Costimulation blockade in pig artery patch xenotransplantation - A simple model to monitor the adaptive immune response in nonhuman primates

Mohamed B. Ezzelarab, Burcin Ekser, Gabriel Echeverri, Hidetaka Hara, Corin Ezzelarab, Cassandra Long, Pietro Bajona, Bertha Garcia, Noriko Murase, David Ayares, David K C Cooper

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Background: CD154 blockade-based immunosuppression successfully prevents both humoral and cellular adaptive immune responses in baboons receiving α1,3-galactosyltransferase gene-knockout (GTKO) pig organs. Using a GTKO pig artery transplantation model in baboons, we evaluated the efficacy of CD28/B7 costimulatory pathway blockade in comparison with CD154 blockade. Methods: Baboons received artery patch grafts from GTKO pigs, with no (Group1), anti-CD154mAb-based (Group2), or CTLA4-Ig-based (Group3) immunosuppressive therapy. Anti-pig IgM and IgG antibody and cellular responses were monitored. Xenografts were immunohistologically evaluated for antibody and complement deposition, and cellular infiltration. Results: Group1 baboons developed increased IgM and IgG antibody and cellular responses against GTKO antigens. In Group2, anti-CD154mAb alone prevented the development of both IgM and IgG antibody and cellular responses,but not cellular infiltration of the graft. In the single baboon that received anti-thymocyte globulin (ATG) + mycophenolate mofetil (MMF) + anti-CD154mAb, cellular infiltration of the graft was not seen. In Group3, CTLA4-Ig with ATG + MMF inhibited the cellular proliferative response to pig antigens but did not prevent the IgG response or cellular infiltration. Conclusions: (i) Artery patch transplantation is a simple model to monitor the adaptive immune response to xenografts; (ii) anti-CD154mAb prevents sensitization but not cellular infiltration (but, without anticoagulation, may result in early thrombosis of a pig xenograft); (iii) although in only one baboon, the addition of ATG and MMF prevents cellular infiltration and (iv) replacement of anti-CD154mAb by CTLA4-Ig (at the doses used), even in combination with ATG and MMF, prevents the cellular proliferative response to GTKO pig antigens but is insufficient to prevent the development of anti-pig antibodies.

Original languageEnglish (US)
Pages (from-to)221-232
Number of pages12
JournalXenotransplantation
Volume19
Issue number4
DOIs
StatePublished - Jul 2012

Keywords

  • CTLA4-Ig
  • anti-CD154 monoclonal antibody
  • artery patch
  • costimulation blockade
  • pig
  • xenotransplantation
  • α1,3-galactosyltransferase gene-knockout

ASJC Scopus subject areas

  • Immunology
  • Transplantation

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