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Linked Suppression across an MHC-Mismatched Barrier in a Miniature Swine Kidney Transplantation Model¹

Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA 02129

We have demonstrated previously that a 12-day course of FK506 permits the induction of tolerance to fully MHC-mismatched renal transplants in miniature swine. In the present study, we examined the mechanism of this tolerance by assessing the possibility that the survival of one-haplotype mismatched third-party kidneys might be prolonged via linked suppression. Ten SLA^d/d miniature swine received fully MHC-mismatched renal allografts from SLA^c/c donors with 12 days of FK506. Six animals received second SLA^c/c kidneys without immunosuppression to confirm tolerance. Regulatory mechanisms were assessed by mixed lymphocyte reaction (MLR) and cell-mediated lympholysis coculture assays and ELISA for regulatory cytokines. Linked suppression was investigated by transplanting SLA^a/c or SLA^a/d allografts into long-term tolerant recipients without immunosuppression. All recipients showed donor-specific unresponsiveness in standard cell-mediated lympholysis and MLR assays. Tolerant cells prestimulated with donor Ag and then cocultured with naive recipient MHC-matched cells inhibited antidonor responses, confirming the presence of regulatory cells. ELISA and MLR assays showed that TGF-β2 was involved in mediating the suppression in vitro. SLA^a/d renal allografts transplanted into tolerant recipients were rejected by postoperative day 8 (median, 7 days; range, 6–8). In contrast, SLA^a/c allografts showed markedly prolonged survival (median, 52 days; range, 28–78; p = 0.0246), suggesting linked suppression. Animals not challenged with a second donor-matched graft did not manifest linked suppression consistent with in vitro data showing that re-exposure to tolerated Ags is important for generation of regulatory cells. To our knowledge, these data represent the first evidence of linked suppression across fully MHC-mismatched barriers in a large animal model.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (R37 AI31046-16) and A.G. received support from the American Society of Transplantation/Juvenile Diabetes Research Foundation Fellowship.

² Address correspondence and reprint requests to Dr. Kazuhiko Yamada, Organ Transplantation Tolerance and Xenotransplantation Laboratory, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129. E-mail address: kaz.yamada{at}tbrc.mgh.harvard.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; MLR, mixed lymphocyte reaction; CML, cell-mediated lympholysis; POD, postoperative day.

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The JI 2008 181: 3729-3730. [Full Text]