We have demonstrated that multiple prior administrations of donor-strain blood while under continuous daily cyclosporine (CSA) cover, consistently (in all of the cases thus far examined), induces a permanent state of donor-specific immunologic tolerance to kidney allografts transplanted across a strong rat histocompatibility barrier (1). Multiple non-specific transfusions combined with concomitant CsA also induces indefinite kidney graft survival in the majority of cases (2,3) (preliminary results). These data exhibit specific synergism to cyclosporine, as opposed to a non-selective immunosuppressant, azathioprine (1-3). It remains unclear whether the non-specific blood regimen exhibits donor-specific tolerance, and what possible cellular mechanisms may be operative in both transfusion models. These underlying mechanisms must be understood. In this revised application, we propose to focus upon these phenomenon by examining the system in detail at the cellular level. Specifically, we will characterize the following: long-term tolerance in LEW recipients of BN renal allografts induced by multiple donor-specific or non-specific blood administrations respectively, under CsA cover. The immune status at day O (tO) and day 50 (t5O) in tolerant LEW recipients will be characterized. Cell mediated immune characterizations of immunologic non-responsiveness will include: donor-specific and third party mixed lymphocyte responses (MLRs); donor- specific and third party cellular cytotoxicity; T-helper, T- suppressor/cytotoxic, MHC class I, and class II FACS analysis; T- and macrophage suppressor function; role of the spleen in mediating the tolerogenic effect; donor-specific and third party skin grafts; donor-specific and third party antibody responses; and residual serum CsA. Lastly, the donor and non-specific transfusion/CsA cover regimens will be compared for their ability to induce similar extensive prolongation in the strong DA to LEW (RT1a to RT11) rat renal allograft combination.
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