Mechanistic studies in tolerance induction to human pluripotent stem cell-derived tissues in T1D model

M.Phil. ; Type 1 diabetes (T1D) is an autoimmune disease that leads to loss of functional pancreatic b-cells and failure in glycaemic control, resulting in hyperglycaemia. Conventional treatment of routine injection of exogenous insulin offers no permanent cure and legitimate control of blood glucose level. Islet transplantation comes as the preferred therapeutic approach to ameliorate clinical symptoms and setback of T1D. Studies addressing the two primary hindrance: scarcity of available islets for transplant and side effects associated with immune intervention post transplantation for prolonging the graft survival and function have been ongoing. Recent advancements in generating pancreatic b-cells from pluripotent stem cells (PSCs) could potentially provide indefinite source for cell replacement therapy. Our research group focuses on replacing general systemic immunosuppressive therapy with tolerance inducing strategies, such as administering short course of coreceptor and costimulation blockade using monoclonal antibodies to induce transplant tolerance to human embryonic stem cells (hESCs) derived xenografts in immunocompetent mice. Yet, the mechanisms underlying the establishment of a state of tolerance have yet been investigated. Moreover, intense research has focused on adaptive immunity mediated transplant rejection; however, the direct role of innate immune response in graft rejection, is comparably less elucidated. Tolerance induction might not only target the adaptive but also the innate immunity. In this thesis, we tried to address: first, we investigated how the innate immunity particularly macrophages react to hESC-derived transplants; second, we studied the cellular and molecular mechanisms by which coreceptor and costimulation blockade induced tolerance to human ESC-derived tissues with a particular focus on regulatory T cells (cellular mechanisms) and microRNAs (molecular mechanisms). ; The mechanism by which macrophages mediate transplant rejection was studied. Endothelial cells (ECs) or ...