Gastrointestinal graft-versus-host-disease (GI-GVHD) is a life-threatening complication occurring after allogeneic hematopoietic cell transplantation (HCT), and a blood biomarker that permits stratification of HCT patients according to their risk of developing GI-GVHD would greatly aid treatment planning. Through in-depth, large-scale proteomic profiling of presymptomatic samples, we identified a T cell population expressing both CD146, a cell adhesion molecule, and CCR5, a chemokine receptor that is upregulated as early as 14 days after transplantation in patients who develop GI-GVHD. The CD4+CD146+CCR5+ T cell population is Th17 prone and increased by ICOS stimulation. shRNA knockdown of CD146 in T cells reduced their transmigration through endothelial cells, and maraviroc, a CCR5 inhibitor, reduced chemotaxis of the CD4+CD146+CCR5+ T cell population toward CCL14. Mice that received CD146 shRNA–transduced human T cells did not lose weight, showed better survival, and had fewer CD4+CD146+CCR5+ T cells and less pathogenic Th17 infiltration in the intestine, even compared with mice receiving maraviroc with control shRNA–transduced human T cells. Furthermore, the frequency of CD4+CD146+CCR5+ Tregs was increased in GI-GVHD patients, and these cells showed increased plasticity toward Th17 upon ICOS stimulation. Our findings can be applied to early risk stratification, as well as specific preventative therapeutic strategies following HCT.
|Original language||English (US)|
|State||Published - May 5 2016|
Bibliographical noteFunding Information:
This work was supported by the NIH (RC1 HL101102, R01 CA168814, P01 CA142106, P01 AI056299), the Amy Strelzer Manasevit Research Program, the Leukemia & Lymphoma Society Scholar Award, and the Lilly Physician Scientist Initiative Award. The authors thank Chrystal Paulos for suggestions on ICOS antibody–coated bead protocols. The authors thank the operators of the Indiana University Melvin and Bren Simon Cancer Center Flow Cytometry Resource Facility for their outstanding technical help. The Flow Cytometry Resource Facility is partially funded by the National Cancer Institute (P30 CA082709). We also acknowledge the help and support of the In Vivo Therapeutics Core of the Indiana University Melvin and Bren Simon Cancer Center (partially funded by the National Cancer Institute [P30 CA082709] and National Institute of Diabetes and Digestive and Kidney Diseases [P01 DK090948]).
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