title: Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in mice.
abstract: Allogeneic hematopoietic cell transplantation (HCT) is effective therapy for hematologic malignancies through T cell-mediated GVL effects. However, HCT benefits are frequently offset by the destructive GVHD, which is also induced by donor T cells. Naive Th can differentiate into Th1 and Th17 subsets and both can mediate GVHD after adoptive transfer into an allogeneic host. Here we tested the hypothesis that blockade of Th1 and Th17 differentiation is required to prevent GVHD in mice. T cells with combined targeted disruption of T-bet and RORγt have defective differentiation toward Th1 and Th17 and skewed differentiation toward Th2 and regulatory phenotypes, and caused ameliorated GVHD in a major MHC-mismatched model of HCT. GVL effects mediated by granzyme-positive CD8 T cells were largely preserved despite T-bet and RORγt deficiency. These data indicate that GVHD can be prevented by targeting Th1 and Th17 transcription factors without offsetting GVL activity.
authors.affiliation: Department of Immunology & Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yu
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Kane
authors.initials: K
authors.lastname: Kaosaard
authors.forename: Kenrick
authors.initials: K
authors.lastname: Semple
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D006086:Graft vs Host Disease / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000235:genetics; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D014184:Transplantation, Homologous / Q000009:adverse effects; D000098815:T-bet Transcription Factor
chemical_list: D000970:Antineoplastic Agents; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor