Optimised combination therapies in order to reverse the diabetic state in type 1 diabetes including the LADA type based on the pathomechanisms: studies in the LEW.1AR1-iddm rat with a comparative view to the human situation

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Cellular composition and cytokine pattern of the immune cell infiltrate in pancreatic islets after diabetes manifestation show the greatest similarities in an animal model of human type 1 diabetes mellitus, the LEW.1AR1.iddm rat, when compared with the pancreas of patients. Thus, this model is particularly suited for validation of successful immunomodulatory prevention therapies.Using biochemical and molecular morphological methods it is the aim of this project to evaluate the effectiveness of new rational antibody combinations in comparison to the successfully established combination therapy of anti-TCR and anti-TNF-alpha as a reference in pancreas and in blood. The particular focus will be on combinations of the T-cell antibody anti-TCR with antibodies against the proinflammatory cytokines IL-1beta, IFN-gamma, IL-17 and the chemokine MCP-1 with respect to the remission of the diabetic metabolic state. Furthermore the efficacy of a combined administration of the two antibodies against the main proinflammatory cytokines, TNF-alpha and IL-1beta, will be determined; however, in the absence of anti-TCR. Additionally the effectiveness of a sequential application of anti-TCR and anti-TNF-alpha will be analysed under the special aspect of a minimisation of the risk of undesirable interactions of the two antibodies. Furthermore, a one-year long-term monitoring of the reference combination anti-TCR plus anti-TNF-alpha will be assessed with respect to the risk of a later reccurrence of diabetic hyperglycemia.The slowly progressive form of autoimmune diabetes called LADA (Latent Autoimmune Diabetes in Adults) has features that make it particularly attractive for possible translation of immunomodulatory combination therapies to humans. In the LEW.1AR1-iddm rat model it was possible for the first time to verify this LADA form in an animal model. So far pancreatic changes have only been described in a few patients with LADA. Therefore a clear pathophysiological delineation is not yet possible. Pancreases from LADA patients and in parallel pancreases from the rat model with a slowly progressing form of autoimmune diabetes will be available for analyses on the gene and protein level using molecular morphology methods with special emphasis on islet infiltration and beta cell changes. In parallel beta cell regeneration processes will be characterised by neogenesis and proliferation analyses. The results of these comparative morphological analyses will provide criteria for distinction between the autoimmune diabetes forms. For the purpose of distinction of the pathological changes in pancreases of patients with early onset type 1 diabetes and the latent form, both with signs of immune cell infiltration, pancreases of patients with type 2 diabetes will be analysed. These studies will be the basis for a future transfer of curative therapy approaches with optimal antibody combinations for type 1 diabetes patients with different speed of disease progression.