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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3322-3330.
Prepublished online as a Blood First Edition Paper on July 21, 2005; DOI 10.1182/blood-2005-05-1860.
 Previous Article | Next Article 
Submitted May 9, 2005
Accepted July 3, 2005
CC chemokine receptor 2 is required for CD8-induced graft-versus-host disease
Theis H Terwey, Theo D Kim, Adam A Kochman, Vanessa M Hubbard, Sydney Lu, Johannes L Zakrzewski, Teresa Ramirez-Montagut, Jeffrey M Eng, Stephanie J Muriglan, Glenn Heller, George F Murphy, Chen Liu, Tulin Budak-Alpdogan, Onder Alpdogan, and Marcel R van den Brink*
Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA
Department of Medicine, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA
* Corresponding author; email: vandenbm{at}mskcc.org.
Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Migration of donor-derived T cells into GVHD target organs plays a critical role in the development of GVHD and chemokines and their receptors are important molecules involved in this process. Here, we demonstrate in murine bone marrow transplantation models that the expression of the inflammatory CC chemokine receptor 2 (CCR2) on donor-derived CD8+ T cells is relevant for the control of CD8+ T cell migration and development of GVHD. Recipients of CCR2-deficient (CCR2-/-) CD8+ T cells developed less damage of gut and liver than recipients of wild type CD8+ T cells which correlated with a reduction in overall GVHD morbidity and mortality. Assessment of donor CD8+ T cell target organ infiltration revealed that CCR2-/- CD8+ T cells have an intrinsic migratory defect to the gut and liver. Other causes for the reduction in GVHD could be excluded, as alloreactive proliferation, activation, IFN- production and cytotoxicity of CCR2-/- CD8+ T cells were intact. Interestingly, the graft-versus-tumor effect mediated by CCR2-/- CD8+ T cells was preserved, which suggests that interference with T cell migration by blockade of CCR2 signaling can separate GVHD from GVT activity.
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