Browsing by Author "Koreth, John"

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    An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition
    (American Society for Clinical Investigation, 2017-06-15) Forcade, Edouard; Paz, Katelyn; Flynn, Ryan; Griesenauer, Brad; Amet, Tohti; Li, Wei; Liu, Liangyi; Bakoyannis, Giorgos; Jiang, Di; Chu, Hong Wei; Lobera, Mercedes; Yang, Jianfei; Wilkes, David S.; Du, Jing; Gartlan, Kate; Hill, Geoffrey R.; MacDonald, Kelli P.A.; Espada, Eduardo L.; Blanco, Patrick; Serody, Jonathan S.; Koreth, John; Cutler, Corey S.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome; Paczesny, Sophie; Blazar, Bruce R.; Pediatrics, School of Medicine
    Chronic graft-versus-host disease (cGvHD) remains a major complication of allogeneic stem cell transplantation requiring novel therapies. CD146 and CCR5 are expressed by activated T cells and associated with increased T cell migration capacity and Th17 polarization. We performed a multiparametric flow cytometry analysis in a cohort of 40 HSCT patients together with a cGvHD murine model to understand the role of CD146-expressing subsets. We observed an increased frequency of CD146+ CD4 T cells in the 20 patients with active cGvHD with enhanced RORγt expression. This Th17-prone subset was enriched for cells coexpressing CD146 and CCR5 that harbor mixed Th1/Th17 features and were more frequent in cGvHD patients. Utilizing a murine cGvHD model with bronchiolitis obliterans (BO), we observed that donor T cells from CD146-deficient mice versus those from WT mice caused significantly reduced pulmonary cGvHD. Reduced cGvHD was not the result of failed germinal center B cell or T follicular helper cell generation. Instead, CD146-deficient T cells had significantly lower pulmonary macrophage infiltration and T cell CCR5, IL-17, and IFN-γ coexpression, suggesting defective pulmonary end-organ effector mechanisms. We, thus, evaluated the effect of TMP778, a small-molecule RORγt activity inhibitor. TMP778 markedly alleviated cGvHD in murine models similarly to agents targeting the Th17 pathway, such as STAT3 inhibitor or IL-17-blocking antibody. Our data suggest CD146-expressing T cells as a cGvHD biomarker and suggest that targeting the Th17 pathway may represent a promising therapy for cGvHD.