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

Abstract
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.
AuthorsSung W Choi, Gerhard C Hildebrandt, Krystyna M Olkiewicz, David A Hanauer, Meghana N Chaudhary, Ines A Silva, Clare E Rogers, Daphne T Deurloo, Jacki M Fisher, Chen Liu, David Adams, Stephen W Chensue, Kenneth R Cooke
JournalBlood (Blood) Vol. 110 Issue 9 Pg. 3447-55 (Nov 01 2007) ISSN: 0006-4971 [Print] United States
PMID17641205 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Ccl5 protein, mouse
  • Ccr1 protein, mouse
  • Chemokine CCL5
  • Receptors, CCR1
Topics
  • Animals
  • Chemokine CCL5 (genetics, metabolism, physiology)
  • Gene Expression Regulation
  • Graft vs Host Disease (etiology, genetics, immunology, mortality)
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Binding (physiology)
  • Receptors, CCR1 (genetics, metabolism, physiology)
  • Stem Cell Transplantation (adverse effects)
  • Survival Analysis
  • T-Lymphocytes (immunology, metabolism)
  • Transplantation, Homologous

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