INDUCTION OF DIABETES IN NOD[-]C57BL 6 EMBRYO AGGREGATION CHIMERAS BYCYCLOPHOSPHAMIDE THROUGH PREFERENTIAL DEPLETION OF C57BL/6 LYMPHOCYTES/

The majority of embryo aggregation (EA) mouse chimeras between non-obe se diabetic (NOD) mice and C57BL/6 (B6) mice show clear signs of insul itis frequently accompanied by beta-cell destruction. Less than 5% of these chimeras, however, spontaneously progress to autoimmune diabetes , an incidence far lower than observed in NOD mice. The resistance in chimeras can be accounted for by the target organ chimerism and/or the immune system chimerism. To investigate the mechanism(s) controlling diabetes resistance in these mice, we studied a total of 92 NOD<->B6 E A chimeras that showed overt lymphoid chimerism and treated 34 chimera s with cyclophosphamide (CY), a compound known to precipitate an acute form of insulin-dependent diabetes mellitus (IDDM) in pre-diabetic NO D mice, by interfering with regulatory mechanisms. We found that CY-tr eated EA chimeras displayed an increase in the NOD:BG lymphocyte ratio and 32% of them developed diabetes that could be adoptively transferr ed to irradiated NOD or NOD-rag-2(-/-) mice. These findings suggest th at lymphocyte chimerism rather than p-cell chimerism accounts for diab etes resistance in NOD<->B6 EA chimeras and that the susceptibility to CY-induced diabetes may be related to the proportion of NOD versus B6 lymphoid cells. (C) 1996 Academic Press Limited