Blood, 15 February 2004, Vol. 103, No. 4, pp. 1229-1236.
Prepublished online as a Blood First Edition Paper on October 9, 2003; DOI 10.1182/blood-2003-06-2167.
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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet-specific autoimmune response in patients with immune thrombocytopenic purpura
Masataka Kuwana,
Shosaku Nomura,
Kingo Fujimura,
Toshiro Nagasawa,
Yoshitomo Muto,
Yoshiyuki Kurata,
Shigeru Tanaka, and
Yasuo Ikeda
From the Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan; the Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; the First Department of Internal Medicine, Kansai Medical University, Osaka, Japan; the Department of Hematology and Oncology, Division of Pharmacotherapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; the Division of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan; the Department of Hematology, Toranomon Hospital, Tokyo, Japan; the Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan; and Eisai Company Ltd, Tokyo, Japan.
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.
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