Clinical and immunologic impact of CCR5 blockade in graft-versus-host disease prophylaxis

Autor: David L. Porter, Ximi K. Wang, Ran Reshef, Ryan H. Moy, Lee P. Richman, Austin P. Huffman, James A. Hoxie, Stephen G. Emerson, Yi Zhang, Robert H. Vonderheide, Lisa Crisalli, Rosemarie Mick
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
viruses
T-Lymphocytes
medicine.medical_treatment
Graft vs Host Disease
Pancreatitis-Associated Proteins
Hematopoietic stem cell transplantation
Lymphocyte Activation
Biochemistry
chemistry.chemical_compound
immune system diseases
Interleukin-15
Immunity
Cellular
Hematopoietic Stem Cell Transplantation
virus diseases
Hematology
Middle Aged
Treatment Outcome
surgical procedures
operative
CCR5 Receptor Antagonists
CXCL9
Female
Adult
Receptors
CCR5
Immunology
chemical and pharmacologic phenomena
CCR5 receptor antagonist
Young Adult
03 medical and health sciences
Immune system
Antigens
Neoplasm
Biomarkers
Tumor
medicine
Humans
Transplantation
Homologous
Lectins
C-Type
Aged
Maraviroc
Transplantation
business.industry
Cell Biology
medicine.disease
Blockade
030104 developmental biology
Graft-versus-host disease
chemistry
business
Zdroj: Blood. 129:906-916
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2016-08-735076
Popis: 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.
Databáze: OpenAIRE
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