LONG-TERM SURVIVAL OF CARDIAC ALLOGRAFTS INDUCED BY COSTIMULATORY BLOCKADE MAY REQUIRE INDIRECT RECOGNITION

Abstract

45 Previous studies have indicated that both the direct and indirect pathways of allorecognition can contribute to allograft rejection in the absence of immunosuppression. The present studies examined the effectiveness of T cell costimulatory blockade when only the direct or indirect pathway was operative in a mouse model of acute vascularized cardiac allograft rejection. To study the pathways in vivo, we used genetically altered mouse strains in the following manner: 1. B6 MHC class II-deficient mice (II-) were used as donors of cardiac grafts to normal B10.D2 recipients to eliminate the direct CD4+ T cell response. 2. II-4+ mice, which are MHC class II-deficient mice expressing a MHC class II transgene only on thymic epithelium, were used as recipients of normal B10.D2 cardiac grafts. These mice have normal numbers of peripheral CD4+ T cells but lack expression of MHC class II on their APCs and, therefore, cannot mount an indirect CD4+ T cell response. The following costimulatory blockade regimens were used: Murine CTLA4Ig (250μg ×1 i.p.) on day 2 or MR1 anti-CD40L antibody (250μg ×1 i.p.) on day 0 posttransplant. (Table)TableThese results support previous findings with skin transplants that either pathway of allorecognition can initiate rejection in the absence of immunosuppression. They also indicate that costimulatory blockade prolongs allograft survival more effectively in recipients that can mount only an indirect response, and in recipients with both pathways, than in recipients that can mount only a direct response. Thus, stimulation through the indirect pathway seems to be important for costimulatory blockade to be effective. (NIH-AI-38397 and 34965)