title: Administration of agonistic anti-4-1BB monoclonal antibody leads to the amelioration of inflammatory bowel disease.
abstract: 4-1BB (CDw 137), a member of the tumor necrosis factor receptor (TNFR) superfamily, is a costimulatory receptor primarily expressed on activated T cells. It has been shown that the administration of agonistic anti-4-1BB monoclonal antibody (mAb) enhances tumor immunity and allogenic immune responses. Paradoxically, we found that the administration of anti-4-1BB mAb reduced the incidence and severity of inflammatory bowel disease. In this study, we investigated the effects of anti-4-1BB mAb in a murine intestinal inflammation model, which induced by the hapten reagent, 2,4,6-trinitrobenzene sulfonic acid (TNBS) and mimics immunologic characteristics of human Crohn's disease (CD). Colitis was induced by rectal administration of 2mg of TNBS in 35% ethanol using a vinyl catheter positioned 4cm from the anus. All mice were sacrificed 3 and 10 days after the TNBS administration. The disease activity index (DAI), histological changes of the colon and production of cytokines (IL-2, IL-4, IL-10 and IFN-gamma) were evaluated. The surface molecules of T cells in peripheral blood, spleen and mesenteric lymph nodes were analyzed by flow cytometry. When mice were treated with anti-4-1BB mAb, improvement in both wasting and histopathologic signs of colonic inflammation was observed. The increase a number of splenic CD4(+)CD25(+) T cells and decreased synthesis of the Th1 cytokine IL-2 also occurred. Interestingly, increased production of Th1 cytokine IFN-gamma and proportion of CD8(+) T cells were observed in mice treated with anti-4-1BB mAb in comparison to the colitic mice. These studies show, for the first time, that agonistic anti-4-1BB mAb can improve experimental colitis by reduction of IL-2 and augmentation of CD4(+)CD25(+) regulatory T cells. TNBS colitis is Th1-mediated and has similar histologic features and distribution of inflammation to CD. This study suggests that anti-4-1BB mAb therapy could be effective in the treatment of patients with CD.
authors: Transplantation Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135-710, South Korea.
authors: Jienny
authors: J
authors: Lee
authors: Eun-Na
authors: EN
authors: Lee
authors: Eun-Young
authors: EY
authors: Kim
authors: Hae-Jung
authors: HJ
authors: Park
authors: Chi-Young
authors: CY
authors: Chang
authors: Da-Yeon
authors: DY
authors: Jung
authors: Su-Young
authors: SY
authors: Choi
authors: Suk-Koo
authors: SK
authors: Lee
authors: Kwang-Woong
authors: KW
authors: Lee
authors: Ghee-Young
authors: GY
authors: Kwon
authors: Jae-Won
authors: JW
authors: Joh
authors: Sung-Joo
authors: SJ
authors: Kim
mesh_terms: D053330:4-1BB Ligand; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D005260:Female; D007167:Immunotherapy; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D015996:Survival Rate; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000819:agonists / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D007376:Interleukin-2; C505974:TNFSF9 protein, human; C505975:Tnfsf9 protein, mouse; D048069:Tumor Necrosis Factors; D014302:Trinitrobenzenesulfonic Acid