INHERENT BETA-CELL DYSFUNCTION INDUCED BY TRANSGENIC EXPRESSION OF ALLOGENEIC MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I ANTIGEN IN ISLET CELLS

Insulin-dependent diabetes mellitus (IDDM) is generally believed to be an autoimmune disease resulting from T-cell dysfunction that produces βcell damage, but it is conceivable that some forms of IDDM are not immunologically mediated. The effect of the expression of a foreign transgenic MHC class 1 antigen (H-2Kb). restricted to pancreatic islet βcells, was tested in vitro and in nude (athymic) mjce to determine whether βcell dysfunction was due to non-immune mechanisms. The models used clearly excluded immune involvement in βcell damage. Fetal pancreas from transgenic and littermate control mice was maintained in orgian culture for up to 18 days and insulin secretion into the medium assessed. For the initial 3-4 days in vitro, fetal control and transgenic pancreas secreted similar amounts of Insulin, but thereafter insulin secretion by the transgenic tissue decreased in comparison with the controls. When the cultured pancreas was transplanted into nude mice, the transgenic issue produced smaller grafts than the control pancreas, but there was wide variation in graft size. Expression of H-2Kb antigens in βcells of nude transgenic mice also resulted in early-onset diabetes. The insulin content in the pancreas of young H-2Kb transgenic euthymic mice, (previously shown not to have insulitis), was reduced but glucagon content was normal. The reduction in in vivo insulin production was similar chronologically to the reduced insulin production by transgenic islets in vitro. These data confirm the non-immune loss of βcell function in MHC-transgenic mice and they may be a model for atypical Type I diabetes. © 1991 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.