title: Clinical and immunologic impact of CCR5 blockade in graft-versus-host disease prophylaxis.
abstract: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Lymphocyte trafficking via chemokine receptors such as CCR5 plays a critical role in alloreactive responses, and previous data suggest that CCR5 blockade with maraviroc results in a low incidence of visceral GVHD. However, the full scope of clinical and immunologic effects of CCR5 blockade in HSCT has not been described. We compared a cohort of patients enrolled on a trial of reduced-intensity allo-HSCT with standard GVHD prophylaxis plus maraviroc to a contemporary control cohort receiving standard GVHD prophylaxis alone. Maraviroc treatment was associated with a lower incidence of acute GVHD without increased risk of disease relapse, as well as reduced levels of gut-specific markers. At day 30, maraviroc treatment increased CCR5 expression on T cells and dampened T-cell activation in peripheral blood without impairing early immune reconstitution or increasing risk for infections. Patients who developed acute GVHD despite maraviroc prophylaxis showed increased T-cell activation, naive T-cell skewing, and elevated serum CXCL9 and CXCL10 levels. Collectively, these data suggest that maraviroc effectively protects against GVHD by modulating alloreactive donor T-cell responses, and that CXCR3 signaling may be an important resistance mechanism to CCR5 blockade in GVHD.
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.|Department of Medicine, New York-Presbyterian Hospital-Weill Cornell Medical College, New York, NY.
authors.forename: Ryan H
authors.initials: RH
authors.lastname: Moy
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.|Division of Hematology/Oncology and.|Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: Austin P
authors.initials: AP
authors.lastname: Huffman
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Lee P
authors.initials: LP
authors.lastname: Richman
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Crisalli
authors.affiliation: Division of Hematology/Oncology and.|Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: Ximi K
authors.initials: XK
authors.lastname: Wang
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: James A
authors.initials: JA
authors.lastname: Hoxie
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.|Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY; and.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Emerson
authors.affiliation: Department of Microbiology and Immunology, Temple University, Philadelphia, PA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.|Division of Hematology/Oncology and.|Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.|Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY; and.
authors.forename: Ran
authors.initials: R
authors.lastname: Reshef
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000032:analysis / Q000276:immunology; D014408:Biomarkers, Tumor / Q000032:analysis / Q000276:immunology; D065100:CCR5 Receptor Antagonists / Q000627:therapeutic use*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D019409:Interleukin-15 / Q000032:analysis / Q000276:immunology; D037181:Lectins, C-Type / Q000032:analysis / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D000073718:Pancreatitis-Associated Proteins; D019713:Receptors, CCR5 / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D065100:CCR5 Receptor Antagonists; C584933:CCR5 protein, human; D019409:Interleukin-15; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D019713:Receptors, CCR5