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Novel Humanized mice to test Therapeutics for Human Type 1 Diabetes

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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The human MHC class II molecules HLA-DR0401 and HLA-DQ8 have been associated with several cases of T1D as well as other autoimmune disorders. Nevertheless, some studies suggest that there is a potential tolerance effect of the HLADR0401 molecule in humans and transgenically expressed in mice that delays and even exempts them from developing autoimmunity. Our laboratory has previously reported that genetically-engineered, soluble MH class II-peptide chimeras prevent, and more importantly reverse early T1D induced by autoreactive T-cells in the NOD mice 16 60. To validate the therapeutic efficacy of anew soluble HLA-DR4GAD65 chimera termed DEF-GAD65 reagent for human use, we have generated a new humanized mouse model for T1D in the laboratory. Initially, we generated a humanized transgenic NOD H-2g7 mouse expressing the human MHC class II molecule HLA-DR0401 NODHLA-DR4 Tg mice, which surprisingly does not develop T1D, nor pancreatic insulitis. We found that NODHLA-DR4 humanized transgenic mice have an altered T-cell compartment as compared to their NOD non-transgenic littermates. We describe a number of experiments demonstrating the resistance of this mouse strain to T1D. Our results strongly suggest that the T1D resistance is due to a combination of several factors such as high number of Foxp3 Treg cells at young age, low INF- inflammatory response to polyclonal and antigen-specific stimulation, and an unusually high CD4 to CD8 ratio in the thymus and peripheral lymphoid organs. Our results indicated that the human MHC class II, HLA-DR0401 has regulatory potency at an early stage of T cell development by altering the thymic output in favor of immune tolerance. In addition to this mouse strain, we generated a NODHLA-DR4 strain expressing the human co-stimulatory molecule B7-1CD80 in pancreatic islets under the rat insulin promoter, by crossing the transgenic NODHLA-DR4 and NODB7-1 mice. Close to 70 of the F1 hybrids NODHLA-DR4B7-1 double tr

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