CCR1/CCL5 (RANTES) receptor-ligand interactions modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation

Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
Blood (Impact Factor: 10.45). 12/2007; 110(9):3447-55. DOI: 10.1182/blood-2007-05-087403
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Acute graft-versus-host disease (GVHD) and leukemic relapse are serious complications of allogeneic stem-cell transplantation (SCT). Recruitment of activated T cells to host target tissues or sites of leukemic infiltration (graft-versus-leukemia [GVL]) is likely mediated by chemokine receptor-ligand interactions. We examined the contribution of donor cell CCR1 expression to the development of GVHD and GVL using a well-established murine SCT model (B6 --> B6D2F1) and CCR1-deficient mice (CCR1(-/-)). Allo-SCT with CCR1(-/-) donor cells significantly reduced systemic and target organ GVHD severity, and CCR1 expression on both T cells and accessory cells contributed to GVHD mortality. Significant GVL activity was preserved following CCR1(-/-) SCT, but the survival advantage diminished with increasing tumor burden. We then explored the effects of CCR1 expression on allo-specific T-cell responses. Although cytolytic effector function was maintained on a per-cell basis, T-cell proliferation and IFNgamma secretion were significantly reduced both in vivo and in vitro. T-cell function was partially dependent on interactions between CCR1 and CCL5. Collectively, these data demonstrate that CCR1 expression on donor cells contributes to the development of both GVHD and GVL, and suggest that CCR1/CCL5 receptor-ligand interactions modulate allo-specific T-cell responses occurring in this context.

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Available from: Clare Rogers, Sep 21, 2015
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    • "Chemokine expression can be enhanced by inflammatory cytokines (Mackay, 2001), and chemokines have an important role in recruiting cells of the innate and adaptive immune system to sites of inflammation (Rollins, 1997; Moser et al., 2004). In addition, chemokines have been suggested to be important for leukocyte activation (Choi et al., 2007), angiogenesis (Addison et al., 2000; Strieter et al., 2005), haematopoiesis (Broxmeyer, 2008), and the organization and function of secondary lymphoid tissues (Cyster, 1999; Muller et al., 2003; Ohl et al., 2003). "
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    ABSTRACT: Bone marrow transplantation (BMT) is the current therapy of choice for several malignancies and severe autoimmune diseases. Graft versus host disease (GVHD) is the major complication associated with BMT. T lymphocytes and other leukocytes migrate into target organs during GVHD, become activated and mediate tissue damage. Chemokines are well known inducers of leukocyte trafficking and activation and contribute to the pathogenesis of GVHD. Here, we review the major animal models used to study GVHD and the role of chemokines in mediating tissue damage in these models. The role of these molecules in promoting potential beneficial effects of the graft, especially graft versus leukemia, is also discussed. Finally, the various pharmacological strategies to block the chemokine system or downstream signaling events in the context of GVHD are discussed.
    Frontiers in Pharmacology 02/2012; 3:23. DOI:10.3389/fphar.2012.00023 · 3.80 Impact Factor
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    • "Blockade of costimulatory molecules such as CTLA4-Ig, anti-OX40L antibody, and anti-ICOS antibody may inhibit GVHD and preserve the GVL effect [92-98]. Chemokine and chemokine receptor modulation by the relevant antibody or antagonist may also inhibit GVHD, but not the GVL effect [99-108]. Novel pharmacologic agents such as the proteasome inhibitor bortezomib plus allogeneic T-cell infusion induce the GVL effect without enhancing GVHD [109]. Furthermore, the histone deacetylase inhibitor suberoylanilide hydroxamic acid induces the GVL effect, but not GVHD [110]. "
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    ABSTRACT: Nonmyeloablative stem cell transplantation (NST) is increasingly used with beneficial effects because it can be applied to older patients with hematological malignancies and those with various complications who are not suitable for conventional myeloablative stem cell transplantation (CST). Various conditioning regimens differ in their myeloablative and immunosuppressive intensity. Regardless of the type of conditioning regimen, graft-versus- host disease (GVHD) in NST occurs almost equally in CST, although a slightly delayed development of acute GVHD is observed in NST. Although graft-versus-hematological malignancy effects (i.e., graft-versus-leukemia effect, graft-versus-lymphoma effect, and graft-versus-myeloma effect) also occur in NST, completely eradicating residual malignant cells through allogeneic immune responses is insufficient in cases with rapidly growing disease or uncontrolled progressive disease. Donor lymphocyte infusion (DLI) is sometimes combined to support engraftment and to augment the graft-versus-hematological malignancy effect, such as the graft-versus-leukemia effect. DLI is especially effective for controlling relapse in the chronic phase of chronic myelogenous leukemia, but not so effective against other diseases. Indeed, NST is a beneficial procedure for expanding the opportunity of allogeneic hematopoietic stem cell transplantation to many patients with hematological malignancies. However, a more sophisticated improvement in separating graft-versus-hematological malignancy effects from GVHD is required in the future.
    The Korean Journal of Internal Medicine 12/2009; 24(4):287-98. DOI:10.3904/kjim.2009.24.4.287 · 1.43 Impact Factor
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    ABSTRACT: RANTES (or regulated upon activation, normal T cell expressed and secreted) belongs to the rapidly growing chemokine family. It is mainly produced by T cells, epithelial cells, monocytes, fibroblasts, and mesanglial cells. Increased RANTES expression has been associated with a wide range of inflammatory disorders and pathologies. Mouse RANTES is the homolog molecule of human RANTES. The two have considerable homology in both sequence and structure. Using hRANTES as immunogen and the technique of rat B lymphocyte hybridoma, we raised two hybridoma cell lines secreting monoclonal antibodies (MAbs) to hRANTES, designated no. 1 and no. 2. Both MAbs can bind the hRANTES in FCM, Western blot analysis, and immunocytochemistry. No. 1 also worked well in immunohistochemistry of rat transplanted intestine, which may recognize the same epitope on human RANTES and rat RANTES. Thus, successful production of rat anti-human RANTES MAbs may provide a useful tool in further exploration of the biological function and pathological significance of RANTES and may provide a new method to judge early rejection after small bowel transplantation.
    Hybridoma (2005) 07/2008; 27(3):175-9. DOI:10.1089/hyb.2007.0562 · 0.34 Impact Factor
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