Transplantation tolerance prevents cardiac allograft vasculopathy in major histocompatibility complex class I-disparate miniature swine

Transplantation. 1998 Feb 15;65(3):304-13. doi: 10.1097/00007890-199802150-00002.

Abstract

Background: The mechanisms and treatment of cardiac allograft vasculopathy (CAV) remain elusive. We have used partially inbred miniature swine to determine the role of class I MHC antigens in the pathogenesis of CAV and to determine whether acquired tolerance to donor antigen can prevent the development of CAV in large animals.

Methods: Previous studies demonstrated that miniature swine treated with 12 days of cyclosporine (CsA) after the transplantation of MHC class I-disparate kidney allografts all became tolerant to the donor kidneys and survived indefinitely. In the present study, heart allografts were transplanted across the same MHC class I disparity in CsA-treated swine.

Results: Unlike kidney allografts, heart allografts were rejected in 33-55 days. By postoperative day 28, all cardiac allografts had developed the intimal proliferation characteristic of CAV. When hearts and kidneys from the same donors were transplanted simultaneously into class I-disparate, CsA-treated recipients, the hosts became tolerant to their cardiac allografts and survived long-term. Furthermore, none of the hearts from the combined heart/kidney recipients developed evidence of CAV. Thus, this report demonstrates that: (1) MHC class I antigens play an important role in the pathogenesis of CAV, (2) the specific unresponsiveness to donor class I antigen induced by a class I-disparate kidney protects a heart transplanted from the same organ donor, and (3) the induction of acquired tolerance prevents the development of CAV.

Conclusion: These findings in a preclinical system establish the significance of antigen-dependent mechanisms in the pathogenesis of CAV and underscore the importance of achieving tolerance in clinical transplantation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Coronary Disease / pathology
  • Coronary Disease / prevention & control*
  • Coronary Vessels / pathology*
  • Cyclosporine / therapeutic use
  • Graft Rejection / immunology
  • Graft Rejection / pathology
  • Heart Transplantation / immunology*
  • Heart Transplantation / pathology*
  • Histocompatibility Antigens Class I*
  • Histocompatibility Testing
  • Immunosuppressive Agents / therapeutic use*
  • Kidney Transplantation / immunology*
  • Kidney Transplantation / pathology
  • Postoperative Complications / prevention & control*
  • Swine
  • Swine, Miniature
  • Time Factors
  • Transplantation, Homologous
  • Tunica Intima / pathology

Substances

  • Histocompatibility Antigens Class I
  • Immunosuppressive Agents
  • Cyclosporine