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Anti-CD4 Monoclonal Antibody-Induced Tolerance to MHC-Incompatible Cardiac Allografts Maintained by CD4⁺ Suppressor T Cells That Are Not Dependent upon IL-4¹

Department of Medicine, University of New South Wales, Liverpool Hospital, Liverpool, New South Wales, Australia

Anti-CD4 mAb-induced tolerance to transplanted tissues has been proposed 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 heterotopic cardiac allografts induced in naive DA rats by treatment with MRC Ox38, a nondepleting anti-CD4 mAb. All grafts survived >100 days but had a minor mononuclear cell infiltrate that increased mRNA for the Th1 cytokines IL-2, IFN-, and TNF-ß, but not for Th2 cytokines IL-4 and IL-6 or the cytolytic molecules perforin and granzyme A. These hosts accepted PVG skin grafts but rejected third-party grafts, which were not blocked by anti-IL-4 mAb. Cells from these tolerant hosts proliferated in MLC and produced IL-2, IFN-, and IL-4 at levels equivalent to naive cells. Unfractionated and CD4⁺ T cells, but not CD8⁺ T cells, transferred specific tolerance to irradiated heart grafted hosts and inhibited reconstitution of rejection by cotransferred naive cells. This transfer of tolerance was associated with normal induction of IL-2 and delayed induction of IFN-, but not with increased 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 nondepleting 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 cytokines or anergy.

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