title: Regulation of postsurgical fibrosis by the programmed death-1 inhibitory pathway.
abstract: Surgical adhesions are a common and often severe complication of abdominal or pelvic injury that cause pelvic pain, bowel obstruction, and infertility in women. Current treatments are of limited effectiveness because little is known about the cellular and subcellular processes underlying adhesiogenesis. Recently, we showed that Th1 alpha beta CD4(+) T cells mediate the pathogenesis of adhesion formation in a rodent model of this disease process. In this study, we demonstrate that in mice these T cells home directly to the site of surgically induced adhesions and control local chemokine production in a manner dependent on the CD28 T cell costimulatory pathway. Conversely, the inhibitory programmed death-1 pathway plays a central role in limiting adhesiogenesis, as programmed death-1 blockade was associated with increased T cell infiltration, chemokine production, and a concomitant exacerbation of disease. Our results reveal for the first time that the development of postsurgical fibrosis is under the tight control of positive and negative T cell costimulation, and suggest that targeting these pathways may provide promising therapies for the prevention of adhesion formation.
authors.affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. mholsti@rics.bwh.harvard.edu
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Holsti
authors.forename: Tanuja
authors.initials: T
authors.lastname: Chitnis
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Panzo
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Arthur O
authors.initials: AO
authors.lastname: Tzianabos
mesh_terms: D000069594:Abatacept; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen / Q000096:biosynthesis; D060890:B7-H1 Antigen; D001798:Blood Proteins / Q000096:biosynthesis; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060908:CTLA-4 Antigen; D002432:Cecum / Q000473:pathology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D005355:Fibrosis; D018796:Immunoconjugates / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides; D010537:Peritoneum / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011183:Postoperative Complications / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D061026:Programmed Cell Death 1 Receptor; D012313:RNA / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology*; D000267:Tissue Adhesions / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; D018925:Chemokines; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; C036763:monocyte-macrophage differentiation antigen; D012313:RNA; D000069594:Abatacept