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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2206-2213.
Prepublished online as a Blood First Edition Paper on November 2, 2004; DOI 10.1182/blood-2004-06-2080.
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TRANSPLANTATION
Stimulation with 4-1BB (CD137) inhibits chronic graft-versus-host disease by inducing activation-induced cell death of donor CD4+ T cells
Juyang Kim,
Woon S. Choi,
Soojin La,
Jae-Hee Suh,
Byoung-Sam Kim,
Hong R. Cho,
Byoung S. Kwon, and
Byungsuk Kwon
From The Immunomodulation Research Center, University of Ulsan, and the Department of Pathology, Ulsan University Hospital, Republic of Korea.
4-1BB, a member of the tumor necrosis factor (TNF) receptor superfamily, is a costimulator for activated T cells. Previous studies have established that treatment with agonistic anti–4-BB monoclonal antibody (3H3) is effective in reversing the progression of spontaneous systemic lupus erythematosus. Its therapeutic effect is mediated by suppression of autoantibody production. In this report, we show that a single injection of 3H3 blocks chronic graft-versus-host disease (cGVHD) in the parent-into-F1 model. In particular, donor CD4+ T cells are rapidly eliminated from host spleens by activation-induced cell death after 4-1BB triggering. Since donor CD4+ T cells are required for the development of cGVHD, and 3H3-mediated inhibition of autoantibody production occurs without donor CD8+ T cells, 3H3 blocks cGVHD by preventing alloreactive donor CD4+ T cells from activating host B cells. Importantly, 3H3 treatment can reverse the progression of advanced cGVHD. Our findings indicate that agonistic anti–4-1BB monoclonal antibody has potential as an immunotherapeutic agent for preventing and treating cGVHD.
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