Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function

Kuroiwa, Takanori; Kakishita, Eizo; Hamano, Teruaki; Kataoka, Yasuro; Seto, Yoshifumi; Iwata, Nobuo; Kaneda, Yasufumi; Matsumoto, Kunio; Nakamura, Toshikazu; Ueki, Takahiro; Fujimoto, Jiro; Iwasaki, Tsuyoshi

doi:10.1172/jci11808

Cited by 107 publications

(113 citation statements)

References 35 publications

(20 reference statements)

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“…HGF has been shown previously to be protective in various animal models of immune-mediated diseases such as myocarditis (32,33), glomerulonephritis (30,34), inflammatory bowel disease (35), collagen-induced arthritis (36), pulmonary fibrosis (37), allogeneic heart transplantation (45), graft-vs.-host disease (46), and asthma (47). According to these studies, HGF may ameliorate both Th1-type-dominated (33,36) and Th2-type-dominated (40,47) autoimmune responses.…”

Section: Discussionmentioning

confidence: 94%

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells

Benkhoucha

Santiago-Raber

Schneiter

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Immune-mediated diseases of the CNS, such as multiple sclerosis and its animal model, experimental autoimmune encephalitis (EAE), are characterized by the activation of antigen-presenting cells and the infiltration of autoreactive lymphocytes within the CNS, leading to demyelination, axonal damage, and neurological deficits. Hepatocyte growth factor (HGF) is a pleiotropic factor known for both neuronal and oligodendrocytic protective properties. Here, we assess the effect of a selective overexpression of HGF by neurons in the CNS of C57BL/6 mice carrying an HGF transgene (HGF-Tg mice). EAE induced either by immunization with myelin oligodendrocyte glycoprotein peptide or by adoptive transfer of T cells was inhibited in HGF-Tg mice. Notably, the level of inflammatory cells infiltrating the CNS decreased, except for CD25 + Foxp3 + regulatory T (T reg ) cells, which increased. A strong T-helper cell type 2 cytokine bias was observed: IFN-γ and IL-12p70 decreased in the spinal cord of HGF-Tg mice, whereas IL-4 and IL-10 increased. Antigen-specific response assays showed that HGF is a potent immunomodulatory factor that inhibits dendritic cell (DC) function along with differentiation of IL-10-producing T reg cells, a decrease in IL-17-producing T cells, and down-regulation of surface markers of T-cell activation. These effects were reversed fully when DC were pretreated with anti-cMet (HGF receptor) antibodies. Our results suggest that, by combining both potentially neuroprotective and immunomodulatory effects, HGF is a promising candidate for the development of new treatments for immune-mediated demyelinating diseases associated with neurodegeneration such as multiple sclerosis.cMet (HGF receptor) | experimental autoimmune encephalitis | immune tolerance | multiple sclerosis | neuroprotection

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Section: Discussionmentioning

confidence: 94%

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells

Benkhoucha

Santiago-Raber

Schneiter

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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176

187

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“…16 Recently, we reported that treatment with HGF is effective for preventing acute GVHD in a murine model. 13,14 We also examined serum HGF concentrations in 38 patients receiving allogeneic BMT, and found that HGF clearly correlated with severity of acute GVHD. To our knowledge, this is the first report indicating that HGF is produced in response to GVHD.…”

Section: Discussionmentioning

confidence: 99%

“…However, as acute GVHD tended to be complicated by bacterial and viral infections, clear discrimination of cytokine production in the immunological GVH reaction from that occurring in infections was difficult. Based on the murine experiment, 13,14 the serum HGF concentration of 2000 pg/ml was effective for preventing GVHD. In our study, the serum HGF concentration in patients with acute GVHD was the same or higher than serum HGF of 2000 pg/ml (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Increased hepatocyte growth factor in serum in acute graft-versus-host disease

Okamoto

Takatsuka

Fujimori

et al. 2001

Bone Marrow Transplant

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Summary:Hepatocyte growth factor (HGF) was reported to be effective in preventing acute graft-versus-host disease (GVHD) in a murine model. We examined serum HGF concentrations in 38 patients receiving allogeneic bone marrow transplants, and investigated the relationship of serum HGF concentrations to severity of acute GVHD. More HGF was present in sera from patients with than without acute GVHD. Serum HGF correlated significantly with grade of acute GVHD. Furthermore, serum HGF correlated with serum concentrations of Creactive protein, ␥-glutamyltranspeptidase (GTP), and aspartate aminotransferase (AST). Serum concentrations of HGF in transplanted patients without GVHD were consistently low, while those in patients with acute GVHD increased with exacerbation. We conclude that HGF was produced during induction of the GVH reaction, and probably increased as a physiological response. Bone Marrow Transplantation (2001) 28, 197-200.

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“…In order to detect apoptotic cells in the gut tissue sections, a modified in vivo TUNEL staining was performed using the ApopTag Plus Peroxidase Kit (Chemicon Inc., Temecula, California, USA), as described previously [43]. The number of apoptotic cells was counted for 100 colonic crypts in four different views.…”

Section: Clinical and Pathological Assessment Of Intestinal Gvhdmentioning

confidence: 99%

“…The level of cytokine expression was examined by quantitative RT-PCR [43]. The extracted RNA from IEL and MLNL was purified (RNeasy MinElute Cleanup Kit, Qiagen, Tokyo, Japan).…”

Section: Quantitative Rt-pcr For Cytokine Mrna Detectionmentioning

confidence: 99%

Reduced p38 mitogen-activated protein kinase in donor grafts accelerates acute intestinal graft-versus-host disease in mice

et al. 2005

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The gastrointestinal tract is a major target of graft-versus-host disease (GVHD), which constitutes a life-threatening complication of bone marrow transplantation. GVHD is mainly caused by the activation of donor-derived lymphocytes, in which cytokine cascades play essential roles. Since p38 MAPK (p38) has been identified as a regulator of cytokine reactions and proposed as a molecular target for anti-inflammatory therapy, we investigated the contribution of p38 to the severity of murine intestinal GVHD. Unexpectedly, p38a +/-donor graft induced more acute GVHD-related mortality and more severe gut injury. The survival of p38a +/-donor-derived intestinal intraepithelial lymphocytes (IEL) was prolonged in vitro and in vivo, and TNF-a expression in the p38a +/-donor-derived IEL was also increased compared with wild-type cells. In contrast, the p38a +/-grafted mice resulted in decreased expansion of donor lymphocytes in mesenteric lymph nodes, and the up-regulation of IL-12p40 and IL-18 was diminished. These findings suggest that p38 has dichotomous effects for inflammatory response in vivo; not only regulates inflammatory cytokine expression and lymphocyte expansion, but also has distinct regulatory functions for IEL in intestinal GVHD. In conclusion, the inhibition of p38 may not be a suitable antiinflammatory strategy for GVHD due to the associated intestinal injury.

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Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function

Cited by 107 publications

References 35 publications

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells

Increased hepatocyte growth factor in serum in acute graft-versus-host disease

Reduced p38 mitogen-activated protein kinase in donor grafts accelerates acute intestinal graft-versus-host disease in mice

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Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function

Cited by 107 publications

References 35 publications

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 + Foxp3 + regulatory T cells

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 + Foxp3 + regulatory T cells

Increased hepatocyte growth factor in serum in acute graft-versus-host disease

Reduced p38 mitogen-activated protein kinase in donor grafts accelerates acute intestinal graft-versus-host disease in mice

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Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells

Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25 ⁺ Foxp3 ⁺ regulatory T cells