Abstract
We have produced and studied several transgenic models of insulin dependent diabetes mellitus (IDDM). For understanding the etiology of IDDM, we have investigated the consequences of expression of host defense molecules in the pancreatic islets. IFN-γ is produced in response to infection and has immune-stimulatory and proliferative activities. To investigate the potential role of IFN-γ in inflammatory autoimmune diseases, transgenic mice expressing IFN-γ in pancreatic beta cells were created. These mice suffer from islet cell loss following the appearance of increasing numbers of lymphocytes within and surrounding the islets. We have studied the islet destruction in these mice and have demonstrated that it is mediated by inflammatory cells. Interestingly a proliferative/regenerative response opposes the lymphocyte destruction. We have recently been characterizing this proliferative axis in the transgenic pancreas. We have acquired evidence that it is initiated by duct cell proliferation and with the appearance of more primitive neuroendocrine progenitor cells along the apical regions of the ducts. The regenerative process in the ins-IFN-γ transgenic mice appears similar to the events that occur during embryonic islet cell development. These studies underscore the lymphokine's ability to initiate a complex “transdifferentiation” pathway within a terminally differentiated structure. Another fascinating molecule with potential relevance for treatment of IDDM is the cytokine IL-10. This molecule appears to have immuno-inhibitory effects that include the suppression of antigen presentation by macrophages. We have recently investigated the effects of the cytokine IL-10 on the pancreatic islets. These efforts were designed to test whether the expression of IL-10 could allow the creation of neutral islet tissue for allografting. Our work demonstrates that this molecule has both the ability to attract lymphocytes in vivo as well as to suppress the anti-islet immune response. We have utilized several experimental protocols to study the in vivo effects of this molecule. The results of these studies argue that this cytokine could be relevant for therapeutic intervention in IDDM. Our methodologies should clarify the potentially pathogenic capabilities of host defense molecules when expressed in vivo. Additional IDDM models, produced by ourselves as well as our colleagues will be discussed.
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Sarvetnick, N., Gu, D., Lee, M. et al. ISLET CELL DESTRUCTION AND GROWTH STUDIED IN TRANSGENIC ANIMAL MODELS. Pediatr Res 33 (Suppl 5), S1 (1993). https://doi.org/10.1203/00006450-199305001-00002
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DOI: https://doi.org/10.1203/00006450-199305001-00002