title: Blockade of complement activation product C5a activity using specific antibody attenuates intestinal damage in trinitrobenzene sulfonic acid induced model of colitis.
abstract: Complement represents a chief component of innate immunity in host defense. However, excessive complement activation has been involved in the pathogenesis of inflammatory diseases. In this study, we investigated the contribution of complement to intestinal pathology of patients and rodents with inflammatory bowel disease. The expression of complement effectors (C3a and C3) was increased remarkably in inflamed colons of IBD patients compared with those of normal counterparts. In accordance with this, the sustained activation of complement in serum and colon (including elevated C3a and C5a levels, enhanced hemolytic activity, downregulated expression of C5a receptors) was observed, following the establishment of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, which peaked at 24 h. Mice pretreated with neutralizing anti-C5a antibodies (-2, 0, and 2 days after TNBS instillation) had significantly reduced weight loss and improved macroscopic/microscopic scores, comparable to the efficacy of prednisolone treatment. Strikingly, treatment with anti-C5a at 24 h after TNBS instillation showed remarkable therapeutic effects, whereas prednisolone did not. The efficacy of anti-C5a administration was associated with decreased release of proinflammatory chemokines and cytokines, inhibition of infiltration of neutrophils into colons, and enhanced Th2 response. These findings suggest a disease-promoting role of complement, particular C5a, in the pathology of TNBS-induced colitis in mice, indicating possible therapeutic potentials for C5a-specific antibody in IBD.
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, People's Republic of China.
authors.forename: Guojiang
authors.initials: G
authors.lastname: Chen
authors.forename: Yuemei
authors.initials: Y
authors.lastname: Yang
authors.forename: Xudong
authors.initials: X
authors.lastname: Gao
authors.forename: Yan
authors.initials: Y
authors.lastname: Dou
authors.forename: Huihui
authors.initials: H
authors.lastname: Wang
authors.forename: Gencheng
authors.initials: G
authors.lastname: Han
authors.forename: Renxi
authors.initials: R
authors.lastname: Wang
authors.forename: Jianan
authors.initials: J
authors.lastname: Wang
authors.forename: Liyan
authors.initials: L
authors.lastname: Wang
authors.forename: Xinying
authors.initials: X
authors.lastname: Li
authors.forename: Renfeng
authors.initials: R
authors.lastname: Guo
authors.forename: He
authors.initials: H
authors.lastname: Xiao
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000276:immunology / Q000627:therapeutic use*; D003092:Colitis / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control* / Q000628:therapy; D003106:Colon / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D003167:Complement Activation / Q000276:immunology; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D018418:Th2 Cells / Q000276:immunology; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a; D014302:Trinitrobenzenesulfonic Acid