Thymus-dependent, anti-CD4-induced tolerance to rat cardiac allografts

Background Treatment with anti-CD4 monoclonal antibodies (mAbs) leads to in duction of transplant tolerance ill rodent models, but the cellular mechani sms responsible are poorly defined. In this study, we used a rat model of c ardiac transplantation to examine the contribution of the thymus gland to a nti-CD4 mAb-induced tolerance. Methods. Pretransplant administration of OX38 mAb partially depletes periph eral CD4 T cells and induces tolerance to fully allogeneic Lewis (RT1(1)) h eterotopic cardiac allografts in DA (RT1(a)) recipients. Using this experim ental model, the contribution of the adult thymus gland and of recent thymi c emigrants to tolerance induction was assessed, and the cellular and humor al alloimmune responses accompanying tolerance defined. Results. OX38 mAb selectively depleted mature CD4 T cells,ut spared CD4 T c ells that had recently emerged from the thymus. Pretransplant thymectomy ab rogated tolerance induction, but the data suggested a role for recent thymi c emigrants rather than for the thymus gland per se, Both nonrejecting card iac allografts in OX38-treated recipients and rejecting grafts in control a nimals were infiltrated to a similar extent by mononuclear cells, including activated T cells. Intragraft mRNA transcripts for interleukin (IL)-2, int erferon-gamma, IL-4, IL-10, and IL-13 were similar in non-rejecting and rej ecting allografts although, with the exception of IL-2, there was a trend t owards reduced cytokine transcripts in tolerant grafts. CD4 T cells from lo ng-term tolerant recipients proliferated normally to donor alloantigen in v itro, and produced IL-2, interferon-gamma, and IL-4 in amounts comparable t o normal CD4 T cells. Tolerant recipients also developed a strong alloantib ody response comprising both IgG1 (Th2-dependent) and IgG2b (Th1-dependent) subclasses. Conclusions. The results of this study suggest that the thymus, through the production of recent thymic emigrants, plays an important role in facilita ting the induction of transplant tolerance after anti-CD4 mAb. Tolerant ani mals displayed strong cell-mediated and humoral alloimmune responses with n o evidence of selective deviation from a Th1 to a Th2-like cytokine pattern .