title: The TIM-1:TIM-4 pathway enhances renal ischemia-reperfusion injury.
abstract: CD4+ T cells contribute to the pathogenesis of ischemia-reperfusion injury, which is the primary cause of delayed graft failure after kidney transplantation. The TIM-1:TIM-4 pathway participates in the activation/differentiation of CD4+ T cells, suggesting that it may modulate ischemia-reperfusion injury. Here, we studied the role of TIM-1 in a murine uninephrectomized renal ischemia-reperfusion injury model. Blocking the TIM-1:TIM-4 pathway with an antagonistic monoclonal antibody protected renal function and diminished reperfusion injury resulting from 30 minutes of ischemia. Histologic examination showed significantly less evidence of renal damage as evidenced by diminished tubular necrosis, preservation of the brush border, fewer cast formations, and less tubular dilation. Blocking TIM-1 also reduced the number of apoptotic cells and diminished local inflammation within ischemic kidneys, the latter shown by decreased recruitment of macrophages, neutrophils, and CD4+ T cells and by reduced local production of proinflammatory cytokines. Furthermore, TIM-1 blockade significantly improved survival after ischemia-reperfusion injury. Taken together, these data suggest that the TIM-1:TIM-4 pathway enhances injury after renal ischemia-reperfusion injury and may be a therapeutic target.
authors.affiliation: Transplant Center, University Hospital Munich, Marchioninistrasse 15, Munich, Germany.
authors.forename: Song
authors.initials: S
authors.lastname: Rong
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Torsten
authors.initials: T
authors.lastname: Kirsch
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Olaf
authors.initials: O
authors.lastname: Boenisch
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
authors.forename: Antje
authors.initials: A
authors.lastname: Habicht
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D000072596:Hepatitis A Virus Cellular Receptor 1; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000473:pathology / Q000601:surgery; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009336:Necrosis; D009392:Nephrectomy; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D018398:Homeodomain Proteins; D008565:Membrane Proteins; C500399:TIM-4 protein, mouse; C064658:RAG-1 protein