Forcade, EdouardPaz, KatelynFlynn, RyanGriesenauer, BradAmet, TohtiLi, WeiLiu, LiangyiBakoyannis, GiorgosJiang, DiChu, Hong WeiLobera, MercedesYang, JianfeiWilkes, David S.Du, JingGartlan, KateHill, Geoffrey R.MacDonald, Kelli P.A.Espada, Eduardo L.Blanco, PatrickSerody, Jonathan S.Koreth, JohnCutler, Corey S.Antin, Joseph H.Soiffer, Robert J.Ritz, JeromePaczesny, SophieBlazar, Bruce R.2017-12-132017-12-132017-06-15Forcade, E., Paz, K., Flynn, R., Griesenauer, B., Amet, T., Li, W., … Blazar, B. R. (2017). An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition. JCI Insight, 2(12), e92111. http://doi.org/10.1172/jci.insight.92111https://hdl.handle.net/1805/14789Chronic 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.en-USPublisher PolicyImmunologyTransplantationArticle