B7 BUT NOT INTERCELLULAR-ADHESION MOLECULE-1 COSTIMULATION PREVENTS THE INDUCTION OF HUMAN ALLOANTIGEN-SPECIFIC TOLERANCE

Presentation of antigen by the major histocompatibility complex to T l ymphocytes without the requisite costimulatory signals does not induce an immune response but rather results in a state of antigen-specific unresponsiveness, termed anergy. To determine which costimulatory sign als are critical for the T cell commitment to activation or anergy, we developed an in vitro model system that isolated the contributions of alloantigen and each candidate costimulatory molecule. Here, we show that transfectants expressing HLA-DR7 and either B7 or intercellular a dhesion molecule 1 (ICAM-1) deliver independent costimulatory signals resulting in alloantigen-induced proliferation of CD4-positive T lymph ocytes. Although equivalent in their ability to costimulate maximal pr oliferation of alloreactive T cells, B7 but not ICAM-1 induced detecta ble interleukin 2 secretion and prevented the induction of alloantigen -specific anergy. These results are consistent with the hypothesis tha t blockade of the ICAM-1:lymphocyte function-associated 1 pathway resu lts in immunosuppression, whereas blockade of the B7:CD28/CTLA4 pathwa y results in alloantigen-specific anergy. This approach, using this mo del system, should facilitate the identification of critical costimula tory pathways which must be inhibited in order to induce alloantigen-s pecific tolerance before human organ transplantation.