(provided by candidate): Pancreatic islet transplantation has emerged as a promising therapy for type 1 diabetes mellitus (T1D). Complete and persistent insulin independence has been accomplished during the first five to seven years after islet transplantation. However, long-term acceptance and survival of transplanted islets is currently limited mainly due to immune-mediated rejection and/or recurrence of autoimmunity. Extensive research efforts have been dedicated to understanding the molecular mechanisms underlying rejection of islet grafts by effector cells of the adaptive immune system. Emerging evidence also suggest a prominent role of the innate immune system in this process, either directly or through cross-talk with the adaptive immune system cells. Such evidence indicate that cross-talk between innate and adaptive immunity is mediated in part via soluble factors (e.g., cytokines, chemokines) produced by myeloid cells that promote recruitment of effector lymphoid cells to transplanted tissues. However, little is known about the cell-cell contacts that may take place between these two arms of the immune system within the grafts. In this application, we aim to establish the role of cell-cell contacts between graft-infiltrating macrophages and effector T lymphocytes in islet rejection. Our preliminary results showed that macrophages infiltrated islet grafts shortly after transplantation in both syngeneic and allogeneic recipient mice, but the number of infiltrating macrophages increased significantly in the allografts during progression of acute rejection. The results also showed that depletion of macrophages in allograft recipients delayed rejection. These results point to macrophage involvement in the initial inflammatory response after islet transplantation in both syngeneic and allogeneic grafts and to an active role during ensuing acute rejection of the allografts. We therefore hypothesized that local cell-cell contacts between macrophages and effector T lymphocytes promote conversion of infiltrating M2 macrophages, typically involved in wound healing and tissue remodeling, to M1 macrophages which subserve effector cell function in islet allograft rejection. To test this hypothesis, we will use our unique technological platform to perform longitudinal, non- invasive in vivo imaging of the immune cells within pancreatic islets after transplantation (Abdulreda et al., 2011). We will accomplish the objective of this application by pursuing the following three specific aims: (1) Macrophages are necessary for efficient islet allograft rejection~ (2) Infiltratng macrophages acquire M1 phenotype during acute rejection~ and (3) Macrophage M2/M1 conversion is mediated through local cell-cell contacts with T lymphocytes. The expected results from these aims will establish local cell-cell contacts within target tissues as a novel cellular mechanism underlying the active role of macrophages in pancreatic islet rejection. Importantly, this new concept will enable localized interventions to improve acceptance of transplanted islets and will minimize/prevent devastating systemic side effects associated with chronic immunosuppression. These findings will have implications in transplantation therapies in general, as well as in cancer and autoimmune conditions.
Limited long-term survival of transplanted pancreatic islets due to immunological responses after islet transplantation to treat type 1 diabetes remains a significant limitation in this promising therapy. The proposed research aims to establish local cell-cell contacts as a novel mechanism contributing to graft rejection. The central hypothesis in this application is that local contacts between graft-infiltrating macrophages and effector T lymphocytes promote (1) conversion of good M2 macrophages to the bad M1 phenotype and (2) the active participation of the M1 macrophages in islet allograft destruction after transplantation. We will test our central hypothesis using our new technological platform that allows non-invasive in vivo imaging of immune responses in real-time in the same islet grafts longitudinally. The results are expected to provide experimental evidence to support the role of local cell-cell contacts in macrophage involvement in pancreatic islet rejection. This will enable new interventions targeted locally against such cellular interactions to improve long-term survival of pancreatic islet grafts. Local intervention will also minimize/prevent devastating side effects associated with chronic systemic immunosuppression. Furthermore, validation of this new concept on the role of local cell-cell contacts within target tissues in promoting immune responses will have therapeutic implications in transplantation therapies and other conditions such as cancer and autoimmune diseases.
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