Tolerogenicity of donor major histocompatibility complex-matched skin grafts in previously tolerant massachusetts general hospital miniature swine

Joshua Weiner, Joseph Scalea, Yoshinori Ishikawa, Masayoshi Okumi, Adam Griesemer, Atsushi Hirakata, Justin Etter, Bradford Gillon, Shannon Moran, Akira Shimizu, Kazuhiko Yamada, David H. Sachs

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Long-term tolerance of class I disparate renal allografts in miniature swine can be induced by a short course of cyclosporine and persists for 3 to 4 months after grafts are removed. Donor class I peptide immunization 6 weeks after graftectomy of tolerated kidneys leads to sensitization, but donor skin grafts do not. Here, we tested the hypothesis that skin grafts prevent rejection after simultaneous peptide administration and skin grafting. Methods: Miniature swine underwent bilateral nephrectomy and class I-mismatched renal transplantation with a 12-day course of cyclosporine A to induce long-term tolerance. Tolerated allografts were then replaced with recipient-matched kidneys, and animals were challenged with simultaneous donor-type skin grafts and peptide. Six weeks later, second donor-matched kidneys were transplanted without immunosuppression, and immune responses were characterized. Results: Animals treated only with peptide (n=2) rejected subsequent renal transplants in 3 to 5 days with strong in vitro antidonor responses. Of five recipients of skin-plus-peptide regimen, two accepted kidneys long term, one demonstrated a modestly prolonged survival (11 days), and two rejected rapidly (5-7 days). The two long-term acceptors maintained donor-specific hyporesponsiveness in vitro. Conclusions: Sensitization by class I peptide in previously tolerant swine could be prevented by simultaneous class I skin grafts. These data suggest that skin grafts may actually augment rather than abrogate downregulation in some cases. A mechanistic hypothesis for this surprising result is that recognition of class I antigens through the direct rather than the indirect pathway of antigen presentation promotes tolerance by expanding regulatory T cells.

Original languageEnglish (US)
Pages (from-to)1192-1199
Number of pages8
JournalTransplantation
Volume94
Issue number12
DOIs
StatePublished - Dec 27 2012
Externally publishedYes

Keywords

  • Allografts
  • Kidney transplantation
  • MHC class I
  • Miniature swine
  • Tolerance

ASJC Scopus subject areas

  • Transplantation

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