title: B7 but not intercellular adhesion molecule-1 costimulation prevents the induction of human alloantigen-specific tolerance.
abstract: Presentation of antigen by the major histocompatibility complex to T lymphocytes 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 signals 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 adhesion molecule 1 (ICAM-1) deliver independent costimulatory signals resulting in alloantigen-induced proliferation of CD4-positive T lymphocytes. Although equivalent in their ability to costimulate maximal proliferation of alloreactive T cells, B7 but not ICAM-1 induced detectable interleukin 2 secretion and prevented the induction of alloantigen-specific anergy. These results are consistent with the hypothesis that blockade of the ICAM-1:lymphocyte function-associated 1 pathway results in immunosuppression, whereas blockade of the B7:CD28/CTLA4 pathway results in alloantigen-specific anergy. This approach, using this model system, should facilitate the identification of critical costimulatory pathways which must be inhibited in order to induce alloantigen-specific tolerance before human organ transplantation.
authors.affiliation: Division of Hematologic Malignancies, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: V A
authors.initials: VA
authors.lastname: Boussiotis
authors.forename: G J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: G
authors.initials: G
authors.lastname: Gray
authors.forename: J
authors.initials: J
authors.lastname: Gribben
authors.forename: L M
authors.initials: LM
authors.lastname: Nadler
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000378:metabolism*; D002478:Cells, Cultured; D018274:Electroporation; D015793:HLA-B7 Antigen / Q000096:biosynthesis / Q000378:metabolism*; D015809:HLA-DR7 Antigen / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D018799:Intercellular Adhesion Molecule-1; D007376:Interleukin-2 / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex; D051379:Mice; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
chemical_list: D015815:Cell Adhesion Molecules; D015793:HLA-B7 Antigen; D015809:HLA-DR7 Antigen; D007376:Interleukin-2; D007519:Isoantigens; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D013755:Tetradecanoylphorbol Acetate