Mesenchymal Stem Cell Therapy for Organ Transplant Immunosuppression
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MSC cell therapy in Organ Transplantation
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Mesenchymal Stem Cell Therapy for Organ Transplant Immunosuppression
- 1. Mesenchymal Stem Cell Therapy as an Immunosuppressive Method in Solid Organ Transplantation. Amit Kumar Bhardwaj M.Sc. Biotechnology PhD Aspirant, India
- 2. Review Article Journal: Frontiers in Immunology Impact Factor 8.786 Reviewed by: Paolo Cravedi, Icahn School of Medicine at Mount Sinai, United States Olivier Detry, University Hospital Center of Liège, Belgium Published: 10 February 2021
- 3. Overview: Mesenchymal Stem Cell (MSC) • Also called as stromal stem cells • Multipotent adult stem cells • They can differentiate into other types of cells like bone cells, skin cells, corneal cells etc.
- 4. Source of Mesenchymal Stem Cell
- 5. Differential Potential of Mesenchymal Stem Cells
- 6. Characteristics of Mesenchymal Stem Cells • They are Plastic-adherent • Fibroblast like structure • Have Self renewable and differentiation capacity • In 2006, The international society for cell & gene Therapy established minimal criteria for defining Mesenchymal Stem Cells : • Plastic adherence • Positive for CD105, CD90, CD73 • Negative for CD45, CD19, CD15
- 7. Function of Mesenchymal Stem Cells • MSC represent a fundamental component of the BM stroma, where they control maintenance, self-renewal and differentiation of hematopoietic stem cells. • MSC have unique and highly potent immune-dampening, immune-regulatory, anti- inflammatory, and pro-reparative properties. • Impaired BM_MSC have been implicated in development of hematological malignancies such as: • Myelodysplastic Syndromes • Leukemia • Multiple Myeloma • BM Failure Syndromes
- 8. Solid Organ Transplant • Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged organ. • Like:- • Kidney • Heart • Liver • Pancreas • Small bowel etc.
- 10. Graft versus host disease (GVHD) is an immune mediated disease due to complex interaction between donor (lymphoid tissue) and recipient's immunity occurring after transplantation. Two types:- Acute (less than 100 days) Chronic (more than 100 days) It occurs when immunologically competent T cells or their precursors are transplanted into recipients who are immunologically compromised. Incidence - 1-2 % Mortality - up to 75% Graft versus host disease (GVHD)
- 11. Immunosuppression • Suppression of the body's immune system and its ability to fight infections and other diseases. • Immunosuppression may be deliberately induced with drugs, as in preparation for bone marrow or other organ transplantation, to prevent rejection of the donor tissue. • It may also result from certain diseases such as AIDS or lymphoma or from anticancer drugs. • Side effects of immunosuppressive drugs increased risk of infection- These drugs make the immune system less able to detect and destroy cancer cells or fight off infections that cause cancer and have increased risk of infection
- 12. Example • How the immunosuppression drugs works • Rituximab- Anti CD20 • Alemtuzumab – Anti CD52 • Basiliximab- Anti-IL-2R • ATG- Anti Thymocyte Globulin • Belatacept- Anti B7 • Tacrolimus-CNI • ETC
- 13. Immunomodulatory feature of MSC on Adaptive Immunity
- 14. • The first evidence of MSC's immunomodulatory effect was provided nearly 20 years ago in a baboon skin allograft model. MSC were shown to suppress allogeneic T-cell proliferation in a mixed lymphocyte reaction and to delay skin allograft rejection • Numerous studies have since demonstrated MSC's ability to: • Inhibit CD4+ T cell activation and proliferation • Preventing CD4+ T cells differentiation into TH1 and TH17 effector cells • As well as reduced CD8+ T-cell cytotoxicity in response to allogeneic stimuli. • Suppress cytokine-induced memory T cell activation. • Can convert not only naïve T cells, but also effector/memory CD4+ T and CD8+ T cells toward a regulatory phenotype.
- 15. • MSC-induced CD4+ Tregs retained a regulatory phenotype and function over time, suppressing ex vivo proliferation of T cells from rheumatoid arthritis patients. • According to a recent study, the transfer of mitochondria from MSC to CD4+ T cells may be a mechanism capable of driving Treg differentiation on its own. • MSC inhibited the proliferation and differentiation of follicular T helper cells in autoimmune disorders (Tfh). • The direct interaction of MSC and B cells primarily influenced B cell differentiation, resulting in decreased plasmablast formation and increased generation of IL-10 secreting regulatory B cells.
- 16. Immunomodulatory feature of MSC on Innate Immunity
- 17. The effect of MSC on antigen-presenting cells is another important immunoregulatory property. MSC in vitro experiments on DC:- • Dendritic cell maturation was hampered by MSC • Downregulating DC's MHC-II and costimulatory molecule expression. • Inhibiting the release of pro-inflammatory cytokines such as IL-12, IFN- gamma, and TNF Alpha • Increased production of the anti-inflammatory cytokine IL-10, resulting in long-term expansion of regulatory T cells (Tregs) In Vivo MSC downregulate DC migration towards lymphoid organs by downregulating CCR7 expression
- 18. Among innate immune system cells, the macrophage is the main target of MSC immunoregulation. • MSC increase macrophage polarization toward the anti-inflammatory M2 phenotype by suppressing pro-inflammatory cytokine secretion while increasing phagocytic activity and IL-10 release. • MSC, either by inducing or undergoing apoptosis, enable macrophages to generate TGF-beta and enhance Treg induction. • MSC play an important role in educating macrophages to promote tissue repair and inflammation resolution.
- 19. Insights from Experimental Models of Solid Organ Transplantation Animal Testing
- 20. Kidney MCS • MSC induced graft tolerance, mediated by the formation of donor-specific FOXP3+ Tregs and tolerogenic dendritic cells. • MSC injection 2 days after transplant failed to expand Tregs and promote long-term graft acceptance. • Rat undergone transplant administered with BM-MSC over expressing CXCR4 preserved renal function. • MSC infusion 2 days after kidney transplantation was associated with transient graft dysfunction characterized by increased complement C3 deposition and neutrophil infiltration. Kidney
- 21. MCS HEART • MSC infusion prior to transplantation produced superior effects than post-transplant administration • MSC-mediated tolerance was noticeably dependent on the production of donor-specific regulatory T cells. • Transfection of MSC with IL-35 or soluble fibrinogen- like protein 2, found to be involved in Treg development and was found to enhance MSC's immunomodulatory impact in preventing acute rejection. • The elevation in Treg cells after MSC injection was also connected with the generation of tolerogenic DC and regulatory B cells, effects that were mediated primarily by PD-L1 expression and an increased proportion of graft M2 macrophages. Heart
- 22. MCS LIVER • MSC administered on the day of transplantation can reduce acute graft rejection and prolong graft survival. • MSC suppress Th1 activation and diminish the production of pro-inflammatory cytokines. • Also, boost the synthesis of anti-inflammatory cytokines and enhance FOXP3+ regulatory T cells. • MSC's ability to generate Tregs was also useful in preventing, but not reversing, the development of post-liver transplant acute GVHD. Liver
- 23. MCS LUNG Lung • The administration of IL-10 overexpressing-BM- MSC together with CsA improved graft function and alleviated 5-day acute rejection. • MSC secretome plays a major role in inhibiting the early phase of acute lung allograft rejection. • Highly activated T cells and an inflammatory environment can hamper MSC-mediated immunosuppression or even promote their conversion into pro-inflammatory cells.
- 24. CLINICAL STUDIES
- 25. Kidney Transplant • MSC have been used in renal transplantation was used for a variety of purposes • inducing operational tolerance to the allograft • treating subclinical rejection • preventing the development of chronic tissue damage • renal function deterioration • reducing the overall dose of induction and/or maintenance immunosuppression. • Phase 1 Clinical Study by Perico N et al. • Autologous BM-MSC in 2 patient were infused seven day after transplant with ATG and Basiliximab • progressive increase in Treg fraction and reduced donor-specific CD8+ memory T cells coupled with reduced donor specific T-cell alloreactivity were noted. • Post transplant MSC administration was shown to be associated with MSC intra-graft migration and pro inflammatory polarization, resulting in severe neutrophilic infiltration and C3 Deposition
- 26. Kidney Transplant • MSC administration the day before transplant seen to induce long term, self sustaining immunoregulatory process responsible for tolerance induction • The heterogeneity of MSC preparations, timing of infusion, concomitant immunosuppression and patient selection needs to always be considered in these trials. • Pre-transplant infusion of third-party umbilical cord-derived MSC (UC-MSC) under standard immunosuppressive therapy was found to be safe and well tolerated in deceased-donor renal transplant recipients
- 27. Liver Transplant Early post-transplant infusion of third-party BM-MSC was assess in 10 patients • MSC did not increase the risk of infection or malignancy, and the rates of graft rejection, survival and histologic analysis of 6-month protocol biopsies were similar between patients who received MSC and controls. • However, MSC failed to induce changes in the immunophenotype, and weaning MSC recipients off immunosuppression was not successful. 27 patients were randomly allocated to receive conventional immunosuppression with or without UC-MSC infusion. At the end of the 12-week follow-up, the patients who received MSC exhibited lower liver enzyme levels, increased frequency or circulating Treg and improved histology compared to controls The therapeutic potential of six doses of UC-MSC was also assessed in 12 liver transplant recipients with ischemic-type biliary lesions. Compared to a group of patients treated with a traditional protocol, those who received MSC had a significantly lower need for interventional therapeutic procedures, lower mortality and higher graft survival.
- 28. Future Prospective • Human MSC did not demonstrate any potential of malignant transformation, even after long-term in vitro expansion, and no association between MSC and cancer has been reported in any of the trials conducted so far • Overall, this provides a strong signal regarding MSC safety, even in this context, but long-term surveillance still needs to be implemented, as most of these trials reported results during a limited follow-up period. • The precise mechanism through which MSC interact with the host immune system has not been completely understood yet. • Standardization of cell manufacturing processes is needed, and establishing the appropriate dose, timing, source and concomitant immunosuppressive therapy is on going. • Clarity would be needed on whether engineering MSC could provide additional benefits over standard preparations.
- 29. Thank You
Editor's Notes
- Good evening sir, So now I am going to present my presentation on the topic which you have asked me to present And that is mesenchymal stem cell therapy as an immunosuppressive method in solid organ transplant So now starting with the presentation
- So as you asked me to review some literatures I have gone through some litratures and I fined this article very imformative which have info about msc effect on adaptive and innate immune cells And some details of pre clinical and clinal studies.
- So starting from the basics I will give you a overview of msc cells Also called as stromal cells And they are multi potent in nature which means they have the capability to differentiate in multiple cells Like bone cells called osteocytes Chondrocyte cells of cartilage Adipocyte cells of fat `
- And we can isolate these MSC In adults the source of msc is bone marrow, adipose tissue, muscle tissue and peripheral blood And fetal source amniotic fluid and fetal tissues And in perinatal source are placenta and umblical cord or umblical cord blood And just for the information Researchers have also found that a stem cell’s potency is tied to its age, therefore making cord tissue MSCs some of the most capable cells around. In contrast, treatments that utilize MSCs from a patient’s fat (adipose) sample have shown weak or unreliable responses. In general, a stem cell is only as good as its source, and if the cells come from an older individual, no amount of expansion will increase their potency.
- In this slide you can see the differential potential of MSC cells They can differentiate in more than 10 types of cells by different processes By doing adipogenesis they can differentiate in adipocytes By doing osteogenesis they can differentiate in osteocytes and By doing chondrogenesis they can differentiate in chondrocytes And so on
- So now talking about the characteristic of msc cells they are plastic adherent and Adherent cells are cells that grow while adhering to the culture vessel And their structure are like fibroblast cells And the most impt the msc cells have self renewable and differentiation capacity And while isolating and culturing these cells we get a heterogenous population of these cells so for that In 2006, The international society for cell & gene Therapy established minimal criteria for defining Mesenchymal Stem Cells : Plastic adherence Positive for CD105, CD90, CD73 Negative for CD45, CD19, CD15
- And now I will talk about some function of mesenchymal stem cells MSC is a fundamental component of the BM stroma, and they control maintenance, self-renewal and differentiation of hematopoietic stem cells. And it has been seen that MSC have unique and highly potent immune-dampening, immune-regulatory, anti-inflammatory, and pro-reparative properties. Impaired functional, replicative, and regenerative capacities of BM-MSC can lead to development of hematological malignancies, such as Myelodysplastic Syndromes Leukemia Multiple Myeloma BM Failure Syndromes
- So what do we really mean by solid organ transplant Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged organ. And kidney heart liver pancreas are some the example of solid organ
- And here the common terms used in transplant Autograft means your own body part transplant to other area of the body And isograft means organ taken from identical twins And allogaft means transplant between different individual of the same species And xeno graft mens transplant between different species
- And after transplant some people suffers from GVHD dieases which is graft versus host dieseas It is an immune mediated disease due to complex interaction between donor (lymphoid tissue) and recipient's immunity occurring after transplantation. And GVHG are of two types Acute can be observed in less than 100 days And chronic can be observed after more than100 days And its occurs when immunologically competent t cells or their precursors are transplanted into recipient who are immunologically compromised like on immunosuppression Incidence rate is 1-2 % And mortality is upto 75%
- Immunosuppression means the suppression of immune system and its ability to fight infection And sometimes immunosuppression deliberately given to patients undergoing bone marrow transplant or solid organ transplant or to prevent rejection of donor tissue And it may also results from certain diseases such as aids or lymphoma or from anti-cancer drugs And immunosuppression drugs have some sideffects like increased risk of infection – and these drugs make the immune system less able to detect and destroy cancer cells that can cause cancer.
- And here are some example of immunosuppression drugs and how it works Some of them is monoclonal antibody which blocks the cell receptors Like rituximab is anti-cd20 monoclonal antibody and it binds to the b cell cd20 receptor molecule which has a important role in development and differentiation of b cell into plasma cells And all these medicine which contain mab in their name is monoclonal antibody like you can notice here Rituximab , alemtuzumab , Basiliximab But ATG is polyclonal and it can bind to multiple receptors So these drugs bind to their respective location and inhibits the immune cells function like differentiate proliferate and cell signaling And because of these immune system of the patients gets depleted
- So now talking about the immunomodulatory feature of MSC on adaptive immunity
- So the first ever effect of MSC immunomodulation was seen 20 years ago in a baboon skin allograft transplant and MSC were shown to suppress allogeneic T-cell proliferation in a mixed lymphocyte reaction and to delay skin allograft rejection And also numerous studies have done since that and observed that MSC inhibits CD4+ T cell activation and proliferation And preventing CD4+ t cells to differentiate in Th1 and th17 cells And also it showed reduced CD8+ t cell cytotoxicity in response to allogeneic stimuli And suppress cytokine induced memory t cell activation And it has also seen that MSC can convert not only Niave t cells but also effector/memory cd4+ and cd8+ t cells toward a regulatory phenotype which helps to suppress the immune response and suppress memory t cell activation
- And it has also seen that msc-induced cd4+ Tregs retained a regulatory phenotype and function overtime, leads to suppressing ex vivo proliferation of T cells from rheumatoid arthritis patients. Also according to some recent studies it founds that the transfer of mitochondria from MSC to CD4+ t cells may be a mechanism capable of driving T reg differentiation on its own And also MSC inhibits the proliferation and differentiation of follicular T helper cells in autoimmune disorder patients And The direct interaction of MSC and B cells primarily influenced B cell differentiation, resulting in decreased plasmablast formation and increased generation of IL-10 secreting regulatory B cells. Which also helps in suppressing the immune system
- Now talking about the Immunomodulatory feature of MSC on Innate Immunity
- And in a in-vitro study of MSC effect on DC was one And it is observed that the The Dendritic cell maturation was hampered by MSC lead to immature D cells Which result in Downregulating DC's MHC-II and costimulatory molecule expression and Inhibiting the release of pro-inflammatory cytokines such as IL-12, IFN-gamma, and TNF Alpha and Increased production of the anti-inflammatory cytokine IL-10, resulting in long-term expansion of regulatory T cells (Tregs) And in a IN-vivo experiments it is also observed that MSC downregulate the DC migration towards lymphoid organs by downregulating CCR7 expression CCR7 is necessary to direct dendritic cells (DCs) to secondary lymphoid nodes and to elicit an adaptative immune response.
- Among innate immune system cells, the macrophage is the main target of MSC immunoregulation. And it was observed that the MSC increases macrophage polarization towards anti-inflammatory M2 phenotype resulting in suppressing pro-inflammatory cytokine secretion while increasing phagocytic activity and IL-10 release. And MSC either by inducing or undergoing apoptosis enable macrophage to generate TGF-beta and enhance T reg Induction T reg cells are also known as suppressor t cells And It also play an important role in educating macrophage to promote tissue repair and inflammation resolution Macrophages are also an important producer of TGF-β, which is activated by the phagocytosis of apoptotic cells. Usually, uptake of apoptotic cells elicits anti-inflammatory effect. Thus, induction of TGF-β is a mechanism involving the anti-inflammatory effect of apoptotic cells
- So now I will talk about the results observed from pre clinical experiments of solid organ transplant
- So in preclinical kidney transplant in animal Its observed that MSC induces the graft tolerance, mediated by the formation of donor-specific FOXP3+ T regulatory and tolerogenic dendritic cells FOXP3 is the transcription factor of T regulatory cells And in other case MSC injection 2 day after transplant failed to expand T regulatory and promote long term graft acceptance And genetically modified MSC over expressing CXCR4 (C-X-C chemokine receptor type 4) gene injected in Rat undergone transplant preserved renal function And MSC infusion 2 days after kidney transplantation was associated with transient graft dysfunction characterized by increased complement C3 deposition and neutrophil infiltration. And here you can see some effects of MSC observed in kidney transplant which is Interstitial Fibrosis and Tubular Atrophy (IFTA) IDO(indoleamine 2,3 Dioxygenase) regulates tryptophane level and tryptophane suppresses t cell proliferation By dramatically reducing the supply of this critical amino acid
- So in preclinical heart transplant in animal it is observed that MSC infusion prior to transplantation produced superior effects than post-transplant administration which we have already seen in the case of kidney transplant MSC-mediated tolerance was noticeably dependent on the production of donor-specific regulatory T cells. Transfection of MSC with IL-35 or soluble fibrinogen-like protein 2, found to be involved in Treg development And was found to enhance MSC's immunomodulatory impact in preventing acute rejection. The elevation in Treg cells after MSC injection was also connected with the generation of tolerogenic DC and regulatory B cells, effects that were mediated primarily by PD-L1 expression and an increased proportion of graft M2 macrophages.
- In case of liver It was observed that MSC administered on the day of transplantation can reduce acute graft rejection and prolong graft survival. MSC also suppress Th1 activation and diminish the production of pro-inflammatory cytokines. Also, boost the synthesis of anti-inflammatory cytokines and the enhance FOXP3+ regulatory T cells. MSC's ability to generate Tregs was also useful in preventing, but not reversing, the development of post-liver transplant acute GVHD.
- In case of lung transplant The administration of IL-10 overexpressing-BM-MSC together with CsA improved graft function and alleviated 5-day acute rejection. And it has also seen that in the place of using MSC cells its secretome plays a major role in inhibiting the early phase of acute lung allograft rejection. But Highly activated T cells and an inflammatory environment can hamper MSC-mediated immunosuppression or even promote their conversion into pro-inflammatory cells.
- So now finally coming on to the clinical studies
- So in clinical study of kidney transplant MSC have been used in renal transplantation was used for a variety of purposes inducing operational tolerance to the allograft treating subclinical rejection preventing the development of chronic tissue damage renal function deterioration reducing the overall dose of induction and/or maintenance immunosuppression. Phase 1 Clinical Study by Perico N et al. They did Autologous BM-MSC in 2 patient were infused seven day after transplant with ATG and Basiliximab progressive increase in Treg fraction and reduced donor-specific CD8+ memory T cells coupled with reduced donor specific T-cell alloreactivity were noted. But Post transplant MSC administration was shown to be associated with MSC intra-graft migration and pro inflammatory polarization, resulting in severe neutrophilic infiltration and C3 Deposition
- And when MSC administration the day before transplant was done and it observed to induce long term, self sustaining immunoregulatory process responsible for tolerance induction Which shows The heterogeneity of MSC preparations, timing of infusion, concomitant immunosuppression and patient selection needs to always be considered in these trials. And in one more experiment Pre-transplant infusion of third-party umbilical cord-derived MSC (UC-MSC) under standard immunosuppressive therapy was found to be safe and well tolerated in deceased-donor renal transplant recipients
- And in the case of liver transplant Early post-transplant infusion of third-party BM-MSC was assess in 10 patients And it was observed that the MSC did not increase the risk of infection or malignancy, and the rates of graft rejection, survival and histologic analysis of 6-month protocol biopsies were similar between patients who received MSC and controls. However, MSC failed to induce changes in the immunophenotype, and weaning MSC recipients off immunosuppression was not successful. And in other study 27 patients were randomly allocated to receive conventional immunosuppression with or without UC-MSC infusion. At the end of the 12-week follow-up, the patients who received MSC exhibited lower liver enzyme levels, increased frequency or circulating Treg and improved histology compared to controls And in another study The therapeutic potential of six doses of UC-MSC was also assessed in 12 liver transplant recipients with ischemic-type biliary lesions. Compared to a group of patients treated with a traditional protocol, those who received MSC had a significantly lower need for interventional therapeutic procedures, lower mortality and higher graft survival.