The Failure of Skin Grafting to Break Tolerance to Class I-Disparate Renal Allografts in Miniature Swine Despite Inducing Marked Antidonor Cellular Immunity

Chimeric Allografts Induced by Short‐Term Treatment With Stem Cell Mobilizing Agents Result in Long‐Term Kidney Transplant Survival Without Immunosuppression: II, Study in Miniature Swine

“…In a rat kidney transplant model (29), we have shown that FK506 alone increased SDF-1 presence in the transplant. We have reported that cells with macrophage phenotypes are liberated from the bone marrow by FK506 and recruited to the injured sites (27,28 It has been reported that rejection of donor skin grafts occurred in 9-11 days in long-term specific tolerance to one haplotype class I plus minor antigen disparate renal allografts in miniature swine (33). Coincident with skin rejection, most animals developed a transient rise in creatinine to 4.9 AE 1.2 mg/dL (n = 10), with normal levels returning in all animals within 2 weeks.…”

Persistence of Dominant T Cell Clones in Accepted Solid Organ Transplants

“…Considering these data all together, we would suggest that although initially recruited by allogeneic activation, T cell subsets invading accepted grafts develop into nonalloaggressive cells that are likely recruited in tolerance-associated processes. Because previous studies have shown that tolerance, in our model, is established through nondeletional mechanisms (10,32), we may envision that part of the activated GITC pool includes a regulatory subset dedicated to the down-modulation of alloaggressive cytotoxic clones, as described in other species (4,33,34).…”

“…The role of the kidney graft itself has been suspected in local regulation of antidonor reactivity because skin grafts bearing kidney-donor class I plus third-party class II Ags were promptly rejected by animals still tolerant to the kidney (10). The role of local regulation in peripheral T cell tolerance has been further strengthened by in vitro experiments comparing the functional properties of PBL and GITC from tolerant animals.…”

Mechanisms of Tolerance: Role of the Thymus and Persistence of Antigen in Calcineurin-Induced Tolerance of Renal Allografts in MGH Miniature Swine

“…Much like our thymectomy experiments, we found that whereas IL-2 administration can prohibit the induction of tolerance if administered perioperatively, treatment with exogenous IL-2 failed to abrogate tolerance in long-term tolerant (LTT) animals (73). To further distill the role of T-cell help required for the anti-donor cellular response in tolerant animals, we challenged LTT animals with skin grafts from class-I donor/class-II third party donors instead of IL-2 (74). We reasoned that the class-II disparate graft may be capable of providing the necessary T-cell help by stimulating the alloreactive CD4+ population.…”

“…We reasoned that the class-II disparate graft may be capable of providing the necessary T-cell help by stimulating the alloreactive CD4+ population. Although recipient animals experienced a brief rejection crisis following skin grafting, they remained tolerant in the long-term (74). Thus, once established, the peripheral mechanism of tolerance is steadily stable, and capable of suppressing further stimulation with donor antigen.…”