Title: Iatrogenic immunization reveals the properties of islet destructive T-cells
Funder: Juvenile Diabetes Research Foundation

Abstract: To define the intrinsic properties of the immune cells that are directly involved in destroying pancreatic beta cells in individuals undergoing islet transplantation. This will lead to a better understanding of why these cells are not controlled by standard immunosuppressive drugs and highlight new ways to prevent the action of these cells both in the context of transplantation and during initial development of T1D. Type 1 diabetes is the result of the specific destruction of the insulin producing pancreatic beta cells. This process is orchestrated by cells of the bodys own immune system (T cells) which target proteins present in the beta cells and lead to their destruction. These self-reactive (or autoimmune) T cells can be detected in the blood of individuals before, during and after the onset of T1D. Recent studies have suggested that similar autoreactive T cells may also be responsible for destroying new beta cells transplanted into individuals undergoing islet transplantation many years after the initial onset of T1D. These T cells are termed memory T cells as they were generated during the initial destruction of beta cells and have persisted in the immune system ever since. This recurrence of autoimmunity occurs despite the immunosuppressive drugs used in these individuals to prevent rejection. These results suggest that autoreactive memory T cells may be particularly resistant to control by standard immunosuppressive drugs and that islet transplantation presents a unique opportunity to study islet destructive memory T cell responses in these individuals.Our proposal seeks to define the intrinsic properties of these memory T cells that are directly involved in destroying pancreatic beta cells in individuals undergoing islet transplantation. This will lead to a better understanding of why these cells are not controlled by standard immunosuppressive drugs and highlight new ways to prevent the action of these cells both in the context of transplantation and during initial development of T1D. Our study has 3 main phases: Firstly, we will identify the type of immune response that is associated with islet destruction (we have shown that not all immune responses directed against islets lead to their destruction, in fact our studies suggest that some responses are able to protect from islet destruction). This will be achieved by measuring immune responses in fresh blood samples from individuals before and at regular intervals following islet transplantation using tried and tested techniques. At every time point we will also measure the function of the islets, which will allow us to identify when and in which patients islet destruction is taking place. This combination of in-depth studies of the immune system of the immune system and comprehensive measurement of islet function should allow the identification of the immune cells that are most closely related to islet destruction and therefore more likely to be directly involved in the killing process rather than being caused by it or unrelated to it. Secondly, we will isolate the cells associated with islet destruction and perform detailed studies on these cells. This will allow us to identify characteristics that are specific to these pathogenic cells and assess their susceptibility (or resistance) to immune suppression and regulation.Finally, we will examine archived pre-tr We anticipate that we will identify novel characteristics of islet destructive memory T cells that may reveal rational targets for islet specific immuno-intervention strategies. We believe we will also identify specific biomarkers for these islet destructive T cells that can be used to better manage immunosuppressive regimens in individual patients. Finally, we may also highlight more accurate methods to assess the likelihood of subsequent islet graft survival in individuals prior to transplantation. It is clear that these studies have several potential benefits for individuals undergoing islet transplan


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE