TRANSPLANTATION TOLERANCE PREVENTS CARDIAC ALLOGRAFT VASCULOPATHY IN MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I DISPARATE MINIATURE SWINE

Background. The mechanisms and treatment of cardiac allograft vasculop athy (CAV) remain elusive, We have used partially inbred miniature swi ne to determine the role of class I MHC antigens in the pathogenesis o f CAV and to determine whether acquired tolerance to donor antigen can prevent the development of CAV in large animals, Methods, Previous st udies demonstrated that miniature swine treated with 12 days of cyclos porine (CsA) after the transplantation of MHC class I-disparate kidney allografts all became tolerant to the donor kidneys and survived inde finitely, In the present study, heart allografts were transplanted acr oss the same MHC class I disparity in CsA-treated swine, Results, Unli ke kidney allografts, heart allografts were rejected in 33-55 days, By postoperative day 28, all cardiac allografts had developed the intima l proliferation characteristic of CAV, When hearts and kidneys from. t he same donors were transplanted simultaneously into class I-disparate , CsA-treated recipients, the hosts became tolerant to their cardiac a llografts 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 impor tant role in the pathogenesis of CAV, (2) the specific unresponsivenes s to donor class I antigen induced by a class I-disparate kidney prote cts a heart transplanted from the same organ donor, and (3) the induct ion 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.