INVOLVEMENT OF OX40-OX40L INTERACTIONS IN THE INTESTINAL MANIFESTATIONS OF THE MURINE ACUTE GRAFT-VERSUS-HOST DISEASE

Background & Aims: The intestinal histology of murine semiallogeneic g raft-versus-host (GVH) disease is characterized by lymphocytic infiltr ates, crypt hyperplasia, and villous atrophy. Mechanisms of T cell-med iated changes of the mucosal architecture were investigated. Methods: The rate of cellular apoptosis and proliferation, changes in the compo sition of extracellular matrix (ECM), and the role of OX40-OX40L inter actions in the pathogenesis of villous atrophy and crypt hyperplasia w ere examined. Results: The rate of apoptosis and the number of prolife rating cells were significantly increased in GVH animals compared with control animals. In addition, expression of tenascin, an ECM componen t, was down-regulated in GVH animals. Inhibition of OX40-OX40L interac tions in GVH animals by administration of an OX40-Ig fusion protein co mpletely prevented the development of crypt hyperplasia and villous at rophy in GVH animals. Tenascin expression was up-regulated in OX40-lg- treated mice compared with GVH animals, suggesting an important functi on of this ECM component in mucosal repair. Conclusions: The OX40-OX40 L interaction is crucial in the pathogenesis of GVH, a T cell-mediated intestinal disease. The data suggest that the ECM component tenascin is probably relevant for the regeneration and maintenance of intestina l tissue architecture.