In Vivo Inhibition of Cytokine Responsiveness and Graft-Versus-Host Disease Mortality by Rapamycin Leads to a Clinical-Pathological Syndrome Discrete From That Observed With Cyclosporin

Rapamycin (RAPA) has been shown t o be a highly effective means of reducing the lethality of graft-versus-host disease (GVHD) in B1O.BR recipients of allogeneic C57BL/6 donor cells. RAPA-treated mice had no clinical (eg, weight loss, diarrhea, lethargy) or histologic evidence of classical acute or chronic GVHD but did develop a clinical-pathological syndrome consisting of ulcerative dermatitis, bile duct proliferation, and a nondestructive peribronchiolar pulmonary infiltration. Because RAPA was found t o interfere with the deletion of self-reactive T cells, we wondered whether the RAPA-induced syndrome was related t o failed negative selection or altered alloreactivity. We now show that the RAPA-induced syndrome is due t o effects on mature, donorderived alloreactive T cells. By titering the number of T cells infused we were able to vary the syndrome incidence. In contrast t o the syndrome seen after cyclosporin A (CsA) administration, the RAPA syndrome did not require an intact