CCR5 blockade decreases peripheral T cell activation, gut GVHD biomarkers and acute GVHD incidence in allo-HSCT recipients.
CXCR3-mediated lymphocyte trafficking may represent an important resistance mechanism to CCR5 blockade in GVHD prophylaxis.
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 that developed acute GVHD despite maraviroc prophylaxis showed increased T cell activation, naïve 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.
- Submitted August 19, 2016.
- Accepted December 20, 2016.
- Copyright © 2017 American Society of Hematology
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