Interferon-gamma is not involved in the intestinal manifestations of the acute murine semiallogenic graft-versus-host disease

Background: The acute murine semiallogenic graft-versus-host disease (GvHD) is known to be associated with Th1 cytokines secreting lymphocytes in the spleen and lymph nodes. However, whether this cytokine secretion pattern is also involved in the intestinal manifestations of acute GvHD (crypt hyperp lasia and villous atrophy) is not known, so far. Methods: We first investig ated the secretion of interleukin (IL) 4 (indicative of Th2-type differenti ation) and interferon (IFN) gamma (Th1-type differentiation) by splenic and by small bowel lamina propria lymphocytes. In addition, animals were treat ed with neutralizing antibodies to IL-4 or IL-12. The effect of this treatm ent on the intestinal morphology was examined. Second. we also investigated the effect of donor-derived IFN-gamma by using donor lymphocytes from IFN- gamma knock-out animals. Third, animals were treated with the fusion protei n OX40-Ig which interferes with the OX40-OX40L interaction and thereby inhi bits the intestinal manifestations of acute GvHD. Results: We found that. w hereas splenic lymphocytes secrete an excess of IFN-gamma, lymphocytes of t he intestinal lamina propria secrete less IFN-gamma and IL-4 than control a nimals. When OX40-Ig is administered to animals with acute GvHD, the intest inal histology normalizes as well as the secretion of IFN-gamma and IL-4, i ndicating that the intestinal morphology is not affected by the secretion o f IFN-gamma by lamina propria lymphocytes. The treatment of animals sufferi ng from acute GvHD with anti-IL-4 and anti-IL-12, which blocks the differen tiation of IFN-gamma secreting T-lymphocytes, did not significantly affect the development of crypt hyperplasia or villous atrophy. Furthermore, donor lymphocytes of IFN-gamma knock-out animals also induced the intestinal man ifestations of acute GvHD. Conclusions: These findings indicate that IFN-ga mma is not crucial for the development of crypt hyperplasia and villous atr ophy in the murine semiallogenic GvHD.