Joshua Weiner

Date of Award

8-2-2010

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Sukru Emre, M.D.

Second Advisor

David H. Sachs, M.D.

Abstract

A POTENTIAL TOLEROGENEIC ROLE OF SKIN GRAFTS IN PREVIOUSLY TOLERANT ANIMALS Joshua Weiner, Kazuhiko Yamada, Joseph Scalea, Yoshinori Ishikawa, Masayoshi Okumi, Adam Griesemer, Atsushi Hirakata, Justin Etter, Akira Shimizu, and David H. Sachs. Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA. (Sponsored by Sukru H. Emre, Department of Surgery, Section of Transplantation and Immunology, Yale University School of Medicine). We have previously shown that long-term tolerance to class I disparate renal allografts in miniature swine is induced by a short course of Cyclosporine A (CyA). In these tolerant animals (TOL), the tolerance has been shown to involve T regulatory cells (Treg) and to persist for 3 to 4 months after the graft is removed. Naïve animals can be sensitized to major histocompatibility complex (MHC) class I mismatched renal allografts by inoculation with either class I peptide or by a donor-type skin graft. Six weeks after graftectomy, peptide immunization similarly sensitized TOL swine, but challenge with donor skin failed to sensitize (n=3). In this study, we further investigated the tolerogenicity of skin grafts under these conditions by challenging simultaneously with peptide and skin graft. Miniature swine underwent bilateral nephrectomy and MHC class I mismatched renal transplantation with a 12-day course of CyA to induce tolerance. 100 days after transplantation, graftectomy was performed and recipient-matched kidneys transplanted. Six weeks later, pigs were simultaneously challenged with donor-type class I peptide and donor-type skin grafts. The effect on in vitro and in vivo immunity was determined. In contrast to animals treated only with peptide, all of which were sensitized to 2nd renal allografts (rejection in 4-6 days) and developed strong anti-donor cellular and antibody responses (n=3), 2/5 recipients showed only a transient anti-donor cellular response and no or little anti-donor antibody production and maintained their second donor-type class I mismatched renal allografts long-term with normal creatinine. An additional animal experienced prolonged survival (11 days), and the final 2 animals rejected within 5-7 days. Challenging with second donor-type skin grafts and third party skin graft indicated that hyporesponsiveness to the donor was specific. In animals tolerant of a class I mismatched renal allograft, which would be expected to be sensitized by class I peptide (indirect pathway of sensitization) at 6 weeks after graftectomy, a simultaneous donor-matched skin graft appeared to prevent sensitization in 2 of 5 and prolong survival in a third. These data are consistent with expansion of Treg following a class I mismatched skin graft, presumably by the direct pathway of activation.

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