Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet-specific autoimmune response in patients with immune thrombocytopenic purpura.
Blockade of the CD40/CD154 signal is a potential immunomodulatory strategy for T-cell-mediated diseases. As a part of a phase 1, multicenter, dose-escalating trial of humanized monoclonal antibody to CD154 (IDEC-131/E6040) in patients with refractory immune thrombocytopenic purpura (ITP), the autoimmune response to glycoprotein IIb/IIIa (GPIIb/IIIa) was evaluated at successive time points. Five patients each were given a single infusion of 1, 2, 5, or 10 mg/kg IDEC-131/E6040 and followed for 3 months. All adverse events were mild, and there were no severe infections or thromboembolic events. No increase in platelet count was observed in patients treated at 1, 2, or 5 mg/kg, but an increase was observed in 3 patients treated at 10 mg/kg. In only the patients treated at 5 or 10 mg/kg, the frequency of B cells producing anti-GPIIb/IIIa antibodies, GPIIb/IIIa-induced T-cell proliferation, and anti-GPIIb/IIIa antibody production by antigen-dependent T-B-cell collaboration were all suppressed in parallel after the treatment, with a slow return to baseline. In contrast, T-cell response to an irrelevant antigen was not affected. These findings suggest that CD40/CD154 blockade therapy is potentially effective for refractory ITP, through selective suppression of autoreactive T and B cells to platelet antigens.
Kuwana
Masataka
M
Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. kuwanam@sc.itc.keio.ac.jp
Nomura
Shosaku
S
Fujimura
Kingo
K
Nagasawa
Toshiro
T
Muto
Yoshitomo
Y
Kurata
Yoshiyuki
Y
Tanaka
Shigeru
S
Ikeda
Yasuo
Y
D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D001402:B-Lymphocytes / Q000276:immunology; D001792:Blood Platelets / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D005260:Female; D006801:Humans; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D023201:CD40 Ligand; C470330:toralizumab