MECHANISM FOR INDUCTION AND MAINTENANCE OF IMMUNOLOGICAL TOLERANCE IN THE ORGAN TRANSPLANTATION TO THE SENSITIZED RATS

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Tolerance induced by the nondepleting anti-CD4 monoclonal antibody (RIB-512) in the sensitized rats is strongly associated with CD4ィイD2+ィエD2IL-4 producing Th2-type regulatory T cells. Tolerance was not adoptively transferable and was easily broken by rIL-2 in the long-term surviving thymectomized recipients, but not in euthymic tolerant rats. Thymectomy of tolerant rats or recipients of tolerance-mediating T cells did not influence the stability and transferability of tolerance, suggesting that fresh thymus emigrants are the cellular source of regulatory T cells.Moreover, antigen is necessary to maintain regulatory T cells. Two weeks after the removal of the grafted heart, transferability of tolerance disappeared, but tolerance did not until 4 weeks after that, suggesting that clonal anergy was still working. On the other hand, two weeks after the removal of the grafted heart in there cipients of tolerance-mediating T cells, tolerance was not broken, suggesting that the recipient was endowed with clonal anergy.Next, intragraft expression of both Th1 (IL-2/IFN-g) and Th2 (IL-4/IL10) cytokines was examined by competitive RT-PCR to dissect the dynamics of regulatory T cells. Long-term grafts in RIB-5/2 treated recipients showed profound depression of Th1 and Th2 cytokines at the graft site. However, when second cardiac graft was transplanted, IFN-g and IL-10 were up-regulated in the primary grafts, and up-regulation of IL-4 was seen in second grafts. However, Th1 and Th2 cytokines returned to the low level in time in both grafts. From the view point of the cytokine pattern at graft sites, once fresh antigen is transplanted, silent regulatory T cells seems to migrate to new Tx and activate.Clonal anergy and regulatory CD4ィイD1+ィエD1Th2-like IL-4 producing cells, which transfer infectious tolerance to new cohorts of test rat recipients, contribute to non-depleting CD4 mAb (RIB-5/2) induced permanent Tx survival in sensitized rat model.