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*
Department of Pediatrics, Division of Bone Marrow Transplantation, and
Department of Therapeutic Radiology, University of Minnesota Hospital and Clinic, Minneapolis, MN 55455
Rapamycin (RAPA), an inhibitor of cytokine responses, is under
investigation in humans for graft-vs-host disease (GVHD) prevention.
The mechanisms responsible for GVHD prevention are unknown. We show
that RAPA is more effective in inhibiting CD8+ or TCR
+ than CD4+ T cell-mediated murine GVHD.
To determine how RAPA inhibited GVHD, thoracic duct lymphocytes (TDL)
were isolated from recipients of allogeneic donor grafts. Compared with
controls, RAPA-treated recipients had a marked decrease in donor TDL T
cell number between days 5 and 24 posttransplant. CD8+ T
cell expansion was preferentially inhibited. RAPA inhibited Th1 or Th1
cytotoxic (Tc1) cytokines, but not Th2 or Tc2, cell generation. In situ
mRNA hybridization also showed that TDL T cells from RAPA-treated mice
had a lower frequency of granzyme B+ cells, indicating that
RAPA inhibited the generation of CTL capable of mediating 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 effectors in this system,
these data suggest that RAPA directly interfered with GVL effector cell
expansion or function. We conclude that RAPA is effective in inhibiting
Th1 or Tc1 cytokine production and CD8+ and
TCR+ T cell-mediated GVHD, but abrogates GVL.
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