RAPAMYCIN INHIBITS THE GENERATION OF GRAFT-VERSUS-HOST DISEASE-CAUSING AND GRAFT-VERSUS-LEUKEMIA-CAUSING T-CELLS BY INTERFERING WITH THE PRODUCTION OF TH1 OR TH1 CYTOTOXIC CYTOKINES

Rapamycin (RAPA), an inhibitor of cytokine responses, is under investi gation in humans for graft-vs-host disease (GVHD) prevention. The mech anisms responsible for GVHD prevention are unknown. We show that RAPA is more effective in inhibiting CD8(+) or TCR gamma delta(+) than CD4( +) T cell-mediated murine GVHD. To determine how RAPA inhibited GVHD, thoracic duct lymphocytes (TDL) were isolated from recipients of allog eneic donor grafts. Compared with controls, RAPA-treated recipients ha d a marked decrease in donor TDL T cell number between days 5 and 24 p osttransplant. CD8(+) T cell expansion was preferentially inhibited. R APA inhibited Th1 or Th1 cytotoxic (Tc1) cytokines, but not Th2 or Tc2 , cell generation. In situ mRNA hybridization also showed that TDL T c ells from RAPA-treated mice had a lower frequency of granzyme B+ cells , indicating that RAPA inhibited the generation of CTL capable of medi ating cytolysis through the release of granzyme B, In another system, RAPA was found to inhibit the GVL response of delayed donor lymphocyte infusions. Since CD8(+) T cells are the primary effecters in this sys tem, these data suggest that RAPA directly interfered with GVL effecto r cell expansion or function. We conclude that RAPA is effective in in hibiting Th1 or Tc1 cytokine production and CD8(+) and TCR gamma delta (+) T cell-mediated GVHD, but abrogates GVL.