Endothelial Induction of fgl2 Contributes to Thrombosis during Acute Vascular Xenograft Rejection

Ghanekar, Anand; Mendicino, Michael; Líu, Hao; He, Wei; Liu, Mingfeng; Zhong, Robert; Phillips, M. James; Levy, Gary; Grant, David

doi:10.4049/jimmunol.172.9.5693

Cited by 95 publications

(97 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Collectively, these studies support the hypothesis that (donor) endothelial cell production of mfgl2, rather than an immune-activated infiltrating leukocyte population, accounts for the fibrin deposition in allorejection (6). These data are further supported by our recent studies in xenotransplantation in which fibrin deposition associated with xenograft rejection was largely intravascular rather than associated with infiltrating inflammatory cells (21). Furthermore, xenografts from mfgl2 Ϫ/Ϫ mice transplanted into rats were devoid of thrombosis.…”

Section: Discussionsupporting

confidence: 77%

Role of Fibrinogen-Like Protein 2 Prothrombinase/Fibroleukin in Experimental and Human Allograft Rejection

Ning

Sun

Han

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 77%

Role of Fibrinogen-Like Protein 2 Prothrombinase/Fibroleukin in Experimental and Human Allograft Rejection

Ning

Sun

Han

et al. 2005

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Fgl2 functions as a strong prothrombinase which directly cleaves prothrombin to thrombin leading to fibrin deposition in the absence of factor Ⅶ or factor Ⅹ [10] . The direct prothrombinase activity of fgl2 is implicated in the pathogenesis of several inflammatory disorders including fulminant hepatitis and severe hepatitis, alloand xeno-graft rejection [4,11,12] . Furthermore, its role is also evidenced in murine and human cytokine induced fetal loss [5,[13][14][15] and neonatal death from contractile dysfunction and rhythm abnormalities during embryonic and postnatal development [16] .…”

Section: Discussionmentioning

confidence: 99%

Fibrinogen-like protein 2/fibroleukin prothrombinase contributes to tumor hypercoagulability via IL-2 and IFN-γ

Chen²,

Yan³

et al. 2008

WJG

View full text Add to dashboard Cite

AIM:To examine the role of Fibrinogen-like protein 2 (fgl2)/fibroleukin in tumor development. Fgl2 has been reported to play a vital role in the pathogenesis in MHV-3 (mouse hepatitis virus) induced fulminant and severe hepatitis, spontaneous abortion, allo-and xenograft rejection by mediating "immune coagulation". METHODS: Tumor tissues from 133 patients with six types of distinct cancers and the animal tumor tissues from human hepatocellular carcinoma (HCC) model on nude mice (established from high metastasis HCC cell line MHCC97LM6) were obtained. RESULTS: Hfgl2 was detected in tumor tissues from 127 out of 133 patients as well as tumor tissues collected from human HCC nude mice.

show abstract

“…Predicted as a type II transmembrane glycoprotein [2], cell membraneassociated FGL2 was shown to exhibit novel prothrombinase activity when associated with cell membranes/phospholipid vesicles [3,4], which has been implicated in the pathogenesis of experimental and human viral-induced fulminant hepatitis [2], cytokine-induced fetal loss syndrome [5], allograft [6] and xenograft rejection [7]. The procoagulant activity was shown to depend on the serine 89 at the linear N terminal domain of FGL2 [4].…”

Section: Introductionmentioning

confidence: 99%

“…2008. 38: 3114- [7]. The procoagulant activity was shown to depend on the serine 89 at the linear N terminal domain of FGL2 [4].…”

mentioning

confidence: 99%

The FGL2‐FcγRIIB pathway: A novel mechanism leading to immunosuppression

et al. 2008

Self Cite

View full text Add to dashboard Cite

Fibrinogen-like protein 2 (FGL2) is a multifunctional protein, which has been implicated in the pathogenesis of allograft and xenograft rejection. Previously, FGL2 was shown to inhibit maturation of BM-derived DC and T-cell proliferation. The mechanism of the immunosuppressive activity of FGL2 remains poorly elucidated. Here, we focus on identification of FGL2-specific receptor(s) and their ability to modulate APC activity and allograft survival. Using flow cytometry and surface plasmon resonance analysis, we show that FGL2 binds specifically to Fc gamma receptor (FccR)IIB and FccRIII receptors, which are expressed on the surface of APC, including B lymphocytes, macrophages and DC. Antibody to FccRIIB and FccRIII, or deficiency of these receptors, abrogated FGL2 binding. IntroductionFibrinogen-like protein 2 (FGL2), also known as fibroleukin, was first cloned from cytotoxic T lymphocytes and was classified as a member of the fibrinogen superfamily due to its homology (36%) with fibrinogen b and g chains [1]. Predicted as a type II transmembrane glycoprotein [2], cell membraneassociated FGL2 was shown to exhibit novel prothrombinase activity when associated with cell membranes/phospholipid vesicles [3,4], which has been implicated in the pathogenesis of Ã These authors contributed equally to this study.Correspondence: Dr. Gary Levy e-mail: glfgl2@attglobal.net DOI 10.1002/eji.200838338 Eur. J. Immunol. 2008. 38: 3114- [7]. The procoagulant activity was shown to depend on the serine 89 at the linear N terminal domain of FGL2 [4].The C terminal globular portion of FGL2 lacks the prothrombinase activity and contains a classical fibrinogen-related domain (FRED), which has been suggested to possess immunomodulatory activity based on several lines of evidence. First, other fibrinogen superfamily members including fibrinogen [8] Results Recombinant FcFGL2 protein binds to APCRecombinant FcFGL2 was generated and purified as described in the Materials and methods. The molecular size of the recombinant proteins was examined by SDS-PAGE, silver staining and Western blotting. FcFGL2 had a molecular weight of approximately 440 kDa under non-reducing conditions, which was confirmed by gel filtration (data not shown), and 110 kDa under reducing conditions (Fig. 1A). These data suggested that FcFGL2 exists as a tetramer, consistent with previous reports [13,21]. The Fc tag had a molecular size of 64 kDa under non-reducing conditions and 33 kDa under reducing conditions, suggesting that Fc is dimeric. Biotinylated FcFGL2 bound to the RAW264.7 cells (mouse macrophage cell lines), BMDC, the B-cell line A20 (which expresses only one Fcg receptor, FcgRIIB), thioglycolate-elicited peritoneal exudates cells (495% macrophages) from C57BL/6J mice, but FcFGL2 did not bind to the B-cell line A20IIA1.6, which does not express FcgRIIB (Fig. 1B) [22]. EL4 cells (a mouse T-cell line) did not bind FcFGL2 (data not shown). As expected, the Fc tag protein alone failed to bind to any of these cells and thus, Fc provided an appropriate negativ...

show abstract

Endothelial Induction of fgl2 Contributes to Thrombosis during Acute Vascular Xenograft Rejection

Cited by 95 publications

References 42 publications

Role of Fibrinogen-Like Protein 2 Prothrombinase/Fibroleukin in Experimental and Human Allograft Rejection

Role of Fibrinogen-Like Protein 2 Prothrombinase/Fibroleukin in Experimental and Human Allograft Rejection

Fibrinogen-like protein 2/fibroleukin prothrombinase contributes to tumor hypercoagulability via IL-2 and IFN-γ

The FGL2‐FcγRIIB pathway: A novel mechanism leading to immunosuppression

Contact Info

Product

Resources

About