Extracellular vesicles from alpha-1 antitrypsin overexpressing cells

Abstract

Provided are compositions comprising exosomes derived from human alpha-1 antitrypsin (AAT) overexpressing immortalized mesenchymal stem cells and methods of use thereof to prevent or treat autoimmune or inflammatory disease.

Description

[0001]Attorney Docket: 206085‐0139‐00WO  EXTRACELLULAR VESICLES FROM ALPHA-1 ANTITRYPSIN OVEREXPRESSING CELLS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No.63 / 639,044, filed April 26, 2024 which is hereby incorporated by reference herein in its entirety.   FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT This invention was made with government support under DK105183, DK 120394 and DK118529, and DK125464 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Chronic pancreatitis (CP) is a progressive inflammatory condition characterized by prolonged pancreatic inflammation (D. Yadav et al., Gastroenterology 144, 1252-1261 (2013); Z. Sun et al., Mol Ther 25, 2490-2501 (2017)). Persistent inflammation is associated with destruction of pancreatic tissue, pancreatic fibrosis and atrophy (L. Kong et al., Bioengineered 12, 1986-1996 (2021)). The loss of organ function likely involves complex mechanisms that ultimately result in chronic pain (D. Yadav et al., Gastroenterology 144, 1252-1261 (2013); C. Brock et al., World J Gastroenterol 19, 7231-7240 (2013)). Ferroptosis is a newly recognized form of regulated cell death resulting from iron accumulation and lipid peroxidation. An imbalance in oxidant stress and antioxidant protection with enzymes such as glutathione peroxidase 4 (GPx4), and superoxide dismutase type 1 (SOD1) eventually leads to cell death (X. Jiang et al. Nat Rev Mol Cell Biol 22, 266-282 (2021)). During chronic inflammation, the pancreas experiences oxidative stress, causing an overload of intracellular iron and initiating the Fenton reaction, ultimately leading to lipid peroxidation and generation of ROS (W. Hu et al., Ferroptosis and Its Role in Chronic Diseases. Cells 11 (2022); J. D. Mancias et al., J Mol Biol 428, 1659-1680 (2016); X. Wang et al., Chem Biol Interact 366, 110148 (2022)). These processes likely contribute to the destruction of pancreatic tissue and 1    Attorney Docket: 206085‐0139‐00WO  exacerbate the inflammatory response, further perpetuating the condition. Experimental studies have demonstrated that targeting ferroptosis can alleviate pancreatic injury and inflammation severity in animal models of acute pancreatitis (K. Liu et al., Cell Mol Gastroenterol Hepatol 13, 483-500 (2022); R. Fan et al., Free Radic Biol Med 173, 29-40 (2021); X. Ma et al., Antioxidants (Basel) 12 (2022)). Pancreatic fibrosis, like fibrosis in other organs of the body, is characterized by the excessive deposition of extracellular matrix components that is likely facilitated by activation and recruitment of blood inflammatory cells (R. Jaster et al., Best Pract Res Clin Gastroenterol 22, 17-29 (2008), Wenyu Gou et al., J Vis Exp. (2022)). In addition, pancreatic stellate cells (PSCs), and pancreatic acinar cells may contribute to fibrotic pathways, although their contribution is not fully explored. The extent to which inflammation and fibrosis are linked pathogenetically to neuronal sensitization and damage responsible for chronic pain, another key feature of CP, also is not known. (Z. Sun et al., Mol Ther 25, 2490-2501 (2017); Wenyu Gou et al., J Vis Exp. (2022); Jakob Lykke Poulsen et al., World J Gastroenterol 19, 7282-7291 (2013); J. Glaubitz et al., Nat Commun 13, 4502 (2022)). Gaining a comprehensive understanding of these intricate connections is essential for developing effective therapeutic strategies. Thus, there remains a need in the art for compositions and methods for treating chronic pancreatitis. This invention fulfils this need in the art. SUMMARY OF THE INVENTION In some embodiments, the invention relates to a composition comprising an exosome derived from an immortalized stem cell modified to express human alpha-1 antitrypsin (AAT). In some embodiments, the stem cell is immortalized by contacting the cell with an immortalization factor selected from the group consisting of SV40 large T antigen (SV40LT), HPV-16 E6 and E7, and EBV, TERT, a p53 or Rb inhibitor, Ras, c-Myc T58A, Bmi1, cdk4, and cyclin D, or a fragment or variant thereof. In some embodiments, the stem cell is immortalized by contacting the cell with SV40LT, or a fragment or variant thereof.   In some embodiments, the stem cell is selected from the group consisting of mesenchymal stem cells, hematopoietic stem cells, umbilical cord or placental derived stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, epithelial stem cells, and skin stem 2    Attorney Docket: 206085‐0139‐00WO  cells. In some embodiments, the immortalized stem cell is an immortalized mesenchymal stem cell. In some embodiments, the invention relates to a method of treating or preventing an autoimmune or inflammatory disease in a subject comprising administering to the subject a composition comprising an exosome derived from an immortalized stem cell modified to express human alpha-1 antitrypsin (AAT). In some embodiments, the autoimmune or inflammatory disease is selected from the group consisting of chronic pain, pancreatitis, type 1 diabetes, type 2 diabetes, sarcoidosis, islet transplantation, alpha-1 antitrypsin deficiency, and acute bacterial and viral infections, including COVID-19. In some embodiments, the disease results in chronic pain. In some embodiments, the invention relates to a method of reducing at least one symptom of an autoimmune or inflammatory disease in a subject comprising administering to the subject a composition comprising an exosome derived from an immortalized stem cell modified to express human alpha-1 antitrypsin (AAT). In some embodiments, the at least one symptom is selected from the group consisting of pain, inflammation, intralobular edema score, necrosis, ferroptosis, autophagy, and fibrosis. In some embodiments, the invention relates to a cell population comprising an immortalized stem cell modified to express human alpha-1 antitrypsin (AAT). In some embodiments, the stem cell is immortalized by contacting the cell with an immortalization factor selected from the group consisting of SV40 large T antigen (SV40LT), HPV-16 E6 and E7, and EBV, TERT, a p53 or Rb inhibitor, Ras, c-Myc T58A, Bmi1, cdk4, and cyclin D, or a fragment or variant thereof. In some embodiments, the stem cell is immortalized by contacting the cell with SV40LT, or a fragment or variant thereof.   In some embodiments, the immortalized stem cell is selected from the group consisting of mesenchymal stem cells, hematopoietic stem cells, umbilical cord or placental-derived stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, epithelial stem cells, and skin stem cells. In some embodiments, the immortalized stem cell is an immortalized mesenchymal stem cell. In some embodiments, the invention relates to a method comprising the steps of: a) obtaining a stem cell, b) immortalizing the stem cell, c) modifying the stem cell to express AAT, and d) isolating exosomes derived from the immortalized stem cell expressing AAT. 3    Attorney Docket: 206085‐0139‐00WO  In some embodiments, the step of immortalizing the stem cell comprises contacting the stem cell with an immortalization factor selected from the group consisting of SV40 large T antigen (SV40LT), HPV-16 E6 and E7, and EBV, TERT, a p53 or Rb inhibitor, Ras, c-Myc T58A, Bmi1, cdk4, and cyclin D, or a fragment or variant thereof. In some embodiments, the step of immortalizing the stem cell comprises contacting the stem cell with SV40LT, or a fragment or variant thereof. In some embodiments, the step of modifying the stem cell comprises contacting the cell with an exogenous nucleic acid molecule encoding AAT or a fragment or variant thereof. In some embodiments, the immortalized stem cell is selected from the group consisting of mesenchymal stem cells, hematopoietic stem cells, umbilical cord or placental-derived stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, epithelial stem cells, and skin stem cells. In some embodiments, the immortalized stem cell is an immortalized mesenchymal stem cell. BRIEF DESCRIPTION OF DRAWINGS The following detailed description of embodiments provided herein will be better understood when read in conjunction with the appended drawings. It should be understood that embodiments provided in the present disclosure are not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings. Figure 1 depicts the results of example experiments demonstrating that immortalization of human mesenchymal stem / stromal cells (MSCs) or a gene edited human MSC with an overexpression of alpha-1 antitrypsin (AAT-MSCs) has been successfully performed using SV40. This immortalization into iAAT-MSCs expands the limited therapeutic lifespan of these MSCs. Figure 2 depicts the results of example experiments demonstrating that iAAT-MSCs formed more colonies than immortalized MSCs without the added AAT gene construct (iMSCs) or non- immortalized MSCs. This increase in growth an proliferation is associated with improved ability to secrete exosomes. Figure 3, comprising Figures 3A-3J, depicts the characterization of hiMSCs, hiAAT-MSCs, and their secreted exosomes. Figure 3A depicts the morphology of iMSCs and iAAT-MSCs in culture under the light microscope (upper panels, scale bar= 200µm) and after the cells were 4    Attorney Docket: 206085‐0139‐00WO  infected with SV40LT, sorted by FACS, and observed under a fluorescent microscope; SV40LT is shown in red, scale bar = 100µm. Figures 3B and 3C depict the mean intensity of exosome size and size distribution derived from iMSCs and iAAT-MSCs determined by nanoparticle tracking analysis (NTA) and laser scattering microscopy. Figure 3D depicts protein expression of CD63, CD81, CD9, and AAT in iMSC and iAAT-MSC exosomes. Figure 3E depicts the results of cluster analysis of the differences in miRNAs expression between iMSC and iAAT-MSC exosomes. miRNAs within the same cluster have the same changing trend in expression levels under different conditions. The color from red to blue represents the log10(TPM+1) value from large to small. Figures 3F and 3H depict histograms of upregulated and downregulated target gene in iAAT-MSCs vs iMSCs, respectively. Figures 3G and 3I depict KEGG enrichment scatter plots of upregulated and downregulated genes in iAAT-MSCs vs iMSCs, respectively. In this KEGG term, the y-axis shows the pathway’s name, and the x-axis shows the Rich factor. The dot size represents the number of target genes, and the color indicates the q-value; BP, biological process; CC, cellular component; MF, molecular function. Figure 3J shows the morphology of iMSC- and iAAT-MSC-EVs as observed by Transmission Electron Microscope (TEM). Figure 4, comprising Figures 4A-4H, depicts the results of example experiments demonstrating that iAAT-MSCs exosomes improve pancreatic morphology and properties in chronic pancreatitis. Figure 4A depicts a schematic diagram of TNBS-induced chronic pancreatitis, exosome administration, and tissue collection and analysis. Figure 4B depicts percentages of changes in body weight at different weeks post-treatment. The arrows signify the infusion of iMSC or iAAT-MSC exosomes; n=5-11 per group. Figure 4C depicts images of pancreas and spleen collected from the control group, TNBS alone, and TNBS mice treated with iMSCs or iAAT-MSCs (treatment mice) after 3 or 6 weeks of TNBS induction. Representative pancreatic sections after H&E staining at 6 weeks of TNBS injection. Figures 4D-4H depict pancreatic scores for pancreas preserved (D), inflammation score (E), interlobular edema (F), necrosis (G), and vacuole accumulation (H) evaluated by a pathologist blinded to group assignment measured at 3 and 6 weeks post-TNBS treatment, n=3-8 per group. Figure 4D-4H bar graphs show, from left to right: control, TNBS, TNBS-iMSC exo, and TNBS-iAAT-MSC exo. Data presented as the means ± SD. *p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. Figure 5, comprising Figures 5A-5I, depicts the results of example experiments demonstrating that iAAT-MSC exosomes mitigate ferroptosis by regulating iron metabolism 5    Attorney Docket: 206085‐0139‐00WO  pathways mediated by FTH1 and NCOA4 in the human pancreas. Figure 5A depicts a model pathway of how TNBS induces ferroptosis. Figure 5B depicts Prussian blue staining demonstrating the accumulation of Fe3+ ions in the human pancreas from healthy donors and CP patients; Bar= 150μm and 75μm (inside the red box). Figure 5C depicts quantification of iron density from Prussian blue-stained human pancreas sections, n=3-4. Figure 5D depicts Prussian blue staining, demonstrating the accumulation of Fe3+ ions in exosome-treated and untreated mice after 6 weeks of TNBS injection; scale bar = 150μm and 75μm. Figure 5D depicts results from a mouse model of TNBS induced pancreatitis (n=4-6) in which quantification of iron density from Prussian blue-stained pancreas sections using ImageJ, in 5 randomly selected fields are impacted by iMSC- and iAAT-MSC-exo infusions. Figure 5F depicts serum iron levels in different groups at 6 weeks after treatment; n=5-11 per group. Figure 5G depicts total mRNA expression levels of FTH1 and NCOA4 in pancreas tissue in control, TNBS-alone, or treated mice at 6 weeks post-treatment were analyzed by RT-PCR analysis. β-actin was used as an internal control for normalization; n=5-11 with technical replicates. Figures 5H and 5I depict the protein expression levels of FTH1 and NCOA4 (H) and quantification (I) of FTH1 in pancreases detected by Western blot analysis. GAPDH was used as the internal control; n=3-4 per group. Figure 5E-5G and 5I bar graphs show, from left to right: control, TNBS, TNBS-iMSC exo, and TNBS-iAAT-MSC exo. Figure 6, comprising Figures 6A-6K, depicts the results of example experiments demonstrating iAAT-MSCs exosomes suppress ferroptosis via GSH / GPx pathways, mediated by NRF2, SOD, and FSP1. Figure 6A depicts a schematic overview of the antioxidative pathways during TNBS-induced ferroptosis. Figures 6B and 6C depict the total mRNA expression levels of (B) GPX4, NRF2; (C) SOD1, and FSP1, which were analyzed in the pancreas of control, TNBS, and TNBS with exosome treatment by RT-PCR after 6 weeks of TNBS injection. β-actin was used as an internal control to standardize the data; n=5-11 with technical replicates. Figure 6B and 6C bar graphs show, from left to right: control, TNBS, TNBS-iMSC exo, and TNBS-iAAT- MSC exo. Figures 6D and 6E depict immunofluorescence staining (D) and quantification (E) of the human pancreas from healthy donors or CP for GPx4. Scale bar= 150 µm. n=3-4. Figure 6F depicts serum human GPx activity from healthy controls and CP patients. Each dot represents a donor. Figure 6G depicts the results of immunofluorescence staining of the pancreas for GPX4, after 6 weeks of TNBS injection. Figure 6H depicts the results of quantifying GPX4 protein 6    Attorney Docket: 206085‐0139‐00WO  expression by determining the integrated density of mouse pancreatic sections; n=2-5. Figure 6I depicts GPx4 activity in control and CP mice treated with exosomes. Figure 6J depicts the results of example experiments wherein glutathione (GSH) was analyzed in serum samples of control and three groups of TNBS-treated mice after 6 weeks of TNBS injection. Data are shown as the means ± SD. Figure 6K depicts accumulation of lipid peroxidases, measured by malondialdehyde (MDA) levels, in four groups of mice after 6 weeks of TNBS injection, n=5- 11. *p < 0.05, **p < 0.01, ***p < 0.001, ****p< 0.0001. ANOVA test. Figure 7, comprising Figures 7A-7J, depicts the results of example experiments demonstrating that exosome treatment reduces fibrosis associated with CP. Figure 7A depicts the results of example experiments wherein the expression levels of α-SMA, a marker for fibrosis, were evaluated in pancreatic tissue sections obtained from healthy individuals and CP patients; Scale bar = 150µm. Figure 7B depicts the results of example experiments wherein the integrated density analysis revealed a significant increase in α-SMA expression in the pancreas of patients diagnosed with CP; n=3-4. Figure 7C depicts human amylase activity in serum samples collected from healthy individuals and CP patients; n=5-43. Figure 7D depicts immunofluorescence staining of the pancreas for α-SMA, after 6 weeks of TNBS injection; Scale bar = 300µm. Figure 7E depicts the results of quantifying α-SMA protein expression by determining the integrated density of pancreatic sections; n=2-5. Figure 7F depicts Masson trichrome staining showing evidence of fibrosis in control, TNBS alone, and TNBS with exosomes after 6 weeks of TNBS injection: Scale bar = 2mm, or 300µm (enlarged photos). Figure 7G depicts the fibrosis score obtained by blinded pathologist in pancreas tissues from sham control, TNBS alone or TNBS plus exosome groups 3 and 6 weeks of TNBS injections. Figure 7H depicts protein expression of TGF-β1, MMP2, and cleaved caspase 3 in the pancreas analyzed by Western blot in the control, TNBS, TNBS+iMSCs exo, and TNBS+iAAT-MSC exo groups after 6 weeks of TNBS injection. GAPDH was used as the loading control. Figures 7I and 7J depict quantification of fibrosis and C-caspase (apoptosis) protein expression by determining the intensities of the bands compared with β-Actin; n=3-4. Figure 7G and 7I bar graphs show, from left to right: control, TNBS, TNBS-iMSC exo, and TNBS-iAAT-MSC exo. Data are presented as the means ± SD. *P < 0.05, **P< 0.01, ***P< 0.001, ****P< 0.0001.  Figure 8, comprising Figures 8A-8H, depicts the results of example experiments demonstrating iMSCs and hiAAT-MSCs exosomes alleviated chronic pancreatitis pain and 7    Attorney Docket: 206085‐0139‐00WO  reduced macrophage infiltration. Figures 8A and 8B depict the results of experiments wherein mechanical sensitivity was assessed using calibrated Von Frey filaments (VFFs) with a 0.40-15 g range. Mice were tested for sensitivity on the hind paw and abdomen at 3, 5, and 6 weeks following TNBS injection. n=5-11. Figure 8A and 8B bar graphs show, from left to right: control, TNBS, TNBS-iMSC exo, and TNBS-iAAT-MSC exo. Figure 8C depicts the results of example experiments wherein the presence and intensity of CD68+ macrophages were evaluated in pancreatic tissue sections obtained from individuals with normal pancreas and patients diagnosed with CP; Bar= 150µm. Figure 8D depicts the results of example experiments demonstrating that the integrated density analysis revealed a significant increase in CD68 expression in the pancreas of patients diagnosed with CP; n=3-4. Figure 8E depicts the results of example experiments wherein CD68 protein expression was measured using Western blot in the control, TNBS, TNBS+iMSCs exo, and TNBS+iAAT-MSC exo therapy groups after 6 weeks of TNBS injection. GAPDH was used as the loading control. Figure 8F depicts the quantification of CD68 protein expression by determining the intensities of the bands compared with β-actin; n=3- 4. Figure 8G depicts the results of example experiments wherein the expression of CD68 was assessed in the DRG 6 weeks after TNBS injection. In the TNBS group, more than 50% of the DRG tissue displayed positive staining for this marker: Bar= 150µm and 75µm. Figure 8H depicts the integrated density analysis revealing a significant decrease in CD68 expression in all groups compared to the TNBS treatment alone group; n=3-4. Data are shown as the means ± SD. *P < 0.05, **P< 0.01, ***P< 0.001, ****P< 0.0001. Figure 9, comprising Figures 9A-9G, depicts the results of example experiments demonstrating that hiMSCs and hiAAT-MSCs exosomes reduce mast cell intensity and pain markers TRPV1 and c-FOS expression. Figure 9A depicts the results of example experiments wherein human pancreatic sections were stained to detect mast cells in CP patients, as indicated by yellow arrows: scale bar = 150μm and 75μm. Figure 9B depicts pancreas sections from CP patients, showing an elevated mast cell density; n=3-4. Figure 9C depicts pancreatic sections (upper line) and dorsal root ganglia (DRG) sections (bottom line) from the sham control, TNBS, and TNBS treated with exosomes, which were stained to detect mast cells. Green arrows indicate mast cells in the DRG, while red arrows indicate mast cells in the pancreas; Bar= 150µm. Figures 9D and 9E depict mast cell density in pancreas (D) and DRG (E); n=4-5 per group. Figure 9F depicts the results of example experiments demonstrating that the expression of 8    Attorney Docket: 206085‐0139‐00WO  TRPV1 and c-FOS, pain receptors associated with chronic pain, was examined in four groups' Dorsal root ganglions (DRG) after 6 weeks of TNBS injection; Scale bar = 150µm and 75µm. Figure 9G depicts the results of the integrated density analysis revealing a significant decrease in TRPV1 expression in the TNBS+hiMSC exosome receiving group compared to the TNBS treatment alone group. n=3-4. Figure 9G bar graph shows, from left to right: control, TNBS, TNBS-iMSC exo, and TNBS-iAAT-MSC exo. Data are shown as the means ± SD. *P < 0.05, **P< 0.01, ***P< 0.001, ****P< 0.0001. Figure 10, comprising Figures 10A-10I, depicts results of example experiments demonstrating that exosomes derived from hiMSCs and hiAAT-MSCs impact both behavioral response and the expression of chronic pancreatitis pain markers. Figure 10A depicts the travel pathway (indicated in red) of illustrative examples of control, TNBS-induced, and exosome treatment mice, which were recorded for 10 minutes in the open field test after a 6-week TNBS injection. The heatmap visualizations (bottom line) showed similarities to the results above. Figures 10B-10D depict graphs displaying the velocity, distance traveled, and entrance into the center area in an open-field test at 3, 5, and 6 weeks after TNBS injection, respectively; n=5-11. Figure 10B-10D bar graphs show, from left to right: control, TNBS, TNBS-iMSC exo, and TNBS-iAAT-MSC exo. At 6 weeks post-TNBS injection, dorsal root ganglia (DRG) from T9-12 were harvested. Figures 10E-10I depict the miRNA expression levels of pain markers, including (E) mRNA levels of TacR1, (F) CGRP, (G) GFR3, (H) Necab1, and (I) Necab3, evaluated using qPCR. β-actin was used as an internal control to standardize the data; n=3-8. Data presented as the means ± SD. *P < 0.05, **P< 0.01, ***P< 0.001, ****P< 0.0001. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions for treating or preventing autoimmune and inflammatory diseases. In some embodiments, the invention provides a composition comprising a membrane-enclosed vesicle from a cell, called an exosome. In some embodiments, the exosome is derived from an immortalized stem cell. In some embodiments the immortalized stem cell overexpresses Alpha-1 antitrypsin (AAT). In some embodiments, the immortalized stem cell is an immortalized mesenchymal stem cell (iMSC). In some embodiments, the exosome is derived from an iMSC overexpressing AAT (iAAT-MSC). In some embodiments, 9    Attorney Docket: 206085‐0139‐00WO  the exosome comprises AAT. In some embodiments, the exosome contains more AAT than exosomes in which the AAT genome has not been inserted. The present invention also relates to methods of treating or preventing autoimmune and inflammatory diseases using the compositions of the invention. In some embodiments, the autoimmune or inflammatory disease is selected from the group consisting of chronic pain, pancreatitis, type 1 diabetes, type 2 diabetes, sarcoidosis, islet transplantation, alpha-1 antitrypsin deficiency, and acute bacterial and viral infections including COVID-19. In some embodiments, the inflammatory disease results in chronic pain. Definitions: Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, each of the following terms has the meaning associated with it in this section. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods. “Encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an RNA (e.g., mRNA), to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (e.g., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of RNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the RNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA. 10    Attorney Docket: 206085‐0139‐00WO  A “vector” is a composition of matter which comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell. Numerous vectors are known in the art including, but not limited to, linear polynucleotides, polynucleotides associated with ionic or amphiphilic compounds, plasmids, and viruses. Thus, the term “vector” includes an autonomously replicating plasmid or a virus. The term should also be construed to include non- plasmid and non-viral compounds which facilitate transfer of nucleic acid into cells, such as, for example, polylysine compounds, liposomes, and the like. Examples of viral vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, and the like. “Expression vector” refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed. An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system. Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes), RNA, and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno- associated viruses) that incorporate the recombinant polynucleotide. “Homologous” refers to the sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. When a position in both of the two compared sequences is occupied by the same base or amino acid monomer subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percent of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared X 100. For example, if 6 of 10 of the positions in two sequences are matched or homologous then the two sequences are 60% homologous. By way of example, the DNA sequences ATTGCC and TATGGC share 50% homology. Generally, a comparison is made when two sequences are aligned to give maximum homology. As used herein, a nucleotide sequence is “substantially homologous” or “substantially identical” to any of the nucleotide sequences described herein when its nucleotide sequence has a degree of identity with respect to the original nucleotide sequence at least 60%, of at least 65%, of at least 70%, of at least 75%, of at least 80%, of at least 85%, of at least 90%, of at least 91%, 11    Attorney Docket: 206085‐0139‐00WO  of at least 92%, of at least 93%, of at least 94%, of at least 95%, of at least 96%, of at least 97%, of at least 98%, of at least 99%, or of at least 99.5%. As used herein, an amino acid sequence is “substantially homologous” or “substantially identical” to any of the amino acid sequences described herein when its amino acid sequence has a degree of identity with respect to the original amino acid sequence of at least 60%, of at least 65%, of at least 70%, of at least 75%, of at least 80%, of at least 85%, of at least 90%, of at least 91%, of at least 92%, of at least 93%, of at least 94%, of at least 95%, of at least 96%, of at least 97%, of at least 98%, of at least 99%, or of at least 99.5%.The identity between two sequences can be determined by using the BLASTP algorithm for amino acid sequences or the BLASTN algorithm for nucleotide sequences (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, Md.20894, Altschul, S., et al., J. Mol. Biol.215: 403-410 (1990)). The term “variant” as used herein with respect to a nucleic acid refers (i) a portion or fragment of a referenced nucleotide sequence; (ii) the complement of a referenced nucleotide sequence or portion thereof; (iii) a nucleic acid that is substantially identical to a referenced nucleic acid or the complement thereof; or (iv) a nucleic acid that hybridizes under stringent conditions to the referenced nucleic acid, complement thereof, or a sequence substantially identical thereto. A variant may be a nucleic acid sequence that is substantially identical over the full length of the full gene sequence or a fragment thereof. The nucleic acid sequence may be 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical over the full length of the gene sequence or a fragment thereof. The term “variant” as used with respect to a peptide or polypeptide refers to a peptide or polypeptide that differs in amino acid sequence by the insertion, deletion, or conservative substitution of amino acids, but retain at least one biological activity. Variant may also refer to a protein with an amino acid sequence that is substantially identical to a referenced protein with an amino acid sequence that retains at least one biological activity. A conservative substitution of an amino acid, i.e., replacing an amino acid with a different amino acid of similar properties (e.g., hydrophilicity, degree and distribution of charged regions) is recognized in the art as typically involving a minor change. These minor changes can be identified, in part, by considering the hydropathic index of amino acids, as understood in the art. (Kyte et al., 1982, J. Mol. Biol. 157:105-132). The hydropathic index of an amino acid is based on a consideration of its 12    Attorney Docket: 206085‐0139‐00WO  hydrophobicity and charge. It is known in the art that amino acids of similar hydropathic indexes can be substituted and still retain protein function. In one aspect, amino acids having hydropathic indexes of ±2 are substituted. The hydrophilicity of amino acids can also be used to reveal substitutions that would result in proteins retaining biological function. A consideration of the hydrophilicity of amino acids in the context of a peptide permits calculation of the greatest local average hydrophilicity of that peptide, a useful measure that has been reported to correlate well with antigenicity and immunogenicity. U.S. Patent No.4,554,101, incorporated fully herein by reference. Substitution of amino acids having similar hydrophilicity values can result in peptides retaining biological activity, as is understood in the art. Substitutions may be performed with amino acids having hydrophilicity values within ±2 of each other. Both the hydrophobicity index and the hydrophilicity value of amino acids are influenced by the particular side chain of that amino acid. Consistent with that observation, amino acid substitutions that are compatible with biological function are understood to depend on the relative similarity of the amino acids, and particularly the side chains of those amino acids, as revealed by the hydrophobicity, hydrophilicity, charge, size, and other properties. A variant may be an amino acid sequence that is substantially identical over the full length of the amino acid sequence or fragment thereof. The amino acid sequence may be 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical over the full length of the amino acid sequence or a fragment thereof. “Fragment” as used herein, refers to a nucleic acid sequence or amino acid sequence. In one embodiment, the fragment is a nucleic acid sequence that encodes a fragment of a protein. The fragment may be a fragment of a protein which retains its biologic activity. “Fragment” may also mean a fragment of a nucleic acid molecule. The fragments can be DNA fragments of the various nucleotide sequences that encode protein fragments. The fragments can be DNA fragments of DNA sequences having homology to at least one of the various nucleotide sequences that encode protein fragments set forth below. A fragment of a protein or nucleic acid may be 100% identical to the full length except missing at least one amino acid / nucleic acid from the N and / or C terminal, in each case with or without signal peptides and / or a methionine at position 1. Fragments may comprise 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% 13    Attorney Docket: 206085‐0139‐00WO  or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more percent of the length of the particular full-length protein or nucleic acid, excluding any heterologous signal peptide added. The fragment may comprise a fragment of a polypeptide that is 95% or more, 96% or more, 97% or more, 98% or more or 99% or more identical to the protein or nucleic acid and additionally comprise an N terminal methionine or heterologous signal peptide which is not included when calculating percent identity. Fragments may further comprise an N terminal methionine and / or a signal peptide such as an immunoglobulin signal peptide, for example an IgE or IgG signal peptide. The N terminal methionine and / or signal peptide may be linked to a fragment of an antibody. A fragment of a nucleic acid sequence may be 100% identical to the full length except missing at least one nucleotide from the 5' and / or 3' end. When the nucleic acid sequence encodes a protein, the fragment of the nucleic acid sequence may be, in each case with or without sequences encoding signal peptides and / or a methionine at position 1. Fragments may comprise 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more percent of the length of the particular full length coding sequence, excluding any heterologous signal peptide added. The fragment may comprise a fragment that encode a polypeptide that is 95% or more, 96% or more, 97% or more, 98% or more or 99% or more identical to the antibody and additionally optionally comprise sequence encoding an N terminal methionine or heterologous signal peptide which is not included when calculating percent identity. Fragments may further comprise coding sequences for an N terminal methionine and / or a signal peptide such as an immunoglobulin signal peptide, for example an IgE or IgG signal peptide. The coding sequence encoding the N terminal methionine and / or signal peptide may be linked to a fragment of coding sequence. “Isolated” as used herein means (1) altered or removed from the natural state and / or (2) separated from at least some of the components with which it was associated when initially produced (whether in nature and / or in an experimental setting) and / or otherwise previously associated, and / or (3) designed, produced, prepared, and / or manufactured by the hand of man. In some embodiments, a nucleic acid or a peptide naturally present in a living subject is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the 14    Attorney Docket: 206085‐0139‐00WO  coexisting materials of its natural state is “isolated.” An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell. In the context of the present disclosure, the following abbreviations for the commonly occurring nucleosides (nucleobase bound to ribose or deoxyribose sugar via N-glycosidic linkage) are used. “A” refers to adenosine, “C” refers to cytidine, “G” refers to guanosine, “T” refers to thymidine, and “U” refers to uridine. Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. Nucleotide sequences that encode proteins and RNA may include introns. The phrase nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s). In addition, the nucleotide sequence may contain modified nucleosides that are capable of being translated by translational machinery in a cell. The term “operably linked” refers to functional linkage between a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter. For example, a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA or RNA sequences are contiguous and, where necessary to join two protein coding regions, in the same reading frame. The term “polynucleotide” as used herein is defined as a chain of nucleotides. Furthermore, nucleic acids are polymers of nucleotides. Thus, nucleic acids and polynucleotides as used herein are interchangeable. One skilled in the art has the general knowledge that nucleic acids are polynucleotides, which can be hydrolyzed into the monomeric “nucleotides.” The monomeric nucleotides can be hydrolyzed into nucleosides. As used herein polynucleotides include, but are not limited to, all nucleic acid sequences which are obtained by any means available in the art, including, without limitation, recombinant means, i.e., the cloning of nucleic acid sequences from a recombinant library or a cell genome, using ordinary cloning technology and PCR™, and the like, and by synthetic means. 15    Attorney Docket: 206085‐0139‐00WO  The term “polyribonucleotide” as used herein is defined as a chain of ribonucleotides. Furthermore, nucleic acids are polymers of ribonucleotides. Thus, nucleic acids and polyribonucleotides as used herein are interchangeable. One skilled in the art has the general knowledge that nucleic acids are polyribonucleotides, which can be hydrolyzed into the monomeric “nucleotides.” The monomeric nucleotides can be hydrolyzed into nucleosides. As used herein polynucleotides include, but are not limited to, all nucleic acid sequences which are obtained by any means available in the art, including, without limitation, recombinant means, i.e., the cloning of nucleic acid sequences from a recombinant library or a cell genome, using ordinary cloning technology and PCR™, and the like, and by synthetic means. In some embodiments, an RNA molecule, polyribonucleotide, polynucleotide or nucleic acid of the present disclosure is a “nucleoside-modified nucleic acid,” which refers to a nucleic acid comprising at least one modified nucleoside. A “modified nucleoside” refers to a nucleoside with a modification. For example, over one hundred different nucleoside modifications have been identified in RNA (Rozenski, et al., 1999, The RNA Modification Database: 1999 update. Nucl Acids Res 27: 196-197). As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof. The term “promoter” as used herein is defined as a DNA sequence recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence. By way of one non-limiting example, a 16    Attorney Docket: 206085‐0139‐00WO  promoter that is recognized by bacteriophage RNA polymerase and is used to generate the RNA by in vitro transcription. The terms “subject,” “patient,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In some non-limiting embodiments, the patient, subject or individual is a mammal, bird, poultry, cattle, pig, horse, sheep, ferret, primate, dog, cat, guinea pig, rabbit, bat, or human. A “disease” is a state of health of a subject wherein the subject cannot maintain homeostasis, and wherein if the disease is not ameliorated then the subject’s health continues to deteriorate. In contrast, a “disorder” in a subject is a state of health in which the subject is able to maintain homeostasis, but in which the subject’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the subject’s state of health. By the term “modulating,” as used herein, means mediating a detectable increase or decrease in the level of a response in a subject compared with the level of a response in the subject in the absence of a treatment or compound, and / or compared with the level of a response in an otherwise identical but untreated subject. The term encompasses perturbing and / or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, such as a human. To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject. An “effective amount” as used herein, means an amount which provides a therapeutic or prophylactic benefit. The term “therapeutic” as used herein means a treatment and / or prophylaxis. A therapeutic effect is obtained by suppression, diminution, remission, prevention, or eradication of at least one sign or symptom of a disease or disorder. The term “therapeutically effective amount” refers to the amount of the subject compound that will elicit the biological or medical response of a tissue, system, or subject that is being sought by the researcher, veterinarian, medical doctor or other clinician. The term “therapeutically effective amount” includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the signs or 17    Attorney Docket: 206085‐0139‐00WO  symptoms of the disorder or disease being treated. The therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated. The term “transfected” or “transformed” or “transduced” as used herein refers to a process by which exogenous nucleic acid is transferred or introduced into the host cell. A “transfected” or “transformed” or “transduced” cell is one which has been transfected, transformed or transduced with exogenous nucleic acid. The cell includes the primary subject cell and its progeny. The phrase “under transcriptional control” or “operatively linked” with reference to a promoter as used herein means that the promoter is in the correct location and orientation in relation to a polynucleotide to control the initiation of transcription by RNA polymerase and expression of the polynucleotide. As used herein, “additional ingredients” include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other “additional ingredients” which may be included in the pharmaceutical compositions of the present disclosure are known in the art and described, for example in Remington’s Pharmaceutical Sciences (1985, Genaro, ed., Mack Publishing Co., Easton, PA), which is incorporated herein by reference. In the context of the present disclosure, the words “exosome” and “extracellular vesicle” (EV) are used interchangeably. The invention is intended to cover both of these small vesicles, understanding that exosomes are a subtype of extracellular vesicles. Some of the biologic activity in the compositions disclosed herein may be in EVs different in size from exosomes. Further, the EV may have biologic activities that depend on the mixture of exosomes and non-exosomal extracellular vesicles. Ranges: throughout this disclosure, various aspects of the present disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of 18    Attorney Docket: 206085‐0139‐00WO  the present disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. As used herein, the term “exosome” refers to a type of extracellular membrane-enclosed vesicle, which contains molecular constituents of the cell in which it was secreted from. Exosomes are formed when secreted by the cells in which it originated from and contains, for example, cell-specific proteins, lipids, and genetic materials. Exosomes are found in many biological fluids, including blood, urine, and cell culture medium. As used herein, a mesenchymal stem cell is equivalent in all form and function to a mesenchymal stromal cell. Both of these names transition often in the medical and scientific literature and refer to a cell with multilineage potential. Description The present invention relates to compositions for treating or preventing autoimmune and inflammatory disease. In some embodiments, the invention provides a composition comprising an extracellular vesicle. In some embodiments, the invention provides a composition comprising a membrane enclosed vesicle from a cell, called an exosome. In some embodiments, the exosome is derived from an immortalized stem cell. In some embodiments the immortalized stem cell overexpresses Alpha-1 antitrypsin (AAT). In some embodiments, the immortalized stem cell is an immortalized mesenchymal stem cell (iMSC). In some embodiments, the exosome is derived from an iMSC overexpressing AAT (iAAT-MSC). In some embodiments, the exosome comprises AAT. The present invention also relates to methods of treating or preventing autoimmune and inflammatory diseases using the compositions of the invention. In some embodiments, the autoimmune or inflammatory disease is selected from the group consisting of chronic pain, pancreatitis, type 1 diabetes, type 2 diabetes, sarcoidosis, islet transplantation, alpha-1 antitrypsin deficiency, and acute bacterial and viral infections including COVID-19. In some embodiments, the inflammatory disease results in chronic pain. 19    Attorney Docket: 206085‐0139‐00WO  Composition In one embodiment, the composition comprises an exosome. Exosomes are small in size with a range of diameters between about 2 nm and about 200 nm. In some embodiments, exosomes have a range of size of diameters, such as between 100 nm and 200 nm. The size of an exosome may be determined by various means known in the art. For example, the size of the exosome may be determined by size fractionation and filtration through a membrane with the relevant size cut-off and determined by tracking segregation of component proteins with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) or by a biological assay. Alternatively, the size may also be determined by electron microscopy. In some embodiments, the composition comprising an exosome may be an autologous composition. That is, the exosome to be administered to a subject is obtained from said subject or cultured from said subject's cells. In one embodiment, cells from a human subject may be harvested and cultured. The cultured human cells may be induced, stimulated, or engineered to secrete an effective amount of exosome necessary for therapeutic use. In one embodiment, cultured human cells may be induced, stimulated, or engineered to secrete an effective amount of exosomes. In some embodiments, the composition comprising an exosome may be an allogenic composition. That is, the exosome to be administered to a subject is obtained from a different subject, but in the same group of species. For example, in a human subject, the exosome is obtained or cultured from a different individual than those receiving the exosome for therapeutic use. In some embodiments, the composition comprising an exosome may be xenogenic composition. That is, the exosome to be administered to a subject is obtained from an organism of a different species. For example, cells from a donor organism is harvested and cultured to induce, stimulate, or engineer to produce an effective exosome composition. In some embodiments, the exosomes of the invention are derived from immortalized stem cells. Examples of stem cells that may be immortalized include mesenchymal stem / stromal cells, umbilical cord or placental derived stem cells, hematopoietic stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, epithelial stem cells, and skin stem cells. In some embodiments, the immortalized stem cells are mesenchymal stem cells. 20    Attorney Docket: 206085‐0139‐00WO  In some embodiments, stem cells are immortalized by contacting the stem cell with an immortalization factor or a nucleic acid molecule encoding an immortalization factor. In certain embodiments, the immortalization factor increases the proliferative capacity of the cells. In some embodiments, the immortalization factor is a viral oncogene, including but not limited to, SV40 large T antigen (SV40LT), HPV-16 E6 and E7, and EBV or a fragment or variant thereof. In one embodiment, the immortalization factor is telomerase reverse transcriptase protein (TERT), or a fragment or variant thereof. In certain embodiments, the immortalization factor comprises an inhibitor of a tumor suppressor, such as an inhibitor of p53 or Rb, or a fragment or variant thereof. In certain embodiments, the immortalization factor comprises an oncogene, including but not limited to Ras, c-Myc T58A, Bmi1, cdk4, and cyclin D, or a fragment or variant thereof. In some embodiments, exosomes are prepared and / or isolated from immortalized stem cells that are modified to overexpress AAT or a variant or fragment thereof. For example, in certain embodiments, the immortalized stem cells are genetically modified to over express AAT by introduction of an exogenous nucleic acid molecule encoding AAT. In some embodiments, the immortalized stem cells overexpress AAT. Introduction to or overexpression of a gene in a stem cell line can be achieved by any method known in the art. Methods of introducing and expressing genes into a cell are known in the art. In brief summary, the expression of natural or synthetic nucleic acids encoding a protein is typically achieved by operably linking a nucleic acid encoding the protein or portions thereof to a promoter, and incorporating the construct into an expression vector. The vectors to be used are suitable for replication and, optionally, integration in eukaryotic cells. Typical vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulation of the expression of the desired nucleic acid sequence. The nucleic acid can be cloned into a number of types of vectors. For example, the nucleic acid can be cloned into a vector including, but not limited to a plasmid, a phagemid, a phage derivative, an animal virus, and a cosmid. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors. Further, the vector may be provided to a cell in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al. (2012, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York), and in other virology and molecular biology manuals. Viruses, which are useful as vectors include, but 21    Attorney Docket: 206085‐0139‐00WO  are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers, (e.g., WO 01 / 96584; WO 01 / 29058; and U.S. Pat. No.6,326,193). A number of viral based systems have been developed for gene transfer into mammalian cells. For example, retroviruses provide a convenient platform for gene delivery systems. A selected gene can be inserted into a vector and packaged in retroviral particles using techniques known in the art. The recombinant virus can then be isolated and delivered to cells of the subject either in vivo or ex vivo. A number of retroviral systems are known in the art. In some embodiments, adenovirus vectors are used. A number of adenovirus vectors are known in the art. In one embodiment, lentivirus vectors are used. For example, vectors derived from retroviruses such as the lentivirus are suitable tools to achieve long-term gene transfer since they allow long-term, stable integration of a transgene and its propagation in daughter cells. Lentiviral vectors have the added advantage over vectors derived from onco-retroviruses such as murine leukemia viruses in that they can transduce non- proliferating cells, such as hepatocytes. They also have the added advantage of low immunogenicity. In one embodiment, the composition includes a vector derived from an adeno- associated virus (AAV). Adeno-associated viral (AAV) vectors have become powerful gene delivery tools for the treatment of various disorders. AAV vectors possess a number of features that render them ideally suited for gene therapy, including a lack of pathogenicity, minimal immunogenicity, and the ability to transduce postmitotic cells in a stable and efficient manner. Expression of a particular gene contained within an AAV vector can be specifically targeted to one or more types of cells by choosing the appropriate combination of AAV serotype, promoter, and delivery method. In some embodiments, the vector also includes conventional control elements which are operably linked to the transgene in a manner which permits its transcription, translation and / or expression in a cell transfected with the plasmid vector or infected with the virus produced by the invention. As used herein, “operably linked” sequences include both expression control sequences that are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control the gene of interest. Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient 22    Attorney Docket: 206085‐0139‐00WO  RNA processing signals such as splicing and polyadenylation (polyA) signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance secretion of the encoded product. A great number of expression control sequences, including promoters which are native, constitutive, inducible and / or tissue-specific, are known in the art and may be utilized. Additional promoter elements, e.g., enhancers, regulate the frequency of transcriptional initiation. Typically, these are located in the region 30-110 bp upstream of the start site, although a number of promoters have recently been shown to contain functional elements downstream of the start site as well. The spacing between promoter elements frequently is flexible, so that promoter function is preserved when elements are inverted or moved relative to one another. In the thymidine kinase (tk) promoter, the spacing between promoter elements can be increased to 50 bp apart before activity begins to decline. Depending on the promoter, it appears that individual elements can function either cooperatively or independently to activate transcription. One example of a suitable promoter is the immediate early cytomegalovirus (CMV) promoter sequence. This promoter sequence is a strong constitutive promoter sequence capable of driving high levels of expression of any polynucleotide sequence operatively linked thereto. Another example of a suitable promoter is Elongation Growth Factor -1α (EF-1α). However, other constitutive promoter sequences may also be used, including, but not limited to the simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the hemoglobin promoter, and the creatine kinase promoter. Further, the invention should not be limited to the use of constitutive promoters. Inducible promoters are also contemplated as part of the invention. The use of an inducible promoter provides a molecular switch capable of turning on expression of the polynucleotide sequence which it is operatively linked when such expression is desired, or turning off the expression when expression is not desired. Examples of inducible promoters include, but are not limited to a metallothionine promoter, a glucocorticoid promoter, a progesterone promoter, and a tetracycline promoter. 23    Attorney Docket: 206085‐0139‐00WO  Enhancer sequences found on a vector also regulates expression of the gene contained therein. Typically, enhancers are bound with protein factors to enhance the transcription of a gene. Enhancers may be located upstream or downstream of the gene it regulates. Enhancers may also be tissue-specific to enhance transcription in a specific cell or tissue type. In one embodiment, the vector of the present invention comprises one or more enhancers to boost transcription of the gene present within the vector. In order to assess the expression of a protein, the expression vector to be introduced into a cell can also contain either a selectable marker gene or a reporter gene or both to facilitate identification and selection of expressing cells from the population of cells sought to be transfected or infected through viral vectors. In other aspects, the selectable marker may be carried on a separate piece of DNA and used in a co-transfection procedure. Both selectable markers and reporter genes may be flanked with appropriate regulatory sequences to enable expression in the host cells. Useful selectable markers include, for example, antibiotic-resistance genes, such as neo and the like. Reporter genes are used for identifying potentially transfected cells and for evaluating the functionality of regulatory sequences. In general, a reporter gene is a gene that is not present in or expressed by the recipient organism or tissue and that encodes a polypeptide whose expression is manifested by some easily detectable property, e.g., enzymatic activity. Expression of the reporter gene is assayed at a suitable time after the DNA has been introduced into the recipient cells. Suitable reporter genes may include genes encoding luciferase, beta-galactosidase, chloramphenicol acetyl transferase, secreted alkaline phosphatase, or the green fluorescent protein gene (e.g., Ui-Tei et al., 2000 FEBS Letters 479: 79-82). Suitable expression systems are well known and may be prepared using known techniques or obtained commercially. In general, the construct with the minimal 5' flanking region showing the highest level of expression of reporter gene is identified as the promoter. Such promoter regions may be linked to a reporter gene and used to evaluate agents for the ability to modulate promoter-driven transcription. In the context of an expression vector, the vector can be readily introduced into a host cell, e.g., mammalian, bacterial, yeast, or insect cell by any method in the art. For example, the expression vector can be transferred into a host cell by physical, chemical, or biological means. Physical methods for introducing a peptide or protein into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and 24    Attorney Docket: 206085‐0139‐00WO  the like. Methods for producing cells comprising vectors and / or exogenous nucleic acids are well-known in the art. See, for example, Sambrook et al. (2012, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). Biological methods for introducing a peptide or protein of interest into a host cell include the use of DNA and RNA vectors. Viral vectors, and especially retroviral vectors, have become the most widely used method for inserting genes into mammalian, e.g., human cells. Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, and the like. See, for example, U.S. Pat. Nos.5,350,674 and 5,585,362. Chemical means for introducing a peptide or protein into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle). In the case where a non-viral delivery system is utilized, an exemplary delivery vehicle is a liposome. The use of lipid formulations is contemplated for the introduction of the nucleic acids into a host cell (in vitro, ex vivo or in vivo). In another aspect, the nucleic acid may be associated with a lipid. The nucleic acid associated with a lipid may be encapsulated in the aqueous interior of a liposome, interspersed within the lipid bilayer of a liposome, attached to a liposome via a linking molecule that is associated with both the liposome and the oligonucleotide, entrapped in a liposome, complexed with a liposome, dispersed in a solution containing a lipid, mixed with a lipid, combined with a lipid, contained as a suspension in a lipid, contained or complexed with a micelle, or otherwise associated with a lipid. Lipid, lipid / DNA or lipid / expression vector associated compositions are not limited to any particular structure in solution. For example, they may be present in a bilayer structure, as micelles, or with a “collapsed” structure. They may also simply be interspersed in a solution, possibly forming aggregates that are not uniform in size or shape. Lipids are fatty substances which may be naturally occurring or synthetic lipids. For example, lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes. Lipids suitable for use can be obtained from commercial sources. For example, dimyristyl phosphatidylcholine (“DMPC”) can be obtained from Sigma, St. Louis, MO; dicetyl phosphate 25    Attorney Docket: 206085‐0139‐00WO  (“DCP”) can be obtained from K & K Laboratories (Plainview, NY); cholesterol (“Choi”) can be obtained from Calbiochem-Behring; dimyristyl phosphatidylglycerol (“DMPG”) and other lipids may be obtained from Avanti Polar Lipids, Inc. (Birmingham, AL). Stock solutions of lipids in chloroform or chloroform / methanol can be stored at about -20°C. Chloroform is used as the only solvent since it is more readily evaporated than methanol. “Liposome” is a generic term encompassing a variety of single and multilamellar lipid vehicles formed by the generation of enclosed lipid bilayers or aggregates. Liposomes can be characterized as having vesicular structures with a phospholipid bilayer membrane and an inner aqueous medium. Multilamellar liposomes have multiple lipid layers separated by aqueous medium. They form spontaneously when phospholipids are suspended in an excess of aqueous solution. The lipid components undergo self-rearrangement before the formation of closed structures and entrap water and dissolved solutes between the lipid bilayers (Ghosh et al., 1991 Glycobiology 5: 505-10). However, compositions that have different structures in solution than the normal vesicular structure are also encompassed. For example, the lipids may assume a micellar structure or merely exist as nonuniform aggregates of lipid molecules. Also contemplated are lipofectamine- nucleic acid complexes. Regardless of the method used to introduce exogenous nucleic acids into a host cell, in order to confirm the presence of the recombinant DNA sequence in the host cell, a variety of assays may be performed. Such assays include, for example, “molecular biological” assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR; “biochemical” assays, such as detecting the presence or absence of a particular polypeptide, e.g., by immunological means (ELISAs and Western blots) or by assays described herein to identify agents falling within the scope of the invention. In some embodiments, the exosomes are derived from mesenchymal stem cells that are immortalized by SV40LT. The resulting immortalized mesenchymal stem cells retain characteristics of mesenchymal stem cells in earlier passage. In some embodiments, the immortalized mesenchymal stem cells (iMSCs) are transfected with a lentiviral vector comprising a nucleic acid sequence encoding AAT. In some embodiments, the iMSCs overexpress AAT. In some embodiments, exosomes derived from iMSCs overexpressing AAT comprise AAT. In some embodiments, exosomes derived from iMSCs overexpressing AAT comprise more than usual amounts of AAT, admixed with other exosomal contents. 26    Attorney Docket: 206085‐0139‐00WO  Different physical or biological properties of the exosome may be used to separate the exosome from other components of immortalized stem cells. Exosomes may be isolated for example based on molecular weight, size, shape, composition or biological activity. For example, centrifugation or ultracentrifugation may be used for separation of the exosomes. The monitoring of the exosomes during preparation and / or separation processes may be carried out using, for example, light scattering, refractive index, fluorescently labeled antibodies, dynamic light scattering or UV-visible detectors. In some embodiments, exosomes may be isolated by commercially available reagents known in the art. Pharmaceutical Compositions In some embodiments, the invention provides a pharmaceutical composition comprising an exosome derived from an immortalized stem cell modified to express AAT, as described elsewhere herein. The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single- or multi-dose unit. Although the description of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as non-human primates, cattle, pigs, horses, sheep, cats, and dogs. Pharmaceutical compositions that are useful in the methods of the invention may be prepared, packaged, or sold in formulations suitable for ophthalmic, oral, rectal, vaginal, parenteral, topical, pulmonary, intranasal, buccal, intravenous, intracerebroventricular, 27    Attorney Docket: 206085‐0139‐00WO  intradermal, intramuscular, or another route of administration. Other contemplated formulations include projected nanoparticles, liposomal preparations, resealed erythrocytes containing the active ingredient, and immunogenic-based formulations. A pharmaceutical composition of the invention may be prepared, packaged, or sold in bulk, as a single unit dose, or as a plurality of single unit doses. As used herein, a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient, which would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient. In addition to the active ingredient, a pharmaceutical composition of the invention may further comprise one or more additional pharmaceutically active agents. Controlled- or sustained-release formulations of a pharmaceutical composition of the invention may be made using conventional technology. As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, intraocular, intravitreal, subcutaneous, intraperitoneal, intramuscular, intradermal, intrasternal injection, intratumoral, intravenous, intracerebroventricular and kidney dialytic infusion techniques. Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a 28    Attorney Docket: 206085‐0139‐00WO  form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e. powder or granular) form for reconstitution with a suitable vehicle (e.g. sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition. The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer's solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer systems. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt. A pharmaceutical composition of the invention may be prepared, packaged, or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, In certain embodiments, the formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder or using a self-propelling 29    Attorney Docket: 206085‐0139‐00WO  solvent / powder-dispensing container such as a device comprising the active ingredient dissolved or suspended in a low-boiling propellant in a sealed container. In certain embodiments, such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. In certain embodiments, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. In certain embodiments, dry powder compositions include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form. Low boiling propellants generally include liquid propellants having a boiling point of below 65°F at atmospheric pressure. Generally, the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic or solid anionic surfactant or a solid diluent (in certain instances having a particle size of the same order as particles comprising the active ingredient). Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of a formulation for parenteral administration, the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition. The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. 30    Attorney Docket: 206085‐0139‐00WO  Such sterile injectable formulations may be prepared using a non-toxic parenterally-acceptable diluent or solvent, such as water or 1,3-butane diol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer’s solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations that are useful include those that comprise the active ingredient in microcrystalline form, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt. As used herein, “additional ingredients” include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other “additional ingredients” which may be included in the pharmaceutical compositions of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (1985, Genaro, ed., Mack Publishing Co., Easton, PA), which is incorporated herein by reference. Immortalized Stem Cells In some embodiments, the invention relates to a cell or cell population. In one embodiment, the cell or cell population comprises one or more stem cells that are immortalized and modified to express AAT. In some embodiments, the stem cells are mesenchymal stem cells. In some embodiments, the population of stem cells are immortalized by contacting the stem cell with an immortalization factor or a nucleic acid molecule encoding an immortalization factor described elsewhere herein. In some embodiments, the immortalized stem cells are modified to express AAT or a variant or fragment thereof. In certain embodiments, the immortalized stem cells are genetically modified to express AAT by introduction of an exogenous nucleic acid molecule encoding AAT. 31    Attorney Docket: 206085‐0139‐00WO  In some embodiments, the immortalized stem cells are transfected with a lentiviral vector comprising a nucleic acid molecule encoding AAT. In some embodiments, the immortalized stem cells are mesenchymal stem cells that are immortalized by SV40LT. Methods of Deriving Exosomes In some embodiments, the invention relates to methods of deriving exosomes from a population of immortalized stem cells modified to express AAT. In some embodiments, the immortalized stem cells are mesenchymal stem cells. In certain embodiments, the method comprises the steps of obtaining a stem cell, immortalizing the stem cell, modifying the stem cell to express AAT, and isolating exosomes derived from the immortalized stem cell expressing AAT. In one embodiment, the step of immortalizing the stem cell comprises contacting the stem cell with an immortalization factor described elsewhere herein, or a fragment or variant thereof. In some embodiments, the immortalization factor is SV40LT, or a fragment or variant thereof. In one embodiment, the step of modifying the stem cell comprises contacting the cell with an exogenous nucleic acid molecule encoding AAT, or a fragment or variant thereof. In some embodiments, the step of modifying the stem cell comprises contacting the cell with a lentiviral vector comprising a nucleic acid sequence encoding AAT, or a fragment or variant thereof. In one embodiment, the step of isolating exosomes comprises culturing 70-80% confluence of the immortalized stem cells expressing AAT, collecting the cell culture medium after 48 hours, and harvesting the exosomes. In some embodiments, the exosomes are harvested by centrifuging the medium at 2,000g for 30 minutes and adding total exosome isolation reagent, followed by ultracentrifugation at 10,000g for 1 hour at 4°C. Methods of Treatment The present invention relates to methods of treating or preventing autoimmune and inflammatory diseases using the compositions of the invention. In some embodiments, the autoimmune or inflammatory disease is selected from the group consisting of chronic pain, chronic pancreatitis, type 1 diabetes, type 2 diabetes, sarcoidosis, islet transplantation, alpha-1 antitrypsin deficiency, and acute bacterial and viral infections including COVID-19.. In some embodiments, the inflammatory disease results in chronic pain. 32    Attorney Docket: 206085‐0139‐00WO  In some embodiments, the invention is a method of administering to a subject a composition comprising at least one exosome derived from immortalized stem cells modified to express AAT. In some embodiments, the immortalized stem cells are immortalized mesenchymal stem cells modified to express AAT (iAAT-MSCs). In one embodiment, the composition is administered to a subject having an autoimmune or inflammatory disease. In one embodiment, the composition is administered to a subject at risk for developing an autoimmune or inflammatory disease. The therapeutic and prophylactic methods of the invention thus encompass the use of pharmaceutical compositions comprising at least one exosome derived from iAAT-MSCs. The pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of from 1 ng / kg / day and 100 mg / kg / day. In one embodiment, the invention envisions administration of a dose, which results in a concentration of the compound of the present invention from 10 nM and 10 µM in a mammal. Typically, dosages which may be administered in a method of the invention to a mammal, such as a human, range in amount from 0.01 μg to about 50 mg per kilogram of body weight of the mammal, while the precise dosage administered will vary depending upon any number of factors, including but not limited to, the type of mammal and type of disease state being treated, the age of the mammal and the route of administration. In certain embodiments, the dosage of the composition will vary from about 0.1 μg to about 10 mg per kilogram of body weight of the mammal. In certain embodiments, the dosage will vary from about 1 μg to about 1 mg per kilogram of body weight of the mammal. The composition may be administered to a mammal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. The frequency of the dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, the type and age of the mammal, etc. It will be appreciated that the composition of the invention may be administered to a subject in conjunction with another agent. In some embodiments, the invention provides methods for reducing symptoms associated with autoimmune and inflammatory diseases. For example, the invention provides methods for reducing inflammation (by reducing mast cell or macrophage infiltration, for example), reducing 33    Attorney Docket: 206085‐0139‐00WO  necrosis, suppressing ferroptosis (iron accumulation) and autophagy, enhancing antioxidant pathways, reducing fibrosis, and alleviating pain (by reducing mast cell or macrophage infiltration, for example). In some embodiments, the invention provides methods for changing the macrophage phenotype to be less inflammatory and more likely to resolve inflammation and pain pathways. In some embodiments, the invention provides methods for reducing symptoms associated with chronic pancreatitis. For example, the invention provides methods for reducing inflammation of the pancreas (by reducing mast cell or macrophage infiltration of the pancreas, for example), reducing necrosis of the pancreas, suppressing ferroptosis and autophagy in pancreatic cells, enhancing antioxidant pathways in the pancreas, reducing pancreatic fibrosis, and alleviating pain (by reducing mast cell or macrophage infiltration of the pancreas, for example). EXPERIMENTAL EXAMPLES Example 1: Exosomes derived from immortalized alpha-1 antitrypsin overexpressing mesenchymal stem / stromal cells: implications for suppressing ferroptosis, fibrosis and pain in chronic pancreatitis The present disclosure is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only and are not intended to be limiting unless otherwise specified. Thus, the present disclosure should in no way be construed as being limited to the following examples, but rather should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present disclosure, and practice the claimed methods. The following working examples therefore are not to be construed as limiting in any way the remainder of the disclosure. Mesenchymal stem / stromal cell (MSC) exosomes are small extracellular vesicles released by MSCs that have recently gained considerable attention. Exosomes contain a diverse range of bioactive molecules, including proteins (enzymes, transcription factors, extracellular matrix proteins, receptors), nucleic acids (mtDNA, ssDNA, dsDNA, mRNA, and miRNA), and lipids, 34    Attorney Docket: 206085‐0139‐00WO  which contribute to their therapeutic effects. MSC exosomes have demonstrated therapeutic potential in various regenerative medicine and tissue engineering fields by regulating cellular processes and facilitating intercellular communication (C. Thery et al., Nat Rev Immunol 2, 569- 579 (2002); S. Nikfarjam et al., J Transl Med 18, 449 (2020)). Exosomes derived from MSCs have been investigated for their diagnostic and therapeutic capabilities in addressing the pathological processes associated with diabetes, respiratory diseases, and cardiovascular diseases (M. Yu et al., Stem Cell Res Ther 11, 350 (2020); M. J. Zargar et al., Stem Cell Res Ther 13, 194 (2022); X. Chen, Q. Luo, Ann Transl Med 10, 372 (2022)). The cargo of bioactive molecules within the MSC exosome, such as growth factors and anti-inflammatory agents, plays a vital role in their therapeutic effects on damaged tissues (S. Gatti et al., Nephrol Dial Transplant 26, 1474- 1483 (2011)). Moreover, MSC exosomes exhibit anti-inflammatory properties, modulating the immune response and reducing tissue inflammation in pancreatic cancers (S. P. Papadakos et al., Int J Mol Sci 23 (2022)). In the context of CP, using exosomes derived from MSCs shows significant promise for diagnostic applications (L. Han et al., Stem Cell Res Ther 13, 153 (2022)). Nevertheless, research is required to elucidate the precise mechanisms and optimize the application of MSC exosomes in treating pancreatic disorders, particularly CP. One advantage of using MSC-exosomes as a therapeutic alternative to cell therapies is that manufacturing is simplified for larger-scale interventions. Although MSCs can be genetically engineered, exosomes from these cells can be assayed to ensure the cellular products of choice are appropriately expressed. MSCs have been generated to overexpress human alpha-1 antitrypsin (AAT), a serine protease inhibitor that is central in reducing inflammation and mitigating oxidative stress imbalance (L. Song et al., Stem Cells Transl Med 10, 320-331 (2021); M. Koulmanda et al., Proc. Natl. Acad. Sci.105, 16242–16247 (2008)). Furthermore, using immortalized cell lines can lead to the generation of infinitely expandable clonal MSCs (T. M. Liu et al., Stem Cells Dev 22, 268-278 (2013)), thereby enhancing reliable and reproducible production of therapeutic exosomes. Exosomes from immortalized human AAT-engineered MSCs (iAAT-MSCs) were characterized herein using exosomes from normal MSCs as controls. The expression levels of miRNAs and mRNAs, along with their predicted target genes, in these exosomes were analyzed, and their potential biological functions were explored using bioinformatic analyses. Furthermore, differential expression markers between CP patients and normal individuals were analyzed while 35    Attorney Docket: 206085‐0139‐00WO  exploring exosome’s therapeutic effects in an in vivo TNBS-induced CP mouse model. The effects of iAAT-MSCs on pancreatic cell death, fibrosis and pain were evaluated. Ferroptosis was identified as a major type of cell death in CP mice and possibly in CP patients. Therapeutic effects of iAAT-MSC exosomes in suppressing ferroptosis, fibrosis, and pain in the TNBS- induced mouse model of CP were also shown. Characterization of iAAT-MSC exosomes: Human MSCs and AAT-MSCs were immortalized by SV40LT transduction to generate immortalized cells referred to as “iMSCs’ and “iAAT-MSCs”. Immortalization of MSCs and AAT-MSCs increases their potency, stemness and expands the limited therapeutic lifespan of MSCs (Fig.1). Further, iAAT-MSCs formed more colonies than iMSCs or non-immortalized MSCs (Fig.2). Both iMSCs and iAAT-MSCs exhibited a similar fibroblast-like morphology under light microscopy and showed expression of SV40LT protein in immunofluorescent staining for SV40 (Fig.3A). The size distribution of exosomes derived from iMSCs and iAAT-MSCs ranged from 50-500 nm, with the majority having a diameter of approximately 150 nm (Fig.3B and Fig.3C). Furthermore, exosomes from both iMSCs and iAAT-MSCs expressed tetraspanin exosome markers, including CD63, CD81, and CD9 (Fig.3D). Notably, the expression of human AAT protein was significantly increased in iAAT-MSC-derived exosomes compared to iMSC exomes (Fig.3D). Exosomes are able to transfer cargo such as miRNAs and proteins to recipient cells, thereby altering cellular phenotypes (S. W. Ferguson et al., Sci Rep 8, 1419 (2018)). Compared to the iMSC exosomes, 42 miRNAs’ expression levels were significantly up or down-regulated in iAAT-MSCs (Fig.3E). Notably, miR-409, 370, 99a, 139, 10a, and 361 were significantly increased in iAAT-MSC exosomes. KEGG pathway analysis shows that these miRNAs were predominantly associated with cytoskeleton proteins, endocytosis, glycerophospholipids, and the PI3K-AKT signaling pathway, which holds pivotal regulatory roles in MSC survival, proliferation, migration, angiogenesis, cytokine production, and differentiation (J. Chen et al., Tissue Eng Part B Rev 19, 516-528 (2013); S. Gao et al., Stem Cell Res 66, 103010 (2023)) (Fig. 3F and Fig.3G) Conversely, miR-93, 21, 474, 27a, 199a, 27b, 98, and 15b exhibited significantly lower expressions in iAAT-MSCs compared to iMSCs (Fig.3E). These miRNAs primarily targeted RNA biogenesis, translation factors, RNA polymerase, and the MAPK signaling pathway, which have implications in the regulation of osteogenic and chondrogenic 36    Attorney Docket: 206085‐0139‐00WO  differentiation in bone marrow mesenchymal stem cells (N. Ma et al., J Orthop Surg Res 14, 434 (2019)) (Fig 3H and Fig.3I). Treatment with iAAT-MSCs exosomes reduces TNBS-induced pancreatic injuries: Previous studies have demonstrated that TNBS-induced rodent models exhibit significant chronic inflammatory processes characterized by increased pancreas atrophy, collagen staining, fatty replacement, infiltration of monocytes and macrophages, and histological damage scores (F. Cattaruzza et al., Am J Physiol Gastrointest Liver Physiol 304, G1002-1012 (2013); R. P. Chow et al., Biomedicines 9 (2021)). In this study, mice were randomly divided into four groups: the control group (sham operation with vehicle injection), TNBS: mice receiving TNBS and PBS injection infusion, iMSC-exo or iAAT-MSC-exo groups: TNBS-treated mice treated with iMSC or iAAT-MSC exosomes. In the latter two groups, mice were injected with 200 µg of exosomes via the tail vein at week one, two, and / or three weeks after TNBS treatment. Mice tissues were collected at 3 or 6 weeks post TNBS infusion. Mice terminated at week 3 received two weekly doses of exosomes while those terminated at 6 weeks received three weekly doses (Fig.4A). TNBS-treated mice showed a noticeable decrease in body weight after TNBS injection that lasted about two weeks. iAAT-MSC exosome-treated mice displayed a faster recovery rate regarding body weight and percentage change of body weight compared to the MSC-exosome group (Fig.3B). The size of the pancreas in TNBS mice was significantly reduced compared to the sham control group at weeks three or six post-TNBS infusion (Fig.4C). However, there were no significant changes observed in pancreas weight between the exosome treatment groups and TNBS groups at either 3 or 6 weeks. Histological evaluation of H&E staining pancreas sections by a pathologist blinded for group assignment further confirmed the presence of increased inflammation, interlobular edema, vacuoles accumulation, and necrosis in the pancreases of TNBS mice compared to the sham controls at three weeks after TNBS injection (Fig.3C). TNBS mice receiving iAAT-MSCs exosome showed significantly reduced inflammation and interlobular edema scores, with the most preserved area at three weeks compared to TNBS alone and iMSC-exosome groups (Fig.4D- Fig 4G). Furthermore, mice receiving iMSC or iAAT-MSC exosomes both demonstrated higher preservation of pancreatic tissue at week six compared to the TNBS group (P < 0.05; Fig.4D). iAAT-MSC exosome mice showed improvement of 37    Attorney Docket: 206085‐0139‐00WO  reduced interlobular edema, reduced necrosis, and preserved normal appearing areas at week 6 (Fig.4E and Fig.4F). iAAT-MSCs exosomes suppress iron accumulation in pancreatic cells: Ferroptosis has been reported in patients with acute pancreatitis and cancer (S. A. El-Benhawy et al., J Egypt Natl Canc Inst 35, 4 (2023); H. Li et al., Chin Med J (Engl) 135, 2026-2034 (2022), suggesting that ferroptosis is an unrecognized mechanisms of cell death in CP mice after TNBS infusion (Fig.5A). The presence of iron deposition was characterized as evidence of possible ferroptosis using Prussian blue staining in human pancreatic tissues. Pancreatic sections of CP patients exhibited evident Fe3+ iron overload. There was no identifiable iron deposition in the pancreases from healthy individuals. In contrast, pancreas from CP patients showed obvious iron deposition (Fig.5B). Quantification of iron density revealed a significant accumulation of iron in CP patients as compared to healthy donors (P<0.05; Fig.5C). Similarly, dramatic iron deposition was also observed in TNBS-treated mice at six weeks post-TNBS injection (Fig.5D). These data show strong evidence of increased iron deposition and the possible pancreatic cell ferroptosis in both human and mouse CP pancreases. In contrast, treatment with iMSCs or iAAT-MSC exosomes significantly lowered iron deposition in the pancreas tissue (p < 0.05 vs. control, Fig. 5E) and serum iron concentrations in CP mice at six weeks post-treatment (Fig.5F). Next, the mechanistic insights of iron deposition and exosome protection was explored. Nuclear receptor coactivator 4 (NCOA-4) can mediate ferritin selective autophagy, leading to an increase in free iron and promote ferroptosis (N. Santana-Codina et al., Pharmaceuticals (Basel) 11 (2018)). NCOA4 specifically recognizes ferritin heavy chain 1 (FTH1) and forms an NCOA4- FTH1 complex, which facilitates the inclusion of ferritin into autophagosomes (Z. Chen et al., J Drug Target 30, 244-258 (2022); H. F. Yan et al., Signal Transduct Target Ther 6, 49 (2021)). Treatment with TNBS induced a dramatic upregulation of FTH1 and NCOA4 mRNA in the pancreas tissue at 6 weeks after treatment (Fig.5G). In contrast, a decrease in NCOA4 gene expression was observed in iMSC-exosome-treated groups compared to the TNBS group, although the difference was not statistically significant (p = 0.1638; Fig.5H and Fig.5I). However, the iMSCs exosome-treated mice exhibited a significant decrease in FTH1 gene expression compared to the TNBS group (p < 0.05; Fig.5G). Furthermore, TNBS mice showed a significant increase in FTH1 protein expression compared to the healthy controls (Pp < 0.01), 38    Attorney Docket: 206085‐0139‐00WO  while iMSCs exosome (p < 0.01 iMSC vs TNBS) and iAAT-MSCs exosome groups showed significantly low expression (p <0.05, iAAT-MSC vs TNBS) (Fig.5F and Fig.5G). Exosome treatments enhance antioxidant pathways in the pancreas: Major antioxidant systems, including GPx4 and ferroptosis suppressor protein (FSP1), are critical in reducing lipid peroxides and protect cells from ferroptosis (H. Li et al., Chin Med J (Engl) 135, 2026-2034 (2022); J. Dworzanski et al., PLoS One 15, e0230374 (2020)). Additionally, nuclear factor erythroid 2-related factor 2 (NRF2) modulates the cellular ferroptosis response (H. Li et al., Chin Med J (Engl) 135, 2026-2034 (2022); H. F. Yan et al., Signal Transduct Target Ther 6, 49 (2021); S. Chen et al., Front Cell Dev Biol 9, 801365 (2021)). Whether exosome treatment enhances the antioxidant pathways in the pancreas of CP mice was tested (Fig.6A). GPx4 expression was measured by PCR, immunostaining in both patient samples and CP mice. Immunostaining showed a reduction in GPX4 expression in pancreatic acini in CP patients compared to healthy individuals and CP patients in the pancreas (Fig.6D and Fig.6E). TNBS treatment reduced NRF2 expression but not GPx4 at mRNA level. Although mRNA expression of GPX4 and NRF2 in the pancreas showed an increase in the exosome treatment groups, the differences were not statistically significant when compared to the TNBS group (P=0.0723, and P=0.3298, respectively; Fig.5B). Moreover, decreased levels of superoxide dismutase (SOD) can contribute to acinar cell damage, triggering inflammation, pancreatic edema, and inflammatory cell aggregation (H. Li et al., Chin Med J (Engl) 135, 2026-2034 (2022)). iAAT-MSCs exosome mice demonstrated a significant increase in SOD1 expression in the pancreas compared to the TNBS group (P<0.01; Fig.6D- Fig.6F). In addition, the iAAT- MSCs exosome treatment group also exhibited a significant increase in FSP1 gene expression compared to the TNBS group (p < 0.05; Fig.6C). A key feature of ferroptosis is the reduction of the activity or levels of GPx4 (H. F. Yan et al., Signal Transduct Target Ther 6, 49 (2021); J. Chen et al., Front Mol Neurosci 13, 110 (2020)). In the CP mice, the immunofluorescence assay for GPx4 revealed lower GPx4 density compared to controls. Treatment with exosomes also showed an increased density of GPx4 expression, and increased serum GPx4 activity (Fig.6G- Fig.6I). This indicates that exosome treatment restored the anti-oxidant capacity of pancreatic cells. The biological characteristics related to cell death mainly include impaired metabolism of iron ions, depletion of GSH, and the presence of harmful byproducts like MDA and 4- 39    Attorney Docket: 206085‐0139‐00WO  hydroxynonenal (4-HNEs) resulting from the breakdown of lipid peroxides. In the context of exosome treatment, the groups receiving exosomes displayed higher serum GSH concentrations like those of healthy controls (Fig.6J). Notably, iAAT-MSC exosome-treated mice exhibited significantly increased GPx activity, likely achieved through the conversion of reduced GSH to oxidized GSSG (H. F. Yan et al., Signal Transduct Target Ther 6, 49 (2021)), in comparison to TNBS-treated mice (P<0.05; Fig.6I). Interestingly, both exosome treatment groups demonstrated significantly lower concentrations of MDA in the pancreas compared to the TNBS group (p < 0.05, Fig.6K). Taken together, these data indicate that ferroptosis is present in both mouse and human CP conditions. Exosomes derived from iAAT-MSCs mitigate pancreatic fibrosis: Pancreatic fibrosis arises from excessive production of extracellular matrix proteins by pancreatic stellate cells (PSCs), leading to acinar cell injury (C. Xu et al., Biochem Pharmacol 93, 449-460 (2015)). Upregulation of α -smooth muscle actin (α-SMA), an correlate of fibrosis (L. Yang et al., PLoS One 7, e31807 (2012)), was evident in the pancreas of CP patients in comparison to the pancreas of healthy donors (p < 0.05; Fig.7A and Fig.7B). There was also a trend of increased amylase activity in CP patients indicating acinar cell damage although the difference was not significant (Fig.7C). To confirm the presence of PSCs in fibrotic areas (L. Yang et al., PLoS One 7, e31807 (2012)) in the TNBS-treated mice, immunofluorescence staining of a-SMA was performed. Significant upregulation of α -SMA was observed in CP mice compared to the control mice (P<0.05; Fig.6A and Fig.6B). Similar to the human CP pancreas, a significant pancreas loss and extensive intralobular fibrosis were observed in the CP mice compared to healthy controls (p < 0.01, Fig.7F and Fig. 7G). In contrast, mice treated with iMSCs or iAAT-MSCs exosomes showed reduced fibrosis scores and pancreatic parenchymal preservation at three weeks post-treatment (Fig.6F and Fig. 6G). Fibrosis was reduced in all TNBS groups at week 6. The western blot analysis demonstrated a progressive upregulation of transforming growth factor-β1 (TGF-β1), matrix metalloproteinase 2 (MMP2), which are proinflammatory cytokines that contribute to tissue fibrosis (C. Xu et al., Biochem Pharmacol 93, 449-460 (2015); S. O'Sullivan et al., Mediators Inflamm 2015, 964131 (2015)), and cleaved-caspase 3, an indicator of cell apoptosis in mice treated with TNBS (Fig. 6H- Fig 6J). Treatment with exosomes significantly reduced expression of TGF-β1, MMP2 and c-Caspase, indicating a decrease in pathways leading to fibrosis following exosome treatment. 40    Attorney Docket: 206085‐0139‐00WO  iAAT-MSCs exosomes alleviate CP pain and attenuate inflammatory marker expression: Pain is another major feature of CP. The impact of exosomes on TNBS-induced pain was therefore measured. The open field test is employed to assess hyperactivity and anxiety levels by measuring the duration and distance traveled within the central area of the maze (D. A. Christakis et al., Sci Rep 2, 546 (2012)). At six weeks after treatment, TNBS-treated mice (representing overstimulation) exhibited a significant increase in the time spent in the center (Fig.10A), higher velocity, greater distance covered within the center, and more frequent entries into the center compared to the control mice (Fig.10B- Fig.10D). In contrast, mice treated with iAAT-MSC or iMSC exosomes exhibited significantly lower velocity, traveled shorter distances, and made fewer entries into the center compared to TNBS mice at week 6 (Fig.10B- Fig.10D). These findings indicate that the exosome-treated mice displayed normal activity levels. Furthermore, TNBS mice demonstrated a substantial increased threshold in paw withdrawal and abdominal sensitivity throughout the experiment compared to the healthy controls measured at week 3, 5, and 6 (p < 0.001 and p <0.05; Fig.8A and Fig.8B). Both iMSC and iAAT-MSC exosome treatments reduced the sensitivity to these stimuli in TNBS mice at weeks 5 and 6, with iAAT-MSC exosomes showed better improvement. Damaged pancreatic acinar cells lead to the infiltration of macrophages. Significantly more CD68+ infiltrating macrophages in the pancreas from CP patients were observed than in normal individuals within pancreatic tissue (P<0.05; Fig.8C and Fig.8D). Presence of CD68+ macrophages were also observed in the TNBS treated mice (Fig.8C). Again, both exosome treatment groups demonstrated significantly lower fluorescence density in CD68 compared to the TNBS group (P<0.0001). They also exhibited a decrease in IBA1 density compared to the TNBS group (iMSC exosomes: p < 0.01; iAAT-MSC exosomes: p < 0.05; Fig. 7G and Fig.7H). Exosome therapy inhibits mast cell infiltration and reduces iron channel protein expression: In addition to monocytes, mast cells are a secondary innate immune cell type within the pancreas that mediates neuropathic pain in acute and CP (R. P. Chow et al., Biomedicines 9 (2021); K. L. Beaudry et al., J Dairy Sci 99, 796-804 (2016); W. A. Hoogerwerf et al., BMC Gastroenterol 5, 8 (2005)). More mast cells were found in the pancreases of CP patients compared with those from normal individuals (p < 0.05; Fig.9A). This was next confirmed in the CP mice. When comparing mast cell density in the pancreas, TNBS mice had significantly 41    Attorney Docket: 206085‐0139‐00WO  higher mast cell density in both tissues compared to the control group at six weeks after TNBS injection (p < 0.0001 for wk3 and p <0.01 for wk 6, respectively; Fig.9C). Moreover, mice treated with iAAT-MSC exosomes also showed significantly fewer mast cells in the pancreas than TNBS mice (p <0.001 for wk 3 and p < 0.0001 for wk 6, respectively). Additionally, iMSC and iAAT-MSC exosomes exhibited lower mast cell density in the T9-T12 dorsal root ganglions (DRGs), with the difference being significant for iAAT-MSC exosomes compared to the TNBS group (P<0.05; Fig.8C- Fig.8E). These data suggest that exosomes reduce pain by suppressing mast cell migration to the pancreas and the DRG. Neurogenic inflammation plays a role in pain-related behaviors in CP. The sensory nerves associated with neurogenic inflammation and inflammatory arthritis cell bodies in DRG (R. P. Chow et al., Biomedicines 9 (2021); P. C. Staton et al., Eur J Pain 11, 283-289 (2007)). Within the DRG, various pain markers, including transient receptor potential ankyrin 1 (TRPA1) (R. P. Chow et al., Biomedicines 9 (2021)), c-FOS (A. Romero et al., Naunyn Schmiedebergs Arch Pharmacol 385, 397-409 (2012)), tachykinin receptor 1 (TacR1) (A. Barik et al., Elife 10 (2021)), neuropeptide calcitonin gene-related peptide (CGRP) (P. C. Staton et al., Eur J Pain 11, 283-289 (2007)), neuronal calcium-binding protein (Necab) family (M. D. Zhang et al., Proc Natl Acad Sci U S A 111, E1149-1158 (2014)) and others, have been found to increase in numerous pain models. Immunofluorescence staining revealed a significant increase in neuronal TRPV1 expression in TNBS mice compared to controls, consistent with previous findings (F. Cattaruzza et al., Am J Physiol Gastrointest Liver Physiol 304, G1002-1012 (2013); R. P. Chow et al., Biomedicines 9 (2021)) (P<0.05, Fig.9E and Fig.9F). In contrast, treatment with exosomes significantly reduced TRPV1 expression in TNBS mice in the iMSC exosome group (P<0.05). Additionally, the iAAT-MSC exosome group displayed non-significant lower expression of c-FOS, similar to the sham control group (Fig.9E and Fig.9F). Notably, iMSC exosome treatments resulted in a significant reduction of TacR1 mRNA expression, similar to the control group, compared to TNBS mice (P<0.05, Fig.10F). While pain markers CGRP, Glial cell line-derived neurotrophic factor family receptor 3 (GFRa3), and Necab1 exhibited lower mRNA expression in the exosome treatment groups (Fig.10G and 10H), the decrease in Necab3 expression was significant in the treatment groups compared to TNBS mice (P<0.05, Fig.10H). Overall, both exosome treatment groups showed improvements in CP pain, with decreased pain marker expression and reduced infiltration of macrophages and mast cells. 42    Attorney Docket: 206085‐0139‐00WO  These experiments show compelling evidence that iron deposition, fibrosis, and mast cell infiltration within the pancreas of patients suffering from CP, mirroring observations in a murine model induced by TNBS. The results underscore the presence of oxidative stress and exocrine cell ferroptosis that is not balanced by adequate anti-oxidative protection in the TNBS-induced mouse model of CP. Additionally, this study reveals that exosomes derived from iAAT-MSCs suppressed ferroptosis pathways, sustained glutathione peroxidase (GPx) activity, and attenuated fibrosis in the damaged pancreas. Moreover, exosome treatment alleviated pain by preventing mast cell and macrophage infiltration into the pancreas and / or the DRG. These findings provide valuable insights into how iAAT-MSCs-derived exosomes contribute to pancreatic repair, thereby advancing the development of a cell-free therapy for CP. Understanding the mechanisms and functions of pancreatic ferroptosis and subsequent fibrosis and pain is also crucial for optimizing treatment strategies for CP and other diseases sharing similar symptomatic profiles. Strong evidence of ferroptosis is shown in both human and mouse CP pancreatic tissues. Differential expression of key ferroptosis-related genes between CP mice and CP mice treated with exosomes from iMSC or iAAT-MSC sources was also observed, suggesting a therapeutic effect of those exosomes. Both mRNA and protein levels of FTH1 and protein levels of HO-1 were significantly elevated in CP samples. These results indicate that TNBS-induced pancreatitis involves iron accumulation, lipid peroxidation, and impairment of redox homeostasis, all of which are essential characteristics of ferroptosis, indicating the involvement of ferroptosis in TNBS-induced CP in mice. Xu et al. demonstrated increased iron overload, and elevated levels of MDA and FTH1, which decreased after Ferrostatin-1 treatment in colitis (J. Xu et al., Biochem Biophys Res Commun 573, 48-54 (2021)). Notably, the anti-ferroptosis markers FSP- 1, SOD1, GPX4, and NRF2 were decreased in CP mice, consistent with findings from studies on diabetic conditions and pancreatic adenocarcinoma (J. Dworzanski et al., PLoS One 15, e0230374 (2020), A. Stancic et al., Oxid Med Cell Longev 2022, 3873420 (2022), E. Dai et al., Nat Commun 11, 6339 (2020)). Other studies demonstrated that treatment with anti-ferroptosis drugs could increase GPx4 levels and decrease COX2 expression in osteoarthritis and CP (X. Wang et al., Chem Biol Interact 366, 110148 (2022), X. F. Xu et al., J Inflamm Res 15, 4737- 4749 (2022)). A decrease in COX2 expression after treatment with exosomes was also observed herein. 43    Attorney Docket: 206085‐0139‐00WO  Consistent with these findings, this study revealed that exosome treatment in CP mice restored redox homeostasis and decreased the expression of iron-dependent genes. Overall, these results shed light on the role of ferroptosis in the pathogenesis of CP. While iAAT-MSC exosomes displayed greater potency in terms of GPx activity and specific anti-ferroptosis markers, iMSC exosomes exhibited more pronounced effects in reducing iron concentrations. Treatment with exosomes resulted in a reduction in α-SMA positive cells and decreased expression of MMP2, TGF-β1, and caspase 3 compared to CP mice. This finding suggests that exosomes have the potential to inhibit pancreatic fibrosis by suppressing the activation of PSCs (L. Yang et al., PLoS One 7, e31807 (2012)), regulating the secretion of extracellular matrix, focal proliferation, and apoptosis (C. Xu et al., Biochem Pharmacol 93, 449-460 (2015)). Additionally, the decreased expression of widely used microglia and macrophage markers, IBA1 and CD68, indicates alterations in the immune microenvironment and neuropathological conditions (D. A. E. Hendrickx et al., J Neuroimmunol 309, 12-22 (2017), A. Hashimoto et al., Toxicol Pathol 48, 509-523 (2020)). Mast cell activation and visceral pain have been associated with conditions such as complex regional pain syndromes, pancreatic cancer, and CP (R. P. Chow et al., Biomedicines 9 (2021), W. A. Hoogerwerf et al., BMC Gastroenterol 5, 8 (2005), D. Yu et al., J Mol Neurosci 69, 235- 245 (2019)). A significant increase in mast cell presence was observed in pancreatic and DRG tissues from CP mice with a history of painful CP, suggesting a potential role for these cells in the pathogenesis of pain. In CP patients, a heightened mast cell density was also noted, aligning with the study of Hoogerwerf et al. (W. A. Hoogerwerf et al., BMC Gastroenterol 5, 8 (2005)). Their study showcased an augmented mast cell density in individuals with painful chronic pancreatitis in contrast to those with painless chronic pancreatitis. Notably, exosome treatments in CP mice led to a decrease in mast cell numbers, along with the expression of pancreas pain markers TRPV1, TacR1, and Necab3 in the DRG, indicating that both iMSC and iAAT-MSC exosomes act peripherally to restore neuroplasticity in the pancreas (R. P. Chow et al., Biomedicines 9 (2021)). These findings align with previous research indicating that increased synthesis of pain peptides in the DRG may contribute to the pathogenesis of chronic inflammatory pain models (P. C. Staton et al., Eur J Pain 11, 283-289 (2007)), colorectal hypersensitivity (T. Tanaka et al., Am J Physiol Gastrointest Liver Physiol 300, G418-424 44    Attorney Docket: 206085‐0139‐00WO  (2011)), and spinal itch circuitry (T. D. Sheahan et al., J Neurosci 40, 8816-8830 (2020)) in rodents. iAAT-MSCs exosomes outperformed iMSCs exosomes in preservation of pancreas tissue, preventing edema, suppressing inflammation, fibrosis and reducing pain. Therefore, they represent a better tool for CP treatment. These features may also be beneficial for other diseases associated with those pathologies. Compared to cell therapy, exosomes offer advantages such as their inability to mutate, replicate, or induce metastasis, making them safer and more accessible than cells. These attributes make exosomes a potential therapeutic option and delivery tool (Z. Shen et al., Front Immunol 12, 749192 (2021); R. Tamura et al., Inflamm Regen 36, 26 (2016); H. Liu et al., JCI Insight 4 (2019)). Furthermore, it is noteworthy that some differentially expressed novel miRNAs were upregulated, and some novel miRNAs were exclusively identified in iAAT- MSCs. This indicates a significant divergence in the miRNA expression profiles between the two types of exosomes. However, the let-7 family members were detected in both exosome types, highlighting their potential to inhibit cancer stemness in pathways associated with pancreatic cancer cells (Y. Ma et al., Cells 10 (2021)). Furthermore, the expression of key miRNAs, such as miR-375, miR-455-3p, and miR-29, within exosomes derived from both iMSCs and iAAT- MSCs, suggests that these components may be important in maintaining normal pancreatic function and alleviating injury to pancreatic acinar cells (Matthew N. Poya et al., PNAS 106, 5813–5818 (2009); Y. Zhan et al., PeerJ 11, e15612 (2023); S. Dey et al., JCI Insight 6 (2021)). Additionally, the presence of miR-144-3p in both types of exosomes indicates their potential effectiveness in suppressing USP22 / SIRT1, ferroptosis, and dysfunction of pancreatic β cells (S. Zhang et al., Diabetol Metab Syndr 14, 89 (2022)). These findings, in line with a systematic analysis study (S. W. Ferguson et al., Sci Rep 8, 1419 (2018)), provide evidence that MSC- derived exosomal miRNAs efficiently target genes related to angiogenesis and vascular development, and show promise in reducing fibrosis. The materials and methods used are described herein. Human iMSCs- and iAAT-MSCs: Human AAT-overexpressing MSCs (AAT-MSCs) were generated by transducing human bone marrow-derived MSCs from a healthy African American male with the lentiviral vector, as previously described (L. Song et al., Stem Cells Transl Med 10, 320-331 (2021)). The transduction process involved transfecting the MSCs with the viruses 45    Attorney Docket: 206085‐0139‐00WO  for 16 hours. Cells expressing GFP were sorted using fluorescence-activated cell sorting (FACS) after 96 hours of viral infection. MSCs transfected with empty vectors were used as MSC controls. To generate immortalized cells, the MSCs or AAT-MSCs were further transduced with SV40LT viral supernatant and subsequently selected using puromycin. Clones were expanded to establish stable cell lines for further experiments. iMSCs and iAAT-MSCs between passages 18- 20 were used in this study. Exosome Isolation and Characterization: iMSCs or iAAT-MSCs at 70-80% confluences were cultured in the serum-free StemPro™ MSC SFM medium (Thermo Fisher, MA, USA). After 48 hours, the cell culture medium was collected, and exosomes were harvested using the Total Exosome Isolation kit (Thermo Fisher, MA, USA). In brief, the medium was centrifuged at 2,000 g for 30 minutes to remove cells and debris before adding the total exosome isolation reagent. Exosomes were then harvested by ultracentrifugation at 10,000 g for 1 hour at 4°C. The resulting pellet was washed and then resuspended in an appropriate volume of PBS. Nanoparticle tracking analysis (NTA) was performed to analyze the particle size, and video images of the exosomes were captured using the ZetaView® BASIC NTA system (Particle Metrix, NC, USA). Small RNA Library Construction, Sequencing, and Data Processing: Four exosome samples were subjected to RNA extraction to generate libraries of small RNA molecules, using the exoRNeasy Maxi Kit (Qiagen, MD, USA). The quality and integrity of the RNA samples were assessed using a NanoPhotometer spectrophotometer (IMPLEN, CA, USA), Qubit® RNA Assay Kit with a Qubit® 2.0 Fluorometer (Thermo Fisher, MA, USA), and Bioanalyzer 2100 system (Agilent Technologies, CA, USA). Only high-quality RNA samples were utilized to construct the sequencing libraries. For constructing mRNA and circRNA libraries, 5 µg of RNA per sample was employed as input material. The library preparation process involved the ligation of 3' and 5' adaptors to the respective ends of small RNA molecules. The resulting double-stranded cDNA libraries were enriched through PCR. Following purification and size selection, libraries with insert sizes ranging from 18 to 40 bp were prepared for sequencing on the Illumina platform with SE50 sequencing. After sequencing, raw data underwent filtration to obtain clean reads. Additionally, quality metrics such as Q20, Q30, and GC contents were determined from the raw data. The small RNA tags obtained from the exosome samples were aligned to the assembled genome using Bowtie (Langmead B et al., Genome Biol 10, R25 (2009)). These aligned tags 46    Attorney Docket: 206085‐0139‐00WO  were then compared against the miRBase 20.0 database to identify known miRNAs. Modified mirdeep2 and srna-tools-cli software were employed to determine potential miRNAs and secondary structures (Friedländer MR et al., Nucleic Acids Res 40, 37-52 (2012)). Furthermore, to eliminate tags originating from repeat sequences, protein-coding genes, rRNAs, snRNAs, tRNAs, and snoRNAs, all small RNA tags were mapped to the Rfam database (http: / / rfam.sanger.ac.uk / search / ), Repeat Masker, and various species-specific data. To predict novel miRNAs, miREvo (Wen M et al., BMC Bioinformatics 13, 140 (2012)) and mirdeep2 (Friedländer MR et al., Nucleic Acids Res 40, 37-52 (2012)) were utilized, considering the distinctive hairpin structure of miRNA precursors. The presence of miRNA families was investigated using the Rfam database. Target genes for the identified miRNAs were predicted using miRanda software (Enright AJ et al., Genome Biol 5, R1 (2003)). The expression levels of miRNAs were estimated using transcripts per million (TPM) (L. Zhou et al., PLoS One 5, e15224 (2010)). Differential expression analysis was performed to identify significantly differentially expressed miRNAs based on a threshold of P<0.05. The target gene candidates of differentially expressed miRNAs were subjected to gene ontology (GO) enrichment analysis using the Gene Ontology database (http: / / geneontology.org / ). Furthermore, the KEGG Orthology Based Annotation System (KOBAS) software was employed to assess the statistical enrichment of target gene candidates in KEGG pathways (Mao X et al., Bioinformatics 21, 3787-3793 (2005)). Human Pancreatic Tissue and Serum samples: Human pancreatic serum samples were collected from a cohort of five healthy donors and 43 patients diagnosed with CP (mean age = 43.75 ± 11.77) (Table 1). Additionally, seven human pancreas tissues were randomly selected for more experimentation. Written consent was obtained from each participant before the study, and the research protocol received approval from the Ethics Committee of the Medical University of South Carolina, ensuring compliance with ethical standards. TABLE 1: demographics of tissue and blood donors 47    Attorney Docket: 206085‐0139‐00WO  CP induction in mice: A total of 51 male C57BL / 6 mice (10-12 weeks old, body weights around 20 gm were obtained from the Jackson Laboratory (Bar Harbor, ME, USA). CP was induced in the mice by administering a single infusion of 0.4% TNBS (50 µL) dissolved in ethanol (10%, v / v) via the bile duct, following established protocols (Wenyu Gou et al., J Vis Exp. (2022)). Pain assessment: Mechanical pain responses in the paw and abdominal areas were measured by applying calibrated von Frey filament (vFFs, North Coast Medical, CA, USA) with gradually increasing forces (R. P. Chow et al., Biomedicines 9 (2021), J. H. Winston et al., Pain 117, 214- 222 (2005)). The application was repeated ten times for 1-2 seconds each. A positive response was documented when the mouse exhibited behaviors such as raising, retracting, or licking the abdominal area. The data represents the minimum applied force by the calibrated vFF that triggered a positive response for each mouse within the experimental groups. All evaluations were carried out blindly. Behavior test by the Open field assessment: Hyperactivity and anxious behaviors were assessed using the Open Field Test (C. de Lombares et al., Aging (Albany NY) 11, 6638-6656 (2019)). The open field apparatus comprised a plexiglass square box measuring 60cm x 60cm x 25cm, with a designated center area marked. Each animal was individually placed in the box for 48    Attorney Docket: 206085‐0139‐00WO  ten minutes. The movements and behaviors of all animals were recorded using a digital camera and subsequently analyzed using the Ethovision system by Noldus. The parameters analyzed included the time spent and distance traveled within the center area, and the average velocity. Histopathological scoring of the pancreas: Pancreas tissues were fixed in paraffin, sectioned into 5 µm slices, and stained with hematoxylin and eosin (H&E) and Masson's Trichrome. The sections were then examined by a pathologist who was blinded to the experimental groups. The pathologist assessed the severity of pancreatitis in five categories of inflammation, necrosis, fibrosis, vacuole formation in acinar cells, and interlobular edema, using a scoring system ranging from 0 to 5 (Y. Fukumura, Pancreas pathological practice and research, K. Suda, Ed. (Karger, 2007), pp.146-153). The total preserved area was evaluated based on the histological features observed throughout the entire slide, expressed as a percentage from 0% to 100%. The Keyence microscope BZ-X800 (NC, USA) was utilized for slide scanning during this process. Immunohistochemistry: Pancreases from treated mice were preserved in paraffin, while dorsal root ganglion (DRG) samples were embedded in an optimal cutting temperature compound (O.C.T; Sakura Finetek, CA, USA), both were sectioned into 5 µm slices. Immunostaining was performed using primary antibodies specific to ferroptosis pathways, fibrosis (α-SMA), and pain / macrophage (TRPV1, c-FOS, IBA1, CD68) markers, along with secondary antibodies listed in Table 1. The slides were visualized using an Invitrogen™ EVOS M5000 Fluorescence Microscope (Thermo Fisher, MA, USA), and staining integrated density was quantified using ImageJ software (NIH). Detection of mast cells: Paraffin-embedded pancreatic samples and O.C.T-embedded DRG tissues underwent May-Grünwald-Giemsa staining following the manufacturer's recommendations (Eng Scientific, NJ, USA). The staining process involved deparaffinization, treatment with May-Grünwald Solution and Giemsa Stain, followed by washing with PBS, dehydration with ethanol, and clearing with xylene. Mast cells were then quantified in 10 randomized fields per section using a light microscope, and the results were reported as mast cells per mm2. Iron deposition in the pancreas: Prussian blue staining was utilized to evaluate the presence of intracellular iron in pancreatic samples (A. Stancic et al., Oxid Med Cell Longev 2022, 3873420 (2022)). The process involved deparaffinization of the sections, followed by 49    Attorney Docket: 206085‐0139‐00WO  staining with an iron stain solution according to the manufacturer's instructions (Iron Stain Kit; Abcam, MA, USA). Nuclear staining with fast red solution, dehydration in ethanol, and resin mounting were subsequently carried out. The identification of blue intracellular particles indicates the presence of iron, and the density of iron-positive cells was determined by examining five randomly selected fields of view per sample under a light microscope. Glutathione (GSH) and Glutatione peroxidase (GPx) Activity Assay: The concentrations of GSH in mouse serum and the activity of GPx in mouse pancreas tissue lysates and human serum samples were determined using separate colorimetric assay kits (Abcam, MA, USA), following the provided protocols. Briefly, the serum samples were deproteinized and incubated with the GSH Assay mixture for 60 mins at room temperature. The GSH concentration was determined as the absorbance value of each sample at 490 / 520 nm using a microplate reader (Bio-Rad Laboratories, Inc.). For GPx activity, the samples were incubated with glutathione reductase and GSH for 15 minutes to deplete all GSSG, and then incubated with cumene hydroperoxide. The absorbance measured at 340 nm was a direct proportion of GPx activity. Serum Amylase Assay: Human blood samples were centrifuged at 4°C for 15 minutes at 1,300 g to separate the serum. Amylase concentrations were measured using an Amylase Activity Assay kit obtained from Sigma-Aldrich, MO, USA, following the manufacturer's instructions. Iron Assay: Serum iron concentration was measured using the Iron Assay kit (Abcam, MA, USA) following the manufacturer's protocol. Briefly, serum samples were incubated with the working solution at 37°C for 30 minutes, followed by incubation with iron probe for 60 minutes at the same temperature. The resulting output was measured immediately using a colorimetric microplate reader, with the absorbance read at 593 nm. Lipid Peroxidation Assay: The concentration of malondialdehyde (MDA) in pancreas lysates was assessed using the Lipid Peroxidation Assay Kit (Abcam, MA, USA) according to the manufacturer's instructions. Briefly, samples were subjected to a reaction with thiobarbituric acid (TBA) at 95°C for 60 minutes. The resulting product was then quantified by measuring the absorbance at 352 nm using a microplate reader. Quantitative real-time PCR: Total RNA was extracted from the pancreas and DRG tissues using an RNA extraction kit (Qiagen, MD, USA). Subsequently, the RNA was utilized to synthesize cDNA with the iScript cDNA Synthesis Kit (Bio-Rad, CA, USA) on an Applied 50    Attorney Docket: 206085‐0139‐00WO  Biosystems Veriti 96-Well Thermal Cycler (Thermo Fisher, MA, USA). Real-time PCR was conducted in triplicate using specific primer pairs (Table 2), the CFX-96 Real-Time PCR system thermal cycler, and SYBR Green Mastermix (Bio-Rad, CA, USA). The expression levels of β- actin were employed as a reference to normalize the gene expression levels. The qPCR data were subsequently analyzed using the LightCycler 96 Relative Quantification software (Bio-Rad). Western Blot: Total proteins from the mouse pancreas were lysed in a protein lysis buffer containing a protease and phosphatase inhibitor cocktail (Sigma-Aldrich, MO, USA). Protein concentrations were determined using the BCA protein assay kit (Thermo Scientific, MA, USA). Equivalent amounts of total cell lysate (20 μg) were separated by electrophoresis on a 10% SDS- PAGE gel and transferred onto nitrocellulose membranes. The membranes were blocked and incubated with individual primary antibodies (Table 2) overnight at 4°C. The next day, the membranes were washed three times and incubated with the corresponding secondary antibodies at room temperature for 1 hour. Finally, the blots were imaged using a ChemiDocTM Imaging System (Bio-Rad, CA, USA) and analyzed using Image J software. β-actin was used as a loading control. 51    Attorney Docket: 206085‐0139‐00WO  Table 2: Antibodies employed using the GraphPad Prism software (Version 9). Statistical comparisons among groups were performed using one-way ANOVA followed by a post-hoc analysis. A p ≤ 0.05 was considered statistically significant.   The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others 52    Attorney Docket: 206085‐0139‐00WO  skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations. 53    Attorney Docket: 206085‐0139‐00WO  EMBODIMENTS The following clauses describe particular Embodiments of the invention. 1. A composition comprising an exosome derived from an immortalized stem cell modified to express human alpha-1 antitrypsin (AAT). 2. The composition of embodiment 1, wherein the stem cell is immortalized by contacting the cell with an immortalization factor selected from the group consisting of SV40 large T antigen (SV40LT), HPV-16 E6 and E7, and EBV, TERT, a p53 or Rb inhibitor, Ras, c- Myc T58A, Bmi1, cdk4, and cyclin D, or a fragment or variant thereof.. 3. The composition of embodiment 1 or 2, wherein the stem cell is immortalized by contacting the cell with SV40LT, or a fragment or variant thereof. 4. The composition of any one of embodiments 1-3, wherein the stem cell is selected from the group consisting of mesenchymal stem cells, hematopoietic stem cells, umbilical cord or placental derived stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, epithelial stem cells, and skin stem cells. 5. The composition of any one of embodiments 1-4, wherein the immortalized stem cell is an immortalized mesenchymal stem cell. 6. A method of treating or preventing an autoimmune or inflammatory disease in a subject comprising administering to the subject the composition of any one of embodiments 1-5. 7. The method of embodiment 6, wherein the autoimmune or inflammatory disease is selected from the group consisting of chronic pain, pancreatitis, type 1 diabetes, type 2 diabetes, sarcoidosis, islet transplantation, alpha-1 antitrypsin deficiency, and acute bacterial and 54    Attorney Docket: 206085‐0139‐00WO  viral infections including COVID-19. 8. The method of embodiment 6 or 7, wherein the disease results in chronic pain. 9. A method of reducing at least one symptom of an autoimmune or inflammatory disease in a subject comprising administering to the subject the composition of any one of embodiments 1-5. 10. The method of embodiment 9 wherein the at least one symptom is selected from the group consisting of pain, inflammation, intralobular edema score, necrosis, ferroptosis, autophagy, and fibrosis. 11. A cell population comprising an immortalized stem cell modified to express human alpha-1 antitrypsin (AAT). 12. The cell population of embodiment 11, wherein the stem cell is immortalized by contacting the cell with an immortalization factor selected from the group consisting of SV40 large T antigen (SV40LT), HPV-16 E6 and E7, and EBV, TERT, a p53 or Rb inhibitor, Ras, c- Myc T58A, Bmi1, cdk4, and cyclin D, or a fragment or variant thereof. 13. The cell population of embodiment 11 or 12, wherein the stem cell is immortalized by contacting the cell with SV40LT, or a fragment or variant thereof. 14. The cell population of any one of embodiments 11-13, wherein the immortalized stem cell is selected from the group consisting of mesenchymal stem cells, hematopoietic stem cells, umbilical cord or placental derived stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, epithelial stem cells, and skin stem cells. 55    Attorney Docket: 206085‐0139‐00WO  15. The cell population of any one of embodiments 11-14, wherein the immortalized stem cell is an immortalized mesenchymal stem cell. 16. A method comprising the steps of: a. Obtaining a stem cell, b. Immortalizing the stem cell. c. Modifying the stem cell to express AAT, and d. Isolating exosomes derived from the immortalized stem cell expressing AAT. 17. The method of embodiment 16, wherein the step of immortalizing the stem cell comprises contacting the stem cell with an immortalization factor selected from the group consisting of SV40 large T antigen (SV40LT), HPV-16 E6 and E7, and EBV, TERT, a p53 or Rb inhibitor, Ras, c-Myc T58A, Bmi1, cdk4, and cyclin D, or a fragment or variant thereof. 18. The method of embodiment 16 or 17, wherein the step of immortalizing the stem cell comprises contacting the stem cell with SV40LT, or a fragment or variant thereof. 19. The method of claim any one of embodiments 16-18, wherein the step of modifying the stem cell comprises contacting the cell with an exogenous nucleic acid molecule encoding AAT or a fragment or variant thereof. 20. The method of any one of embodiments 16-19, wherein the immortalized stem cell is selected from the group consisting of mesenchymal stem cells, hematopoietic stem cells, umbilical cord or placental derived stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, epithelial stem cells, and skin stem cells. 56    Attorney Docket: 206085‐0139‐00WO  21. The method of any one of embodiments 16-20, wherein the immortalized stem cell is an immortalized mesenchymal stem cell. 57

Claims

Attorney Docket: 206085‐0139‐00WO  Claims 1. A composition comprising an exosome derived from an immortalized stem cell modified to express human alpha-1 antitrypsin (AAT).

2. The composition of claim 1, wherein the stem cell is immortalized by contacting the cell with an immortalization factor selected from the group consisting of SV40 large T antigen (SV40LT), HPV-16 E6 and E7, and EBV, TERT, a p53 or Rb inhibitor, Ras, c- Myc T58A, Bmi1, cdk4, and cyclin D, or a fragment or variant thereof..

3. The composition of claim 2, wherein the stem cell is immortalized by contacting the cell with SV40LT, or a fragment or variant thereof.

4. The composition of any of claims 1-3, wherein the stem cell is selected from the group consisting of mesenchymal stem cells, hematopoietic stem cells, umbilical cord or placental derived stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, epithelial stem cells, and skin stem cells.

5. The composition of any of claims 1-4, wherein the immortalized stem cell is an immortalized mesenchymal stem cell.

6. A method of treating or preventing an autoimmune or inflammatory disease in a subject comprising administering to the subject the composition of any of claims 1-5.

7. The method of claim 6, wherein the autoimmune or inflammatory disease is selected from the group consisting of chronic pain, pancreatitis, type 1 diabetes, type 2 diabetes, sarcoidosis, islet transplantation, alpha-1 antitrypsin deficiency, and acute bacterial and viral infections including COVID-19. 58   Attorney Docket: 206085‐0139‐00WO  8. The method of claim 7, wherein the disease results in chronic pain.

9. A method of reducing at least one symptom of an autoimmune or inflammatory disease in a subject comprising administering to the subject the composition of any of claims 1-5.

10. The method of claim 9 wherein the at least one symptom is selected from the group consisting of pain, inflammation, intralobular edema score, necrosis, ferroptosis, autophagy, and fibrosis.

11. A cell population comprising an immortalized stem cell modified to express human alpha-1 antitrypsin (AAT).

12. The cell population of claim 11, wherein the stem cell is immortalized by contacting the cell with an immortalization factor selected from the group consisting of SV40 large T antigen (SV40LT), HPV-16 E6 and E7, and EBV, TERT, a p53 or Rb inhibitor, Ras, c- Myc T58A, Bmi1, cdk4, and cyclin D, or a fragment or variant thereof.

13. The cell population of claim 11 or 12, wherein the stem cell is immortalized by contacting the cell with SV40LT, or a fragment or variant thereof.

14. The cell population of any of claims 11-13, wherein the immortalized stem cell is selected from the group consisting of mesenchymal stem cells, hematopoietic stem cells, umbilical cord or placental derived stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, epithelial stem cells, and skin stem cells.

15. The cell population of any of claims 11-14, wherein the immortalized stem cell is an immortalized mesenchymal stem cell.

16. A method comprising the steps of:   a. Obtaining a stem cell,   b. Immortalizing the stem cell.   c. Modifying the stem cell to express AAT, and Attorney Docket: 206085‐0139‐00WO  d. Isolating exosomes derived from the immortalized stem cell expressing AAT.

17. The method of claim 16, wherein the step of immortalizing the stem cell comprises contacting the stem cell with an immortalization factor selected from the group consisting of SV40 large T antigen (SV40LT), HPV-16 E6 and E7, and EBV, TERT, a p53 or Rb inhibitor, Ras, c-Myc T58A, Bmi1, cdk4, and cyclin D, or a fragment or variant thereof.

18. The method of claim 16 or 17, wherein the step of immortalizing the stem cell comprises contacting the stem cell with SV40LT, or a fragment or variant thereof.

19. The method of claim any of claims 16-18, wherein the step of modifying the stem cell comprises contacting the cell with an exogenous nucleic acid molecule encoding AAT or a fragment or variant thereof.

20. The method of any of claims 16-19, wherein the immortalized stem cell is selected from the group consisting of mesenchymal stem cells, hematopoietic stem cells, umbilical cord or placental derived stem cells, embryonic stem cells, induced pluripotent stem cells, neural stem cells, epithelial stem cells, and skin stem cells.

21. The method of any of claims 16-20, wherein the immortalized stem cell is an immortalized mesenchymal stem cell.

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