Suppression of autoreactive T-cell response to glycoprotein IIb/IIIa by blockade of CD40/CD154 interaction: implications for treatment of immune thrombocytopenic purpura.
The potential immunosuppressive effect of an anti-CD154 monoclonal antibody (mAb) on the pathogenic autoreactive T-cell response was evaluated using an in vitro culture system with glycoprotein IIb/IIIa (GPIIb/IIIa)-reactive T cells from patients with immune thrombocytopenic purpura (ITP). The anti-CD154 mAb did not inhibit T-cell proliferation, but suppressed anti-GPIIb/IIIa antibody production, in bulk peripheral blood mononuclear cell cultures stimulated with GPIIb/IIIa. Repeated antigenic stimulation of GPIIb/IIIa-reactive CD4(+) T-cell lines in the presence of anti-CD154 mAb resulted in the loss of proliferative capacity and helper function for promoting anti-GPIIb/IIIa antibody production. These anergic T-cell lines showed a cytokine profile of low interferon gamma and high interleukin 10 and suppressed anti-GPIIb/IIIa antibody production. Our results indicate that blockade of the CD40/CD154 interaction induces generation of autoantigen-specific anergic CD4(+) T cells with regulatory function and could be a therapeutic option for suppressing pathogenic autoimmune responses in patients with ITP.
Kuwana
Masataka
M
Institute for Advanced Medical Research and Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. kuwanam@sc.itc.keio.ac.jp
Kawakami
Yutaka
Y
Ikeda
Yasuo
Y
D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D001324:Autoantigens / Q000276:immunology*; D019013:CD40 Antigens / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000032:analysis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology*; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000188:drug therapy / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D019013:CD40 Antigens; D016207:Cytokines; D007166:Immunosuppressive Agents; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D023201:CD40 Ligand