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Heymann F.,RWTH Aachen | Hammerich L.,RWTH Aachen | Storch D.,RWTH Aachen | Bartneck M.,RWTH Aachen | And 7 more authors.
Hepatology | Year: 2012

Chemokines critically control the infiltration of immune cells upon liver injury, thereby promoting hepatic inflammation and fibrosis. The chemokine receptor CCR8 can affect trafficking of monocytes/macrophages, monocyte-derived dendritic cells (DCs) and T-helper cell (Th) subsets, but its role in liver diseases is currently unknown. To investigate the functional role of CCR8 in liver diseases, ccr8 -/- and wild-type (WT) mice were subjected to chronic experimental injury models of carbon tetrachloride (CCl 4) administration and surgical bile duct ligation (BDL). CCR8 was strongly up-regulated in the injured liver. Ccr8 -/- mice displayed attenuated liver damage (e.g., ALT, histology, and TUNEL) compared to WT mice and were also protected from liver fibrosis in two independent injury models. Flow cytometry revealed reduced infiltrates of liver macrophages, neutrophils and natural killer cells, whereas hepatic CD4 + T cells increased. The main CCR8-expressing cells in the liver were hepatic macrophages, and CCR8 was functionally necessary for CCL1-directed migration of inflammatory but not for nonclassical monocytes into the liver. Moreover, the phenotype of liver macrophages from injured ccr8 -/- animals was altered with increased expression of DC markers and enhanced expression of T-cell-attracting chemokine macrophage inflammatory protein 1-alpha (MIP-1α/CCL3). Correspondingly, hepatic CD4 + T cells showed increased Th1 polarization and reduced Th2 cells in CCR8-deficient animals. Liver fibrosis progression, but also subsequent T-cell alterations, could be restored by adoptively transferring CCR8-expressing monocytes/macrophages into ccr8 -/- mice during experimental injury. Conclusions: CCR8 critically mediates hepatic macrophage recruitment upon injury, which subsequently shapes the inflammatory response in the injured liver, affecting macrophage/DC and Th differentiation. CCR8 deficiency protects the liver against injury, ameliorating initial inflammatory responses and hepatic fibrogenesis. Inhibition of CCR8 or its ligand, CCL1, might represent a successful therapeutic target to limit liver inflammation and fibrosis progression. (Hepatology 2012) © 2011 American Association for the Study of Liver Diseases.

Van Der Touw W.,Mount Sinai School of Medicine | Burrell B.,Mount Sinai School of Medicine | Lal G.,Mount Sinai School of Medicine | Bromberg J.S.,Mount Sinai School of Medicine | And 2 more authors.
Transplantation | Year: 2012

BACKGROUND: The role of natural killer (NK) cells in organ transplantation is poorly understood because studies link these cells to both regulatory and inflammatory functions. NK cells exacerbate inflammation and adaptive immunity under conditions of allograft rejection, but little is known regarding their roles in allograft tolerance. We test the hypothesis that NK cells have regulatory function and promote tolerance induction to murine cardiac allografts. METHODS: Murine hearts were transplanted as fully vascularized heterotopic grafts from BALB/c donors into C57BL/6 recipients. Allograft tolerance was achieved using donor splenocyte transfusion + anti-CD40L monoclonal antibody (mAb) before transplantation. The requirement for NK cells in tolerance induction was tested by administering anti-NK1.1-depleting mAb or anti-NKG2D-blocking mAb. Intragraft and peripheral immune cell populations were determined by flow cytometry and immunohistochemistry. CD4 T-cell alloantigen-specific responses and donor-specific alloantibody were also determined. RESULTS: NK cell-depleted recipients acutely reject allografts despite anti-CD40L blockade, but rejecting recipients lacked alloantibody and alloantigen-specific CD4 T-cell responses. NK cell depletion resulted in elevated numbers of graft-infiltrating macrophages. NKG2D blockade in tolerized recipients did not cause acute rejection but increased macrophage graft infiltration and increased the expression of NKG2D ligand Rae-1γ on these cells. CONCLUSIONS: Our data show that NK cells are required for tolerance induction in recipients given donor splenocyte transfusion + anti-CD40L mAb. Our data suggest NK cells regulate monocyte or macrophage activation and infiltration into allografts by a mechanism partially dependent on NKG2D receptor-ligand interactions between NK cells and monocytes/macrophages. Copyright © 2012 by Lippincott Williams & Wilkins.

Mayer L.,Immunology Institute
Journal of Gastroenterology | Year: 2010

The pathogenesis of all immune-mediated inflammatory diseases has been carefully studied over the past several decades, but it is only recently that we have come to appreciate common pathways and genes. This is especially true for the inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis, where a keener appreciation of the contributions of genetics, environment, and immune response have been dissected. In fact, in many ways, IBD has become the model for studying such disorders. The complex nature of interactions is continuing to be defined, and novel therapies targeting defects in these interactions have been developed and are being tested in the clinic. The era of bench to bedside has finally matured, and cures for debilitating diseases are now in sight. This review describes our current state of knowledge of each component of IBD pathogenesis. What has evolved is a clearer picture and novel targets for therapy. © 2009 Springer.

Garaude J.,French Institute of Health and Medical Research | Blander J.M.,Immunology Institute
OncoImmunology | Year: 2012

The use of innate immune receptor agonists in cancer therapies has sufered from manydrawbacks. Our recent observations suggest that some of these hurdles can be overcome by introducing fagellin into tumor cells to promote tumor antigen presentation by dendritic cells (dcs) and simultaneously trigger two types of pattern recognition receptors (Prrs). © 2012 Landes Bioscience.

Hammerich L.,RWTH Aachen | Bangen J.M.,RWTH Aachen | Govaere O.,Catholic University of Leuven | Zimmermann H.W.,RWTH Aachen | And 10 more authors.
Hepatology | Year: 2014

Chronic liver injury promotes hepatic inflammation, representing a prerequisite for organ fibrosis. We hypothesized a contribution of chemokine receptor CCR6 and its ligand, CCL20, which may regulate migration of T-helper (Th)17, regulatory, and gamma-delta (γδ) T cells. CCR6 and CCL20 expression was intrahepatically up-regulated in patients with chronic liver diseases (n = 50), compared to control liver (n = 5). Immunohistochemistry revealed the periportal accumulation of CCR6+ mononuclear cells and CCL20 induction by hepatic parenchymal cells in liver disease patients. Similarly, in murine livers, CCR6 was expressed by macrophages, CD4 and γδ T-cells, and up-regulated in fibrosis, whereas primary hepatocytes induced CCL20 upon experimental injury. In two murine models of chronic liver injury (CCl4 and methionine-choline-deficient diet), Ccr6-/- mice developed more severe fibrosis with strongly enhanced hepatic immune cell infiltration, compared to wild-type (WT) mice. Although CCR6 did not affect hepatic Th-cell subtype composition, CCR6 was explicitly required by the subset of interleukin (IL)-17- and IL-22-expressing γδ T cells for accumulation in injured liver. The adoptive transfer of WT γδ, but not CD4 T cells, into Ccr6-/- mice reduced hepatic inflammation and fibrosis in chronic injury to WT level. The anti-inflammatory function of hepatic γδ T cells was independent of IL-17, as evidenced by transfer of Il-17-/- cells. Instead, hepatic γδ T cells colocalized with hepatic stellate cells (HSCs) in vivo and promoted apoptosis of primary murine HSCs in a cell-cell contact-dependent manner, involving Fas-ligand (CD95L). Consistent with γδ T-cell-induced HSC apoptosis, activated myofibroblasts were more frequent in fibrotic livers of Ccr6-/- than in WT mice. Conclusion: γδ T cells are recruited to the liver by CCR6 upon chronic injury and protect the liver from excessive inflammation and fibrosis by inhibiting HSCs. © 2013 by the American Association for the Study of Liver Diseases.

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