title: Blockade of multiple costimulatory receptors induces hyporesponsiveness: inhibition of CD2 plus CD28 pathways.
abstract: T-lymphocyte activation requires engagement of the T cell receptor with antigen-major histocompatibility complex, and simultaneous ligation of costimulatory pathways via the lymphocyte receptors CD2 and CD28/ CTLA4. Anti-CD2 monoclonal antibody (mAb) blocks the interaction of the antigen-presenting cell receptor CD48 with its ligand CD2, whereas CTLA4Ig binds with high affinity to the antigen-presenting cell ligands B7-1 and B7-2, blocking their interaction with CD28/CTLA4. We tested the immunosuppressive effects of simultaneously blocking both costimulatory pathways. Using donor C57BL/6J (H2b) hearts transplanted to CBA/J (H2k) recipients, anti-CD2 mAb plus CTLA4Ig administered at the time of transplantation prolonged cardiac allograft mean survival time to >120 days compared with untreated controls (12.2+/-0.5 days, P<0.01), anti-CD2 mAb alone (24.8+/-1.0 days, P<0.01), or CTLA4Ig alone (55.0+/-2.0 days, P<0.01). Retransplantation of these recipients with donor-specific and third-party grafts demonstrated that hyporesponsiveness and tolerance were achieved. In vitro stimulation of lymphocytes from tolerant recipients with donor-specific alloantigen resulted in normal cytotoxic T lymphocyte and mixed lymphocyte reaction responses, showing that clonal deletion or anergy did not occur, but that graft adaptation or suppression likely helped to maintain long-term graft survival. In vitro combinations of anti-CD2 mAb and CTLA4Ig suppressed the generation of allogeneic cytotoxic T lymphocytes (58%) and the mixed lymphocyte reaction (36%); CTLA4Ig was more effective in this regard and the two agents were not synergistic. Anti-CD2 mAb and CTLA4Ig suppressed mitogen-driven proliferation in differential fashions, suggesting that they affected independent signaling pathways. Anti-CD2 mAb and CTLA4Ig also inhibited interleukin (IL)-2, IL-4, and IL-2 receptor (CD25). These data indicate that anti-CD2 mAb plus CTLA4Ig induces hyporesponsiveness and tolerance. The mechanism is likely related to the initial disruption of independent pathways of T-lymphocyte activation leading to antigen-specific long-term graft survival.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston 29425, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Woodward
authors.forename: L
authors.initials: L
authors.lastname: Qin
authors.forename: K D
authors.initials: KD
authors.lastname: Chavin
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.forename: T
authors.initials: T
authors.lastname: Tono
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: J S
authors.initials: JS
authors.lastname: Bromberg
authors.forename: P
authors.initials: P
authors.lastname: Baliga
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology*; D018801:CD2 Antigens / Q000187:drug effects* / Q000276:immunology; D018106:CD28 Antigens / Q000187:drug effects* / Q000276:immunology; D060908:CTLA-4 Antigen; D003602:Cytotoxicity, Immunologic; D003888:Desensitization, Immunologic; D000939:Epitopes; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy; D051381:Rats; D015290:Second Messenger Systems / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000648:ultrastructure*; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018801:CD2 Antigens; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D000939:Epitopes; D018796:Immunoconjugates; D007519:Isoantigens; D000069594:Abatacept