Inhibitors of Src-family tyrosine kinases favour Th2 differentiation

Two potent pyrazolo-pyrimidine inhibitors of Src-family kinases were found to enhance interleukin 4 (IL-4) and reduce interferon gamma (IFN-gamma) pro duction in cultures of splenocytes from ovalbumin-specific TCR-transgenic B ALB/c mice. The effect,vas increased by addition of a monoclonal antibody b inding to domains 3/4 of CD4, while other antibodies binding to domain 1 ha d the opposite effect. The inhibitors suppressed CD40 ligand (CD40L) expres sion on activated CD4 T cells,,which may explain this Th2 differentiating e ffect. More generally, the effect fits within the overall framework of sign al attenuation in T cells driving this form of differentiation. The inhibit ors did not revert previously induced Th1 differentiation in serial culture s of the TCR-transgenic cells. Drugs,vith this activity are of obvious inte rest as probes and potential therapeutic agents in autoimmune disease. (C) 1999 Academic Press.