title: CTLA4-Ig: a novel immunosuppressive agent.
abstract: Activation of naive T-cells requires two signals: one is antigen-specific and based on T-cell receptor (TCR) recognition of a peptide-MHC complex and the second is antigen-nonspecific and delivered by specific T-cell receptors after ligation with their ligands (costimulatory molecules) expressed by antigen-presenting cells (APCs). Engagement of the B7 family of molecules on APCs with their T-cell associated ligands, CD28 and CTLA-4 (CD152), provides a pivotal costimulatoty signal in T-cell activation. The lack of costimulation after engagement of the T-cell receptor by antigen, results in a state of antigen-specific unresponsiveness, termed anergy. Manipulation of CD28/B7 pathway has therefore been envisioned as a potential strategy for achieving therapeutically useful immunosuppression or tolerance. CTLA4-Ig has been initially developed by Bristol-Myers Squibb as a competitive inhibitor of CD28/B7 pathway (BMS-188667). Thereafter, CTLA4-Ig was produced by Repligen and also in some individual laboratories. In various animal models, discussed in this paper, CTLA4-Ig has been shown to inhibit T-cell-dependent antibody responses, significantly prolong transplanted organ survival, induce long-term donor-specific tolerance in some models, slow progression of autoimmune disease and to have immunomodulatory function in several other immunological disease models. Recently, CTLA4-Ig has entered Phase I clinical trials for the treatment of psoriasis, a T-cell mediated skin disease and treatment of graft-versus-host disease in allogeneic bone marrow transplantation. Large clinical randomised trials on the use of CTLA4-Ig are missing, nevertheless, its immunosuppressive effects coupled with features such as specificity of interaction and low toxicity, make CTLA4-Ig a promising new therapeutic agent for induction of donor-specific immunological tolerance, the ultimate goal of clinical immunosuppression.
authors.affiliation: Brigham and Women 's Hospital, Renal Division, Immunogenetics and Transplantation, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. nnajafian@rics.bwh.harvard.edu
authors.forename: N
authors.initials: N
authors.lastname: Najafian
authors.forename: M H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D018106:CD28 Antigens / Q000187:drug effects / Q000276:immunology; D060908:CTLA-4 Antigen; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept