title: Role of fibrinogen-like protein 2 prothrombinase/fibroleukin in experimental and human allograft rejection.
abstract: Immune coagulation is a major contributor to the pathogenesis of xenograft rejection, viral-induced hepatocellular injury and cytokine-induced fetal loss syndrome. In this study, we investigated the contribution of the novel gene product, fibrinogen-like protein 2 (fgl2) prothrombinase, in mediating immune injury in experimental and human acute allograft rejection. Using a mouse heterotopic cardiac transplant model, mouse fgl2(mfgl2)/fibroleukin mRNA transcripts and protein were highly expressed in macrophages, CD4- and CD8-positive T lymphocytes, and endothelial cells in rejecting cardiac allografts in association with deposits of fibrin. Although mfgl2-deficient mice rejected allografts at similar rates to littermate controls, survival of grafts from mfgl2-deficient mice were prolonged and deposition of intravascular fibrin was diminished. Treatment of wild-type mice with a neutralizing anti-fgl2 Ab ameliorated histological evidence for allorejection and intravascular fibrin deposition, and resulted in an increase in graft survival. To address further the relevance of fgl2 in acute allograft rejection, we examined kidney biopsies from patients who had undergone renal transplantation. Human fgl2 mRNA transcripts and protein were markedly expressed mainly in renal tubule cells, infiltrating lymphoid cells including macrophages, CD8(+) T cells, mature B cells (plasma cells), and endothelial cells. Dual staining showed fibrin deposition was localized mainly to blood vessels, in the glomerulus and interstitium and the lumen of tubules, and occurred in association with human fgl2 expression. These data collectively suggest that fgl2 accounts for the fibrin deposition seen in both experimental and human allograft rejection and provide a rationale for targeting fgl2 as adjunctive therapy to treat allograft rejection.
authors.affiliation: Laboratory of Infectious Immunology, Department of Infectious Disease, Institute of Immunology, Huazhong University of Science and Technology, Wuhan, China. qning@tjh.tjmu.edu.cn
authors.forename: Qin
authors.initials: Q
authors.lastname: Ning
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Meifang
authors.initials: M
authors.lastname: Han
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Chuanglong
authors.initials: C
authors.lastname: Zhu
authors.forename: Weijie
authors.initials: W
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.forename: Jinwen
authors.initials: J
authors.lastname: Li
authors.forename: Weiming
authors.initials: W
authors.lastname: Yan
authors.forename: Feili
authors.initials: F
authors.lastname: Gong
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: He
authors.forename: Cheryl
authors.initials: C
authors.lastname: Koscik
authors.forename: Robert
authors.initials: R
authors.lastname: Smith
authors.forename: Reginald
authors.initials: R
authors.lastname: Gorczynski
authors.forename: Gary
authors.initials: G
authors.lastname: Levy
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Luo
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D006801:Humans; D007106:Immune Sera / Q000008:administration & dosage; D007150:Immunohistochemistry; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D013925:Thromboplastin / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
chemical_list: C095202:FGL2 protein, human; C490637:Fgl2 protein, mouse; D007106:Immune Sera; D005337:Fibrin; D005340:Fibrinogen; D013925:Thromboplastin