ANTI-CD4 MONOCLONAL ANTIBODY-INDUCED TOLERANCE TO MHC-INCOMPATIBLE CARDIAC ALLOGRAFTS MAINTAINED BY CD4(-CELLS THAT ARE NOT DEPENDENT UPON IL-4() SUPPRESSOR T)

Anti-CD4 mAb-induced tolerance to transplanted tissues has been propos ed as due to down-regulation of Th1 cells by preferential induction of Th2 cytokines, especially IL-4, This study examined the role of CD4() cells and cytokines in tolerance to fully allogeneic PVG strain hete rotopic cardiac allografts induced in naive DA rats by treatment with MRC Ox38, a nondepleting anti-CD4 mAb, All grafts survived >100 days b ut had a minor mononuclear cell infiltrate that increased mRNA for the Th1 cytokines IL-2, IFN-gamma, and TNF-beta, but not for Th2 cytokine s IL-4 and IL-6 or the cytolytic molecules perforin and granzyme A. Th ese hosts accepted PVG skin grafts but rejected third-party grass, whi ch were not blocked by anti-IL-4 mAb, Cells from these tolerant hosts proliferated in MLC and produced IL-2, IFN-gamma, and IL-4 at levels e quivalent to naive cells. Unfractionated and CD4(+) T cells, but not C D8(+) T cells, transferred specific tolerance to irradiated heart graf ted hosts and inhibited reconstitution of rejection by cotransferred n aive cells. This transfer of tolerance was associated with normal indu ction of IL-2 and delayed induction of IFN-gamma, but not with increas ed IL-4 or IL-10 mRNA, Transfer of tolerance was also not inhibited by anti-IL-4 mAb, This study demonstrated that tolerance induced by a no ndepleting anti-CD4 mAb is maintained by a CD4+ suppressor T cell that is not associated with preferential induction of Th2 cytokines or the need for IL-4; nor is it associated with an inability to induce Th1 c ytokines or anergy.