title: Stimulation with 4-1BB (CD137) inhibits chronic graft-versus-host disease by inducing activation-induced cell death of donor CD4+ T cells.
abstract: 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.
authors.affiliation: The Immunomodulation Research Center, University of Ulsan, San29, Mukeo-dong, Nam-ku, Ulsan 680-749, Republic of Korea.
authors.forename: Juyang
authors.initials: J
authors.lastname: Kim
authors.forename: Woon S
authors.initials: WS
authors.lastname: Choi
authors.forename: Soojin
authors.initials: S
authors.lastname: La
authors.forename: Jae-Hee
authors.initials: JH
authors.lastname: Suh
authors.forename: Byoung-Sam
authors.initials: BS
authors.lastname: Kim
authors.forename: Hong R
authors.initials: HR
authors.lastname: Cho
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
authors.forename: Byungsuk
authors.initials: B
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000917:Antibody Formation / Q000187:drug effects; D015703:Antigens, CD; D001323:Autoantibodies / Q000187:drug effects; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D016923:Cell Death / Q000187:drug effects; D002908:Chronic Disease; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D014184:Transplantation, Homologous; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001323:Autoantibodies; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9