title: Tolerogenicity of donor major histocompatibility complex-matched skin grafts in previously tolerant Massachusetts general hospital miniature swine.
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.
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA 02129, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Weiner
authors.forename: Joseph
authors.initials: J
authors.lastname: Scalea
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Okumi
authors.forename: Adam
authors.initials: A
authors.lastname: Griesemer
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirakata
authors.forename: Justin
authors.initials: J
authors.lastname: Etter
authors.forename: Bradford
authors.initials: B
authors.lastname: Gillon
authors.forename: Shannon
authors.initials: S
authors.lastname: Moran
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006650:Histocompatibility Testing; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007114:Immunization / Q000379:methods; D016030:Kidney Transplantation / Q000276:immunology* / Q000379:methods; D009392:Nephrectomy; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D016038:Skin Transplantation / Q000276:immunology* / Q000379:methods; D013552:Swine; D013556:Swine, Miniature; D014184:Transplantation, Homologous
chemical_list: D015395:Histocompatibility Antigens Class I; D010455:Peptides