Type 1 diabetes: primary antigen/peptide/register/trimolecular complex
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Type 1A diabetes (autoimmune) is now immunologically predictable in man, but preventable only in animal models. What triggers the development of autoimmunity in genetically susceptible individuals remains unknown. Studies of non-obese diabetic (NOD) mice reveal that interactions between T-cell receptors of diabetogenic T cell and an MHC class II loaded with an autoantigen are key determinates of the disease. With insulin as the primary target in the NOD mouse, likely man, and possibly the RT1-U rat models, therapeutic targeting of the components of these anti-insulin trimolecular complexes we believe provide a fulcrum for development of preventive therapy. In particular for the NOD mouse model, there is extensive evidence that the dominant insulin peptide driving disease initiation is insulin B chain amino acids 9-23 (SHLVEALYLVCGERG) recognized predominantly by germ-line sequences of a specific T-cell receptor Valpha (TRAV5D-4), and small molecules or monoclonal antibodies directed at this recognition complex can prevent diabetes.
KeywordsIslet Autoantibody Diabetes Beta cells Autoimmunity Pancreas
This work was supported by grants from the National Institute of Health (R01 DK 032083, U19AI050864, P30 DK 057516, NO1 AI 15416), the International Autoimmunity Center, the Juvenile Diabetes Research Foundation, the Brehm Coalition, the Helmsley Foundation, and the Children’s Diabetes Foundation.
Conflict of interest
Dr. Eisenbarth is on two university provisional patents for treating autoimmunity with small molecules. There is also a research grant from Novartis in the same area. Part of Dr. Sosinowski’s research is funded by a grant from Novartis.
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