, 15 hours before surgery, 12 hours before surgery, 6 hours before surgery, 5 hours before surgery, 4 hours before surgery, 3 hours before surgery, 2 hours before surgery, 1 hour before surgery or 0.5 hours before surgery. The post-operative period can include about 0.5 days after transplantation surgery, about 1 day after, about 2 days after, about 3 days after, about 4 days after, about 5 days after, about 6 days after, 7 days after, about 10 days after, about 14 days after, about 1 month after, about 0-7 days after, about 0 days–1 month after, about 1 day-1 month after, about 1-10 days after, about 0-14 days after, about 1-7 days after, about 1-10 days after or about 1-14 days after.

[0083] The term "induction therapy" as used herein can be immunosuppressive therapy administered during the induction period to reduce the risk of implant rejection. Generally, induction strategies can include (i) a strategy using high doses of conventional immunosuppressants, or (ii) a more commonly used strategy that uses a combination of T cell depletion or interleukin (IL) 2 receptor blocking antibodies with lower doses of conventional reagents.

[0084] As used herein, the term "maintenance phase" can be a period of time after the induction phase.

[0085] The term "maintenance therapy" is immunosuppressive therapy administered after the induction phase (when the risk of acute rejection is reduced) to suppress the immune response to the graft. Maintenance therapy is typically administered at a lower level than induction therapy and is decreased over time to help reduce the overall risk of infection and malignancy. Conventional maintenance regimens include combinations of immunosuppressive agents with different mechanisms of action. This strategy minimizes the morbidity and mortality associated with each class of agent while maximizing overall efficacy.

[0086] The term "combination" includes the administration of two therapeutic agents (e.g., CHP and an immunosuppressive agent other than CHP) simultaneously, in parallel, or sequentially, without a specific time limit. In one embodiment, the two agents are present in the cell or in the patient simultaneously or exert their biological or therapeutic effects simultaneously. In one embodiment, the two therapeutic agents are in the same composition or unit dosage form. In another embodiment, the two therapeutic agents are in separate compositions or unit dosage forms.

[0087] As used herein, the term "recipient" refers to an animal, including but not limited to a primate (e.g., human), bovine, porcine, ovine, caprine, equine, canine, feline, rabbit, rat, or mouse. In an embodiment, the term "recipient" refers to a mammalian subject, such as a human subject. In one embodiment, the recipient is a human.

[0088] Rejection of a graft or rejection of an implant

[0089] In one aspect, the present invention relates to preventing and treating rejection of a graft by a transplant recipient, particularly acute and / or chronic rejection.

[0090] Grafts include tissues and organs of the kidney, pancreas, liver, intestine, heart, lung, and / or vascularized composite allograft (VCA) (e.g., uterus, abdominal wall, penis, face / scalp, other upper extremities).

[0091] Hyperacute rejection occurs within minutes to hours after transplantation and is due to preformed antibodies against the transplanted tissue antigens. It is characterized by hemorrhage and thrombotic occlusion of the graft vasculature. Binding of the antibody to the endothelium activates complement, and the antibody and complement induce many changes in the graft endothelium that promote intravascular thrombosis and lead to vascular occlusion, resulting in irreversible ischemic injury to the transplanted organ. Hyperacute rejection is typically mediated by pre-existing IgM alloantibodies, such as antibodies against ABO blood group antigens expressed on red blood cells. This type of rejection, mediated by natural antibodies, is a major cause of xenograft rejection. Hyperacute rejection due to natural IgM antibodies is no longer a major problem for allografts because allografts are usually selected to match the donor and recipient ABO types.

[0092] Acute rejection is a process of vascular and parenchymal injury mediated by T cells, macrophages, and antibodies, typically beginning after the first week of transplantation. T lymphocytes play a major role in acute rejection by responding to alloantigens present on vascular endothelial and parenchymal cells, including MHC molecules. Activated T cells cause direct lysis of graft cells or produce cytokines that recruit and activate inflammatory cells, which cause necrosis. Both CD4+ and CD8+ cells can contribute to acute rejection. The destruction of allogeneic cells in the graft is highly specific and is characteristic of CD8+ cytotoxic T lymphocyte killing. CD4+ T cells may be important in mediating acute graft rejection by secreting cytokines in the graft and inducing a delayed-type hypersensitivity-like reaction, and some evidence suggests that CD4+ T cells are sufficient to mediate acute rejection. Antibodies can also mediate acute rejection after the transplant recipient mounts a humoral immune response against vascular wall antigens, and the antibodies produced bind to the vascular wall and activate complement.

[0093] Chronic rejection (CR) or chronic allograft dysfunction (CAD) of a solid organ allograft or graft, regardless of its type, develops slowly over a period of months or years. The process is characterized by narrowing and occlusion of the lumen of arteries and arterioles secondary to intimal smooth muscle cell proliferation.

[0094] Some studies have shown that the onset of acute rejection, particularly severe, recurrent, and late rejection episodes, is a major risk factor for chronic rejection.

[0095] To achieve successful transplantation, several rejection patterns must be overcome. A variety of methods have been used to prevent rejection. This includes the administration of immunosuppressive agents, usually several types to prevent various modes of attack, such as inhibiting T cell attack, antibodies, as well as cytokine and complement effects. Immunoadsorption of anti-HLA antibodies before transplantation can reduce hyperacute rejection. Before transplantation, the recipient or host can be administered anti-T cell reagents, such as the monoclonal antibody OKT3, antithymocyte globulin (ATG), cyclosporine A or tacrolimus (FK 506). Additionally, glucocorticoids and / or azathioprine (or other purine analogues) can be administered to the recipient or host before transplantation. Drugs used to assist in preventing transplant rejection include, but are not limited to, ATG or antilymphocyte globulin (ALG), OKT3, daclizumab, basiliximab, corticosteroids, 15-deoxyspergualin, LF15-0195, cyclosporine, tacrolimus, purine analogues such as azathioprine, methotrexate, mycophenolate mofetil, 6-mercaptopurine, brequinar, brequinar sodium, leflunomide, cyclophosphamide, sirolimus, everolimus, anti-CD4 monoclonal antibodies, CTLA4-Ig, rituximab, anti-CD154 monoclonal antibodies, anti-LFA1 monoclonal antibodies, anti-LFA-3 monoclonal antibodies, anti-CD2 monoclonal antibodies and anti-CD45.

[0096] Delayed graft function

[0097] Delayed graft function (DGF) is defined as the need for dialysis in the first week after transplantation and is the most common early post-transplant complication. DGF is one of the major predictors of poor graft survival in cadaveric donor kidney transplantation. DGF is common, affecting 20 - 60 out of 100 kidneys transplanted from deceased donors. DGF is a manifestation of acute kidney injury (AKI) with attributes specific to the transplantation process. Also, DGF is a major obstacle to allograft survival as it may coincide with acute rejection and chronic allograft nephropathy (CAN).

[0098] Cyclo-histidine-proline and compositions containing cyclo-histidine-proline

[0099] Cyclo-histidine-proline (cyclo His-Pro, CHP) is a naturally occurring cyclic dipeptide that is structurally related to thyrotropin-releasing hormone (TRH). Cyclo-histidine-proline (CHP) is a peptide inherent in animal and human tissues and body fluids. CHP is present in blood, semen, gastrointestinal tract, urine, etc., and is a metabolite particularly rich in the prostate. Cyclic histidine-proline (CHP) is known to have various physiological functions, such as antidiabetic, anti-obesity, anti-inflammatory and antioxidant effects.

[0100] According to one aspect of the present invention, CHP or a pharmaceutically acceptable salt, stereoisomer or solvate thereof is used as the active agent or active ingredient of the method and composition. It should be understood that the term "CHP" as used in the present invention sometimes collectively refers to CHP, its pharmaceutically acceptable salts, its stereoisomers or solvates.

[0101] According to the embodiments described herein, CHP is used to broadly include the above-mentioned CHP, its pharmaceutically acceptable salts, its stereoisomers, solvates, unless otherwise specified.

[0102] Cyclo(-His-Pro) (CHP) is as follows:

[0103]

[0104] As a non-limiting example of a CHP solvate, CHP monohydrate is as follows:

[0105]

[0106] In one embodiment, CHP is substantially pure.

[0107] In one embodiment, CHP is a CHP hydrate. In yet another embodiment, the CHP hydrate is characterized in that the XRPD diffraction pattern includes peaks at about 17 ± 0.2° and about 27.3 ± 0.2° in 2θ. One embodiment of a substantially pure CHP hydrate is characterized in that the X-ray powder diffraction pattern contains at least three peaks selected from the following: 13.7, 17, 18.1, 20.2 and 27.3° (2θ ± 0.2°). Another embodiment is characterized in that the XRPD diffraction pattern contains at least two peaks selected from the following: 10, 13.7, 17, 18.1, 20.2 and 27.3° (2θ ± 0.2°). The CHP hydrate, as one of the CHP solvates, can be prepared by the method described in US Application 16 / 448,083, the content of which is incorporated herein by reference in its entirety.

[0108] CHP synthesized from different biochemical sources, including histidine-proline-rich glycoproteins. High levels of CHP are present in many food sources and are readily absorbed in the intestine without being chemically or enzymatically destroyed.

[0109] A composition suitable for reducing or suppressing rejection of a graft in a recipient animal, treating the recipient animal to prolong the survival period of the recipient animal and / or treating the graft (before transplantation) to prolong the survival period of the graft in the recipient animal may comprise CHP, a pharmaceutically acceptable salt, stereoisomer or solvate thereof, or consist essentially of the same, and may comprise a pharmaceutically acceptable carrier or excipient. The composition may be administered or used alone to reduce or suppress rejection of a graft in a recipient animal, treat the recipient animal to prolong the survival period of the recipient animal, treat the recipient animal to prolong the survival period of the graft in the recipient animal, and / or treat the graft to prolong the survival period of the graft in the recipient animal. The composition may be administered or used in combination with an immunosuppressant (different from CHP) to reduce or suppress rejection of a graft in a recipient animal, treat the recipient animal to prolong the survival period of the recipient animal, and / or treat the graft to prolong the survival period of the graft in the recipient animal, and / or delay or suppress graft failure, and / or prevent or treat delayed graft function, and / or reduce the amount of immunosuppressant administered during the induction period and / or maintenance period. A composition comprising CHP and an immunosuppressant (different from CHP) or consisting essentially of CHP and an immunosuppressant may be administered simultaneously, concurrently or sequentially.

[0110] The composition can be used to reduce or decrease the amount of an immunosuppressant (other than CHP) administered to a transplant recipient during or at the time of or after transplantation (post-transplantation). A composition comprising CHP and an immunosuppressant (other than CHP) or consisting essentially of CHP and an immunosuppressant (other than CHP) may be administered simultaneously, concurrently or sequentially.

[0111] In one embodiment, CHP may be present in the composition in an amount of about 0.5 to about 10,000 mg, about 1 to 5,000 mg, about 1 to 2,000 mg, or about 10 to about 1,000 mg. In another embodiment, the amount of CHP present in the administered pharmaceutical composition may be about 5 to about 3,000 mg, about 50 to about 2,000 mg, about 100 to about 2,000 mg, about 50 to about 1,000 mg, about 100 to about 1,000 mg, about 150 to about 2,000 mg, about 200 to about 1,000 mg, about 50 to about 800 mg, about 100 to about 700 mg, about 50 to about 600 mg, or about 100 to about 1,500 mg, calculated as anhydrous CHP. The composition may be a pharmaceutical composition, food or dietary supplement. In a specific embodiment, the composition is a pharmaceutical composition.

[0112] In another embodiment, the composition is adapted to treat a graft to extend the survival period of the graft in a recipient animal. The composition can be a liquid in which the graft is infused. In one embodiment, the concentration of the liquid formulation is from about 1 mg / L to about 200 mg / ml, from about 5 mg / ml to about 150 mg / ml, from about 10 mg / ml to about 100 mg / ml. In another embodiment, the concentration of the liquid formulation is about 1 mg / L, about 2 mg / L, about 3 mg / L, about 4 mg / L, about 5 mg / L, about 6 mg / L, about 7 mg / L, about 8 mg / L, about 9 mg / L, about 10 mg / L, 11 mg / L, about 12 mg / L, about 13 mg / L, about 14 mg / L, about 15 mg / L, about 20 mg / L, about 25 mg / L, about 30 mg / L, about 35 mg / L, about 40 mg / L, about 45 mg / L, about 50 mg / L, about 55 mg / L, about 60 mg / L, about 65 mg / L, about 70 mg / L, about 75 mg / L, about 80 mg / L, about 85 mg / L, about 90 mg / L, about 95 mg / L, about 100 mg / L, about 110 mg / L, about 120 mg / L, about 130 mg / L, about 140 mg / L, about 150 mg / L, about 160 mg / L, about 170 mg / L, about 180 mg / L, about 190 mg / L or about 200 mg / L.

[0113] In another embodiment, the composition is adapted to be administered to a recipient animal that will receive, has received or has already received a graft. The composition can comprise a known immunosuppressive agent. Alternatively, CHP and the immunosuppressive agent can be administered simultaneously or sequentially in separate formulations. In another embodiment, the composition can consist essentially of CHP. In another embodiment, a composition comprising CHP alone or further comprising an optional immunosuppressive agent can further comprise another therapeutic active agent. Alternatively, a composition comprising CHP alone or further comprising an optional immunosuppressive agent can be administered or used separately from another composition comprising another therapeutic active agent.

[0114] In some embodiments, another therapeutic agent can include biomolecules, bioactive agents, small molecules, drugs, prodrugs, drug derivatives, proteins, peptides, vaccines, adjuvants, imaging agents (e.g., fluorescent moieties), polynucleotides, or metals. In another embodiment, the active agent is a metal element, metal cation, metal complex, or metal compound, where the metal can be copper, zinc, magnesium, manganese, iron, cobalt, chromium, or a combination thereof. In one embodiment, the metal is zinc, and the zinc compound can be zinc gluconate, zinc acetate, zinc sulfate, zinc picolinate, zinc orotate, or zinc citrate. In another embodiment, the metal is magnesium, and magnesium compounds can be used, such as magnesium oxide, magnesium citrate, magnesium chloride, magnesium glycinate, magnesium diglycinate, magnesium aspartate, magnesium lactate, or magnesium chloride. In another embodiment, the metal is manganese, and the manganese compound can include amino acid manganese chelates (e.g., manganese diglycinate chelate, manganese aspartate, manganese gluconate, manganese picolinate, manganese sulfate, manganese citrate, or manganese chloride). In one embodiment, the metal is copper, and the copper compound can include copper oxide, copper sulfate, amino acid copper chelates, and copper gluconate. In yet another embodiment, the metal is iron, and the iron can exist in various forms, such as ferrous salts and ferric salts (e.g., ferrous sulfate, ferrous gluconate, ferric citrate, or ferric cobalt sulfate). In one embodiment, the metal is cobalt, and the cobalt compound can include cobalt acetate, cobalt sulfate, cobalt picolinate, cobalt orotate, or cobalt citrate.

[0115] In an exemplary embodiment, the pharmaceutical composition of this embodiment can be administered in a variety of ways, including orally, topically, parenterally, intravenously, intradermally, colonically, rectally, intramuscularly, or intraperitoneally.

[0116] The pharmaceutical composition can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. Injectable preparations can be in unit dosage forms in ampoules or multi-dose containers, optionally with added preservatives. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass, plastic, etc. The preparation can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain agents such as suspending agents, stabilizers, and / or dispersing agents.

[0117] For example, the parenteral preparation can be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among acceptable carriers and solvents, water, 0.9% saline solution, or other suitable aqueous media can be used.

[0118] In one embodiment, the concentration of the intravenous solution preparation is from about 1 mg / L to about 200 mg / ml, from about 5 mg / ml to about 150 mg / ml, from about 10 mg / ml to about 100 mg / ml. In another embodiment, the concentration of the intravenous solution preparation is about 1 mg / L, about 2 mg / L, about 3 mg / L, about 4 mg / L, about 5 mg / L, about 6 mg / L, about 7 mg / L, about 8 mg / L, about 9 mg / L, about 10 mg / L, 11 mg / L, about 12 mg / L, about 13 mg / L, about 14 mg / L, about 15 mg / L, about 20 mg / L, about 25 mg / L, about 30 mg / L, about 35 mg / L, about 40 mg / L, about 45 mg / L, about 50 mg / L, about 55 mg / L, about 60 mg / L, about 65 mg / L, about 70 mg / L, about 75 mg / L, about 80 mg / L, about 85 mg / L, about 90 mg / L, about 95 mg / L, about 100 mg / L, about 110 mg / L, about 120 mg / L, about 130 mg / L, about 140 mg / L, about 150 mg / L, about 160 mg / L, about 170 mg / L, about 180 mg / L, about 190 mg / L or about 200 mg / L.

[0119] In another embodiment, the pharmaceutical composition can be formulated as a diffusion (slow infusion) preparation or an intravenous bolus injection.

[0120] In another embodiment, the pharmaceutical composition can be administered orally or formulated for oral administration. The administration can be by immediate-release tablets and capsules or enteric-coated tablets, etc. When preparing a pharmaceutical composition comprising at least one compound described herein, the active ingredient is usually diluted with an excipient and / or the active ingredient is encapsulated in a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient is used as a diluent, it can be in the form of a solid, semi-solid or liquid substance which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, cachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0121] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, cellulose, USP or sterile water, syrup bases and methylcellulose. The preparations may additionally include: lubricants such as talc, magnesium stearate and stearic acid; wetting agents; emulsifying and suspending agents; preservatives such as methyl paraben and propyl paraben; sweetening agents; and flavoring agents.

[0122] In some embodiments, the pharmaceutical composition is formulated into unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount (therapeutically effective amount) of the active substance calculated to produce the desired therapeutic effect, as well as a suitable pharmaceutical excipient (e.g., tablets, capsules, ampoules). The compounds are generally administered in pharmaceutically effective amounts. In some embodiments, each dosage unit contains from about 1 mg to about 100 mg of the CHP compound. In some embodiments, each dosage unit contains from about 2 mg to about 60 mg, from about 3 mg to about 50 mg, from about 4 mg to about 40 mg, from about 5 mg to about 30 mg, from about 6 mg to about 20 mg, from about 8 mg to about 15 mg, or from about 8 mg to about 10 mg of the CHP compound.

[0123] In other embodiments, each dosage unit contains about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg of the CHP compound.

[0124] To prepare solid compositions such as tablets, the active ingredient is mixed with a pharmaceutical excipient to form a solid blend composition that is a homogeneous mixture containing the compound of the present invention. When referring to these blend compositions as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0125] The tablets or pills of the present invention can be powder-coated or otherwise compounded to provide dosage forms with the advantage of extended action or protection from the acidic conditions of the stomach. For example, a tablet or pill can contain an inner dosage and an outer dosage component, the latter in the form of an envelope over the former. These two components can be separated by an enteric layer that is used to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be released in a delayed manner. A variety of materials can be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate. In one embodiment, the film coating is a polyvinyl alcohol-based coating.

[0126] Compounds useful in the compositions and methods include those in any pharmaceutically acceptable form thereof described herein, including isomers such as diastereoisomers and enantiomers, salts, solvates, and polymorphs, as well as racemic mixtures and pure isomers of the compounds described herein, where applicable.

[0127] Suitable excipients include binders, fillers, disintegrants, lubricants, antioxidants, chelating agents, and colorants.

[0128] In another embodiment, the compositions disclosed herein can be a food or a dietary supplement. The food composition or dietary supplement composition can contain pharmaceutically acceptable excipients as described herein for pharmaceutical compositions.

[0129] Methods

[0130] According to one aspect of the invention, a method of suppressing an immune response is disclosed, which comprises or consists essentially of the step of administering to an animal in need of such treatment an effective amount of cyclic histidine-proline (cycloHis-Pro or CHP), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof. In this embodiment, the immune response can include acute rejection and / or chronic rejection of a graft by the animal recipient.

[0131] In another embodiment, the invention provides a method of suppressing an immune response to a transplanted organ, tissue, or cell, which comprises or consists essentially of administering to a mammal in need thereof an effective amount of CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof. In this embodiment, the transplanted organ, tissue, or cell includes an organ, tissue, or cell of the lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc. In this embodiment, the immune response can include acute rejection and / or chronic rejection of a graft by the animal recipient.

[0132] Another aspect of the invention provides a method of prolonging the survival period of a graft in a recipient animal, which comprises or consists essentially of treating the graft with a composition comprising CHP, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a solvate thereof. In this embodiment, the graft includes an organ, tissue, or cell of the lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc.

[0133] Another aspect of the invention provides a method of prolonging the survival period of a recipient of a transplanted animal, which comprises or consists essentially of administering to the animal recipient an effective amount of a composition comprising CHP, a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. In this embodiment, the graft includes an organ, tissue, or cell of the lung, liver, kidney, heart, pancreas, intestine, abdominal wall, face / scalp, uterus, penis, etc.

[0134] For any of the above methods, CHP can be administered to a subject in an amount of from about 0.001 to about 3000 mg / kg. In some embodiments, an effective amount of CHP can be about 0.001 - 0.005 mg / kg, 0.005 - 0.01 mg / kg, 0.01 - 0.02 mg / kg, 0.02 - 0.04 mg / kg, 0.04 - 0.06 mg / kg, 0.06 - 0.08 mg / kg, 0.08 - 1 mg / kg, 1 - 5 mg / kg, 5 - 6 mg / kg, 6 - 7 mg / kg, 7 - 8 mg / kg, 8 - 10 mg / kg, 10 - 15 mg / kg, 15 - 20 mg / kg, 20 - 25 mg / kg, 25 - 30 mg / kg, 30 - 35 mg / kg, 35 - 40 mg / kg, 40 - 45 mg / kg, 45 - 50 mg / kg, 50 - 100 mg / kg, 100 - 150 mg / kg, 150 - 200 mg / kg, 200 - 300 mg / kg, 300 - 400 mg / kg, 400 - 500 mg / kg, 500 - 600 mg / kg, 600 - 700 mg / kg, 700 - 800 mg / kg, 800 - 900 mg / kg, 900 - 1000 mg / kg, 1000 - 1100 mg / kg, 1100 - 1200 mg / kg, 1200 - 1300 mg / kg, 1300 - 1400 mg / kg, 1400 - 1500 mg / kg, 1500 - 1600 mg / kg, 1600 - 1700 mg / kg, 1700 - 1800 mg / kg, 1800 - 1900 mg / kg, 1900 - 2000 mg / kg, 2000 - 2100 mg / kg, 2100 - 2200 mg / kg, 2200 - 2300 mg / kg, 2300 - 2400 mg / kg, 2400 - 2500 mg / kg, 2500 - 2600 mg / kg, 2600 - 2700 mg / kg, 2700 - 2800 mg / kg, 2800 - 2900 mg / kg or 2900 - 3000 mg / kg. The amount is based on the amount of anhydrous CHP.

[0135] For any of the above methods, CHP can be administered to an animal recipient in an amount of about 1 to about 3000 mg / day. In some embodiments, an effective amount of the CHP can be about 1 - 10 mg / day, 10 - 50 mg / day, 50 - 100 mg / day, 100 - 150 mg / day, 150 - 200 mg / day, 200 - 300 mg / day, 300 - 400 mg / day, 400 - 500 mg / day, 500 - 600 mg / day, 600 - 700 mg / day, 700 - 800 mg / day, 800 - 900 mg / day, 900 - 1000 mg / day, 1000 - 1100 mg / day, 1100 - 1200 mg / day, 1200 - 1300 mg / day, 1300 - 1400 mg / day, 1400 - 1500 mg / day, 1500 - 1600 mg / day, 1600 - 1700 mg / day, 1700 - 1800 mg / day, 1800 - 1900 mg / day, 1900 - 2000 mg / day, 2000 - 2100 mg / day, 2100 - 2200 mg / day, 2200 - 2300 mg / day, 2300 - 2400 mg / day, 2400 - 2500 mg / day, 2500 - 2600 mg / day, 2600 - 2700 mg / day, 2700 - 2800 mg / day, 2800 - 2900 mg / day or 2900 - 3000 mg / day. The amount is based on the amount of anhydrous CHP.

[0136] Regarding any of the above methods, the method can further comprise administering an immunosuppressant as described below. The immunosuppressant can be included in the same or a different formulation as the composition containing CHP. When the immunosuppressant is included in a separate formulation, the immunosuppressant can be administered simultaneously or sequentially with CHP.

[0137] Regarding the above administration methods, the pharmaceutical composition described herein can be administered to the recipient at the above doses via one or more of the above administration routes before, during, and / or after the transplantation surgery. In some embodiments, before transplantation, CHP can be administered to the recipient via a first administration route for 0.5–24 hours, 0.5–18 hours, 0.5–12 hours, 0.5–9 hours, 0.5–6 hours or 0.5 - 3 hours. In some embodiments, CHP can be administered starting from 0.5–3 hours before anesthesia and ending within 0 - 12 hours, 1 - 8 hours or 2 - 6 hours after waking up from anesthesia. The recipient can be further administered CHP via a second administration route for 1 - 30 days. The first administration route and the second administration route can be the same as or different from each other. In a non - limiting exemplary embodiment, the first administration route can be intravenous, and the second administration route can be intraperitoneal, intravenous, oral, or a combination thereof.

[0138] Regarding the above-mentioned administration method, the method may further comprise administering CHP to the graft donor before extracting the graft from the donor, and / or providing CHP to the graft extracted from the donor before transplantation into the recipient.

[0139] Immunosuppressants

[0140] Various drugs for delaying transplant rejection (i.e., prolonging survival) act in various ways. Immunosuppressants are widely used.

[0141] Examples of biologic immunosuppressants used in induction therapy may include but are not limited to various polyclonal or monoclonal antibodies.

[0142] ALG (anti-lymphocyte globulin), ATG (anti-T lymphocyte globulin), antithymocyte globulin (TG) - antithymocyte antibody (obtained by immunizing rabbits), lymphogolobulin (LG) - antithymocyte globulin (obtained by immunizing horses), etc. These polyclonal antibodies show cytotoxicity against antibodies to various T cell markers and removal of lymphocytes from peripheral blood. Polyclonal antibodies can produce leukopenia and thrombocytopenia.

[0143] Muromonab (OKT3) is a lymphocyte-depleting monoclonal antibody produced by hybridizing B lymphocytes secreting murine antibodies with a non-secreting myeloma cell line. On the first and second days of treatment with OKT3, potentially life-threatening adverse reactions may occur, which is why it is now used only when thymoglobulin is contraindicated due to leukopenia or thrombocytopenia. Lemtuzumab (Campath 1H) is a recombinant DNA-derived humanized monoclonal antibody against the cell surface glycoprotein CD52. Humanized anti-CD25 monoclonal antibodies include basiliximab (SIMULECT TM ) and daclizumab (ZENAPAX TM ). These antibodies target the alpha chain of the IL-2 receptor and block IL-2-mediated responses. Rituximab (RITUXAN TM , MABTHERA TM ) is a monoclonal anti-CD20 antibody that targets the CD20 antigen on B lymphocytes. Efalizumab (RAPTIVA TM ) which is a humanized CD11a-specific IgG1 that targets the lymphocyte function-associated antigen-1 (LFA-1) molecule; Alefacept (AMEVIVE TM ) which is a humanized LFA-3-IgG1 fusion protein that binds to CD2 in T lymphocytes and interferes with T cell activation; Bortezomib (VELCADE TM) is a proteasome inhibitor that inhibits T cell function and can also be used during the induction period.

[0144] During the maintenance phase, various immunosuppressive agents can be used, which can include but are not limited to calcineurin inhibitors (CNIs) (e.g., cyclosporine (CsA) and tacrolimus (Tac)), mycophenolate mofetil (MMF), mycophenolic acid (MPA), mTOR inhibitors (e.g., sirolimus (RAPAMUNE TM ), everolimus (CERTICAN TM ), corticosteroids (e.g., prednisone and methylprednisolone), etc. These immunosuppressive agents can be administered alone or in combination.

[0145] Inhibitors of purine or pyrimidine biosynthesis are also used to inhibit graft rejection (or implant rejection). These substances prevent DNA synthesis, thereby inhibiting the ability of cells to divide, including T cell division. As a result, T cell activity is inhibited by preventing the formation of new T cells. Purine synthesis inhibitors include azathioprine, methotrexate, mycophenolate mofetil (MMF), and mizoribine (MZB, BREDININ TM ). Pyrimidine synthesis inhibitors include sodium brequinar and leflunomide. Cyclophosphamide is an inhibitor of both purine and pyrimidine synthesis.

[0146] Many other drugs and methods for delaying allograft rejection are known and used by those skilled in the art. Inhibitors (blockers) of the CD40 ligand-CD40 interaction and / or blockers of the CD28-B7 interaction have been proposed for administration to the recipient (U.S. Patent No. 6,280,957). Published PCT patent application WO 01 / 37860 teaches the administration of anti-CD3 monoclonal antibody and IL-5 to inhibit the Th1 immune response. Published PCT patent application WO 00 / 27421 teaches a method for preventing or treating corneal allograft rejection by administering a tumor necrosis factor-α antagonist. U.S. Patent Application Publication US2003 / 0180301 discloses the treatment of chronic graft rejection by administering an antagonist of TGF-β.

[0147] Side effects of CNIs include, for example, nephrotoxicity, enhanced early post-transplant graft dysfunction, dose-related reversible renal vasoconstriction, chronic interstitial fibrosis, acute microvascular disease, hypertension, gastrointestinal dysfunction, anorexia, nausea, vomiting, diarrhea, and abdominal discomfort, hair loss, etc. MMR (CELLCEPT TM ) and enteric-coated MPA (MYFORTIC TM) Side effects include, for example, gastrointestinal side effects such as diarrhea, nausea of varying degrees, flatulence, dyspepsia, vomiting, marked esophagitis, and gastritis. Most of these symptoms respond to a reduction in the drug dose. Adverse effects of sirolimus can include, for example, tubular toxicity, hypokalemia, hypomagnesemia, proteinuria, nephritic syndrome, etc. Corticosteroids inhibit dendritic cells, inhibit the transcription of cytokine genes and all stages of T cell activation; and the non-specific immunosuppressive effect is lymphopenia.

[0148] The following non-limiting examples are illustrative descriptions of the present invention.

[0149] Example

[0150] Example 1. Heterotopic kidney transplantation in rats

[0151] Donor surgery: After removing the abdominal hair from the donor rat under general anesthesia, the surgical area was disinfected and covered with a surgical drape. After a midline incision in the abdominal wall, a kidney was exposed, 8 IU / kg of heparin was administered intravenously, followed by nephrectomy.

[0152] Surgical table: Unnecessary tissues were removed to anastomose the artery, vein, and ureter of the removed kidney to the blood vessels and ureter of the recipient, and it was covered and stored with gauze soaked in 4°C saline.

[0153] Recipient surgery: After removing the abdominal hair of the recipient rat under general anesthesia, the surgical area was disinfected and covered with a surgical drape. After a midline incision in the abdominal wall, the right kidney was exposed, removed, and the donor renal artery and vein were anastomosed end-to-end to the abdominal vein. After incising the bladder, the ureter of the donor kidney was sutured. After confirming good renal perfusion ( Figure 1 ), the abdominal wall was closed, and the animal was placed on a 37°C blanket for recovery.

[0154] Example 2. Survival rates of the control group and the CHP treatment group

[0155] As a secondary MHC-incompatible model, the kidney transplantation model using F344 rats as donors and LEWIS rats as recipients was used. After removing the right kidney of the recipient on day 0 (D0), the donor kidney was transplanted into the recipient. The left kidney of the recipient was removed on day 3 (D3). The transplantation and CHP treatment protocols were as Figure 2 shown. One hour before kidney transplantation, CHP was administered intravenously at a dose of CHP 40 mg / kg, and then CHP 40 mg / kg was administered intraperitoneally three times a week.

[0156] The mean survival days (SMD) of 7 control animals without CHP administration was 9 days, and the SMD of 4 animals administered CHP was 326 days (n = 4) ( Figure 3A and 3B)。It has been confirmed that recipient animals treated with CHP on the day before transplantation, on the day of surgery, after surgery (i.e., induction period), and during the maintenance period showed significantly prolonged survival rates.

[0157] The results showed that CHP could significantly prolong the average survival period of the recipients.

[0158] Example 3. Representative ultrasound images of the control group, CHP-treated group, and inbred (syngeneic) transplantation group

[0159] In the control group, CHP-treated group (F344 to LEWIS rats), and inbred (LEWIS to LEWIS rats) kidney transplantation models, ultrasound was performed once a week to examine the smooth flow of blood to the transplanted kidney. From Figure 4 the images, it can be seen that the blood flow to the kidney in the CHP-treated group was smooth, indicating normal function of the transplanted kidney, while the kidney transplant recipients without CHP treatment ("syngeneic TPL") showed a significant reduction in blood flow to the kidney. When the function of the transplanted kidney was smooth, the blood flow to the kidney was confirmed by color Doppler, and the RI index also showed values between 0.5 and 0.7. When the function of the transplanted kidney declined, the blood flow to the kidney decreased, and the RI index also showed values of 0.7 or higher.

[0160] Example 4. Observation results of representative transplanted tissues in the control group and CHP-treated group

[0161] In the CHP-treated group (TPL + CHP), not only were focal glomerular necrosis and severe tubulointerstitial changes reduced, but the findings accompanied by boundary changes suggested a rapid reduction in acute cell-mediated rejection and microvasculitis.

[0162] In terms of overall renal histology, important changes were observed in the CHP-treated group, such as acute tubular injury, i.e., acute inflammatory cell infiltration around the tubules or glomeruli, thrombosis in the capillaries, and arterial wall inflammation. These phenomena are considered to be the effects of CHP's ability to inhibit acute rejection that occurs within a few days after transplantation. Figure 5 are the results of transplanted kidney tissues on the 7th day of rejection in the left positive control group (syngeneic TPL) and on the 45th day of rejection in the CHP-treated group (TPL + CHP).

[0163] Example 5. Evaluation of implant function

[0164] The body weight (g), blood urea nitrogen (BUN) (mg / dL), creatinine (mg / dL), and Uproc / Crea ratio (mg / mg) of the animal group treated with CHP (TPL + CHP) and the syngeneic group were measured weekly within 46 weeks after transplantation, and the results are shown in Figure 6A – Figure 6D。At 3 weeks, the serum creatinine of the inbred negative control group (syngeneic) was 0.71 mg / dL, and a similar value of 0.82 mg / dL was observed in the CHP-treated group (TPL+CHP).

[0165] The results indicate that after transplantation, the transplanted organs of the CHP-treated animals functioned fully throughout the survival period of the recipient animals.

[0166] Figure 7 shows a quantitative comparison graph of BUN and serum creatinine levels five days after transplantation in recipient rats. Each data point represents the following groups: syngeneic transplant recipients (syngeneic; n = 3), transplant recipients without CHP administration (TPL; n = 5), and CHP-treated transplant recipients (TPL+CHP; n = 5). Recipients treated with CHP showed significant decreases in BUN (from 193.5 ± 8.54 to 41.98 ± 5.69; p-value < 0.0001) and serum creatinine levels (from 7.23 ± 0.39 to 1.32 ± 0.13; p-value < 0.0001). This significant improvement in key renal function indices highlights a substantial advancement in post-transplant care, reducing the reliance on immunosuppressive therapy and extending recipient survival time and graft survival rate.

[0167] Figure 8 Representative immunohistochemical images of PAS and Nrf2 staining are shown, where the scale bar represents 100 μm (at x100 magnification). All animals were sacrificed five days after kidney transplantation. Administration of CHP to the transplant recipient group reduced tubular atrophy, tubulitis, endothelialitis, and leukocyte infiltration, while increasing the level of the antioxidant stress marker Nrf2 (nuclear factor erythroid-2-related factor). These findings highlight the potential of CHP to play a protective (e.g., anti-inflammatory and antioxidant) role in the transplant rat model.

[0168] Although the present invention has been described with reference to presently considered to be preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. On the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

[0169] All publications, patents, and patent applications are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

Claims

1. A composition for prolonging the survival period of a xenotransplant recipient and / or prolonging the survival period of a xenograft in a recipient, characterized in that, The composition contains an effective amount of cyclo-His-Pro (CHP), its pharmaceutically acceptable salts, stereoisomers or solvates as active ingredients, and a pharmaceutically acceptable carrier.

2. The composition according to claim 1, wherein The heterologous graft is treated with cyclo-His-Pro (CHP), its pharmaceutically acceptable salts, stereoisomers or solvates before transplantation into the recipient.

3. The composition according to claim 1, wherein the composition is administered to the recipient together with an immunosuppressant.

4. The composition according to claim 1, wherein, The composition is administered to the recipient 0.5 - 18 hours or 18 - 36 hours before anesthesia for the transplantation surgery of the heterologous graft to the recipient.

5. The composition according to claim 1, wherein, The composition is administered to the recipient as maintenance therapy after transplantation.

6. The composition according to claim 3, wherein The composition and the immunosuppressant are administered to the recipient simultaneously, in parallel or sequentially.

7. The composition according to claim 3, wherein The composition is administered to the recipient 0.5 - 18 hours or 18 - 36 hours before anesthesia for the transplantation surgery of the heterologous graft to the recipient.

8. The composition according to claim 3, wherein, The composition is administered to the recipient as maintenance therapy after transplantation.

9. The composition according to claim 1, wherein, The heterologous graft is tissue, organ or cells of the lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus or penis.

10. The composition according to claim 3, wherein, The heterologous graft is tissue, organ or cells of the lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus or penis.

11. The composition according to claim 1, wherein, The administration of the composition can inhibit the immune response of the recipient to the heterologous graft.

12. The composition according to claim 1, wherein, The effective amount of CHP, its pharmaceutically acceptable salts, stereoisomers or solvates is about 0.001 - 0.005 mg / kg, 0.005 - 0.01 mg / kg, 0.01 - 0.02 mg / kg, 0.02 - 0.04 mg / kg, 0.04 - 0.06 mg / kg, 0.06 - 0.08 mg / kg, 0.08 - 1 mg / kg, 1 - 5 mg / kg, 5 - 6 mg / kg, 6 - 7 mg / kg, 7 - 8 mg / kg, 8 - 10 mg / kg, 10 - 15 mg / kg, 15 - 20 mg / kg, 20 - 25 mg / kg, 25 - 30 mg / kg, 30 - 35 mg / kg, 35 - 40 mg / kg, 40 - 45 mg / kg, 45 - 50 mg / kg, 50 - 100 mg / kg, 100 - 150 mg / kg, 150 - 200 mg / kg, 200 - 300 mg / kg, 300 - 400 mg / kg, 400 - 500 mg / kg, 500 - 600 mg / kg, 600 - 700 mg / kg, 700 - 800 mg / kg, 800 - 900 mg / kg, 900 - 1000 mg / kg, 1000 - 1100 mg / kg, 1100 - 1200 mg / kg, 1200 - 1300 mg / kg, 1300 - 1400 mg / kg, 1400 - 1500 mg / kg, 1500 - 1600 mg / kg, 1600 - 1700 mg / kg, 1700 - 1800 mg / kg, 1800 - 1900 mg / kg, 1900 - 2000 mg / kg, 2000 - 2100 mg / kg, 2100 - 2200 mg / kg, 2200 - 2300 mg / kg, 2300 - 2400 mg / kg, 2400 - 2500 mg / kg, 2500 - 2600 mg / kg, 2600 - 2700 mg / kg, 2700 - 2800 mg / kg, 2800 - 2900 mg / kg or 2900 - 3000 mg / kg.

13. A composition for inhibiting or reducing the immune response of a recipient to a xenograft, reducing the rejection of a xenograft by a recipient, and / or reducing the dosage of an immunosuppressant used by a xenograft recipient during and / or after transplantation of the xenograft, the composition comprising an effective amount of cyclo-His-Pro (CHP), its pharmaceutically acceptable salts, stereoisomers or solvates as an active ingredient, and a pharmaceutically acceptable carrier.

14. The composition according to claim 13, wherein, Treat the graft with cyclo-His-Pro (CHP), its pharmaceutically acceptable salts, stereoisomers or solvates before transplantation into the recipient.

15. The composition according to claim 13, wherein Administer the composition to the recipient 0.5 - 18 hours or 18 - 36 hours before anesthesia for the transplantation surgery of the xenograft to the recipient.

16. The composition according to claim 13, wherein, The composition is administered to the recipient as maintenance therapy after transplantation.

17. The composition according to claim 13, wherein, The composition and the immunosuppressant are administered simultaneously, in parallel, or sequentially.

18. The composition according to claim 13, wherein The heterologous graft is tissue, an organ, or cells of the lung, liver, kidney, pancreas, heart, intestine, abdominal wall, scalp, uterus, or penis.

19. The composition according to claim 13, wherein, The effective amount of CHP, its pharmaceutically acceptable salts, stereoisomers, or solvates is about 0.001 - 0.005 mg / kg, 0.005 - 0.01 mg / kg, 0.01 - 0.02 mg / kg, 0.02 - 0.04 mg / kg, 0.04 - 0.06 mg / kg, 0.06 - 0.08 mg / kg, 0.08 - 1 mg / kg, 1 - 5 mg / kg, 5 - 6 mg / kg, 6 - 7 mg / kg, 7 - 8 mg / kg, 8 - 10 mg / kg, 10 - 15 mg / kg, 15 - 20 mg / kg, 20 - 25 mg / kg, 25 - 30 mg / kg, 30 - 35 mg / kg, 35 - 40 mg / kg, 40 - 45 mg / kg, 45 - 50 mg / kg, 50 - 100 mg / kg, 100 - 150 mg / kg, 150 - 200 mg / kg, 200 - 300 mg / kg, 300 - 400 mg / kg, 400 - 500 mg / kg, 500 - 600 mg / kg, 600 - 700 mg / kg, 700 - 800 mg / kg, 800 - 900 mg / kg, 900 - 1000 mg / kg, 1000 - 1100 mg / kg, 1100 - 1200 mg / kg, 1200 - 1300 mg / kg, 1300 - 1400 mg / kg, 1400 - 1500 mg / kg, 1500 - 1600 mg / kg, 1600 - 1700 mg / kg, 1700 - 1800 mg / kg, 1800 - 1900 mg / kg, 1900 - 2000 mg / kg, 2000 - 2100 mg / kg, 2100 - 2200 mg / kg, 2200 - 2300 mg / kg, 2300 - 2400 mg / kg, 2400 - 2500 mg / kg, 2500 - 2600 mg / kg, 2600 - 2700 mg / kg, 2700 - 2800 mg / kg, 2800 - 2900 mg / kg, or 2900 - 3000 mg / kg.

20. Use of cyclo - his - pro (CHP), its pharmaceutically acceptable salts, stereoisomers, or solvates in the preparation of the following medicaments: (i) prolonging the survival period of a heterologous transplant recipient; (ii) prolonging the survival period of a heterologous graft in a recipient; (iii) inhibiting or reducing the immune response of a recipient to a heterologous graft; (iv) reducing the rejection reaction of a recipient to a heterologous graft; and / or (v) reducing the dosage of an immunosuppressant administered to a heterologous transplant recipient during and / or after heterologous graft transplantation.

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