Mechanism of tolerance to class I mismatched renal allografts in miniature swine -: Regulation of interleukin-2 receptor α-chain expression on CD8 peripheral blood lymphocytes of tolerant animals

Background. Donor-specific tolerance to renal allografts in miniature swine is uniformly induced across a two-haplotype class I plus minor histocompatibility antigen disparity by a la-day course of cyclosporine. Recent studies have demonstrated that the thymus is essential for rapid and stable tolerance induction, because either prior thymectomy or a series of thymic biopsies induce a spontaneously reversible rejection crisis after the la-day course of cyclosporine. The present study examined the peripheral cellular mechanisms of tolerance by analyzing cytotoxic effector pathways in peripheral blood lymphocytes (PBL) of tolerant animals. Methods. The phenotype and cytotoxic T lymphocyte response of alloantigen-activated PBL cultures using cells from a series of tolerant animals with stable renal function (no thymic manipulation), or during a rejection crisis (induced by thymic biopsies), were studied. The in vitro findings were correlated with the in vivo clinical course of experimental animals. Results. The data demonstrated that in vivo and in vitro tolerance was associated with a specific deficiency of interleukin-alpha receptor (IL-SR) alpha-chain upregulation on CD8 single-positive (SP) T cells expressing high levels of CD8 (CD8(high)) when PBL from tolerant animals are stimulated with donor class I alloantigen. Stimulation by third party class I alloantigen, or by donor antigen during a rejection crisis, produced efficient cytotoxic T lymphocyte responses and expression of IL-2R alpha on CD8(high) SP cells. Conclusion. Antigen-specific regulation of the IL-2R alpha expression on CD8(high) SP PBL is a principal event associated with and potentially involved in the mechanism of tolerance in this preclinical large animal model.