Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute graft-versus-host disease (a-GVHD) is initiated primarily by immunologically competent cytotoxic T cells (CTLs) that express anti-host specificities. However, the host lymphoid compartment in which these precursor CTLs are initially stimulated remains unclear. Here we show that gut Peyer's patches (PPs) are required to activate anti-host CTL responses in a well characterized murine acute graft-versus-host reaction (a-GVHR) model, involving transfer of parent lymphocytes into F1 hybrid recipients. The a-GVHR was prevented when recruitment of donor T cells into PP was interrupted either by disrupting the gene encoding chemokine receptor CCR5 or by blocking integrin alpha(4)beta(7)-MAdCAM-1 (mucosal vascular addressin) interactions. Mice deficient for PPs failed to develop a-GVHD in two models of disease induction. Thus, blockade of CTL generation in PPs might offer new strategies for circumventing a-GVHD.
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PMID:Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. 1255 92

CD4+CD25+ regulatory T cells (T(regs)) have been shown to inhibit graft-versus-host disease (GVHD) in murine models, and this suppression was mediated by T(regs) expressing the lymphoid homing molecule l-selectin. Here, we demonstrate that T(regs) lacking expression of the chemokine receptor CCR5 were far less effective in preventing lethality from GVHD. Survival of irradiated recipient animals given transplants supplemented with CCR5-/- T(regs) was significantly decreased, and GVHD scores were enhanced compared with animals receiving wild-type (WT) T(regs). CCR5-/- T(regs) were functional in suppressing T-cell proliferation in vitro and ex vivo. However, although the accumulation of T(regs) within lymphoid tissues during the first week after transplantation was not dependent on CCR5, the lack of function of CCR5-/- T(regs) correlated with impaired accumulation of these cells in the liver, lung, spleen, and mesenteric lymph node, more than one week after transplantation. These data are the first to definitively demonstrate a requirement for CCR5 in T(reg) function, and indicate that in addition to their previously defined role in inhibiting effector T-cell expansion in lymphoid tissues during GVHD, later recruitment of T(regs) to both lymphoid tissues and GVHD target organs is important in their ability to prolong survival after allogeneic bone marrow transplantation.
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PMID:Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease. 1600 22

The chemokine receptor CCR5 plays roles in the trafficking of effector cells towards the site of inflammation. We retrospectively examined the impact of the CCR5 variation (rs1800023, -2086A>G) on transplant outcomes in a cohort of 329 patients who underwent unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. A multivariate analysis showed that the recipient CCR5 -2086A/A genotype was significantly associated with a lower relapse rate but not with the development of graft-versus-host disease (GVHD) or transplant-related mortality, thereby resulting in better disease-free and overall survival rates than other variations. The donor CCR5 -2086A/A genotype was associated with a lower incidence of grades 3-4 acute GVHD, which did not improve the survival outcomes. These findings suggest that the recipient CCR5 -2086A/A genotype affects the induction of the graft-versus-tumor effect without augmenting the development of GVHD. CCR5 genotyping in transplant recipients may therefore be a useful tool for evaluating pretransplantation risks.
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PMID:The recipient CCR5 variation predicts survival outcomes after bone marrow transplantation. 2848 38