Multidose streptozotocin induction of diabetes in BALB/cBy mice induces a T cell proliferation defect in thymocytes which is reversible by interleukin-4

Thymic T cell function in streptozotocin-treated (STZ) diabetic mice has be en examined. STZ administration suppresses thymic T cell proliferation in r esponse to mitogen stimulation in vitro, Secretion of IL-4 was dramatically reduced; however, secretion of IL-2 or IFN-gamma was not significantly inh ibited. RT-PCR analysis of thymocyte RNA revealed that levels of IL-4 mRNA were dramatically decreased in STZ-treated mice. Levels of mRNA encoding IF N-gamma were similar, but the appearance was delayed in thymocytes derived from STZ-treated mice, implying differential regulation of IL-4 and IFN-gam ma. Defective thymocyte proliferation was partially restored by exposure to IL-2 in vitro; however, IL-4 completely reversed the STZ-induced defect. A dministration in vivo of IL-4 before STZ treatment reversed the STZ-induced thymocyte proliferation defect and prevented both pancreatic islet destruc tion and hyperglycemia. Thymocyte cell surface differentiation markers were not appreciably different from control mice. Collectively these experiment s suggest that STZ treatment of mice reduces expression of IL-4 which is as sociated with development of autoimmune diabetes. (C) 1999 Academic Press.