Our previous in vitro data have demonstrated that regulatory mechanisms are involved in tolerance of class I-mismatched renal allografts in miniature swine treated with 12 days of high dose Cyclsporin A. In the present study, we attempted to induce tolerance of class I-mismatched kidneys by adoptive transfer of cells and/or kidneys from long-term tolerant animals. Fifteen SLAdd miniature swine received 1.5 Gy whole body irradiation and class I-mismatched (SLAgg) kidneys from naïve pigs with or without co-transplanted kidneys and/or adoptively transferred cells from long-term tolerant (LTT) SLAdd recipients of SLAgg grafts. Additionally, three SLAdd miniature swine received class I mismatched kidney with adoptively transferred cells from LTT SLAdd recipients. Naïve kidneys transplanted without a LTT kidney were rejected within 9 days. All recipients of naive kidneys along with cells and kidney grafts from LTT animals showed markedly prolonged survival of the naive renal grafts (day 28, >150 and >150 days). These studies suggest that (1) tolerated kidneys have potent regulatory effects, and (2) cells from LTT animals infused in conjunction with kidney grafts augment these regulatory effects. To our knowledge, these studies represent the first demonstration of successful adoptive transfer of tolerance in large animals.
We have previously demonstrated that long-term tolerance (LTT) of an MHC class-I mismatched renal allograft can be achieved with a short course of cyclosporine. In order to examine regulatory mechanisms underlying tolerance in this model, we assessed the contributions of factors within the graft and in the peripheral blood for their relative roles in the maintenance of stable tolerance. Twelve LTT recipients of MHC class-I mismatched primary kidneys were subjected to a treatment consisting of donor-specific transfusion (DST) followed by leukapheresis, in order to remove peripheral leukocytes, including putative regulatory T cells (Tregs). Following treatment, two controls were followed clinically and 10 animals received a second, donor-MHC-matched kidney. Neither control animal showed evidence of rejection, while 8 of 10 re-transplanted animals developed either rejection crisis or full rejection of the second transplant. In vitro assays confirmed that the removed leukocytes were suppressive and that CD4+Foxp3+ Treg reconstitution in blood and kidney grafts correlated with return to normal renal function in animals experiencing transient rejection crises. These data indicate that components of accepted kidney grafts as well as peripheral regulatory components both contribute to the tolerogenic environment required for tolerance of MHC class-I mismatched allotransplants.
Background We have previously reported that MGH miniature swine which had accepted class-I mismatched kidneys long-term (LT) following 12 days of high dose Cyclosporine (CyA), uniformly accepted donor-MHC matched kidneys without immunosuppression but rejected donor-MHC matched split-thickness skin grafts (STSG) by day 25, without changes in renal graft function or anti-donor in vitro responses. We have now tested whether this “split tolerance” would also be observed for the primarily-vascularized skin of vascularized composite allografts (VCAs). Methods Group 1 animals (n=3) received donor-MHC matched VCAs <70 days following primary kidney transplant (KTx). Group 2 animals (n=3) received a second donor-matched t KTx followed by a donor-matched VCA >200 days after primary KTx. Results Animals in Group 1 lost the epidermis on days 28, 30, and 40, with all other components of the VCAs remaining viable. Histology showed cellular infiltration localized to dermal-epidermal junction. One of 3 recipients of VCAs including epidermis in Group 2 accepted all components of the VCAs (>200 days). The other two recipients lost only the epidermis at day 45 and 85, with survival of the remainder of the VCA long-term. Conclusions All tissues of a VCA are accepted long-term on animals tolerant of class-I mismatched kidneys, with the exception of epidermis, the survival of which is markedly prolonged compared to STSG, but not indefinite. Exposure of tolerant animals to second donor-matched kidneys prior to VCA increases the longevity of the VCA epidermis, suggesting an increase in the immunomodulatory mechanisms associated with tolerance of the kidney.
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