title: Notch pathway plays a novel and critical role in regulating responses of T and antigen-presenting cells in aGVHD.
abstract: Graft-versus-host disease (GVHD) induced by host antigen-presenting cells (APCs) and donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). Notch signaling pathway is a highly conserved cell-cell communication that is important in T cell development. Recently, Notch signaling pathway is reported to be involved in regulating GVHD. To investigate the role of Notch inhibition in modulating GVHD, we established MHC-mismatched murine allo-BMT model. We found that inhibition of Notch signaling pathway by γ-secretase inhibitor in vivo could reduce aGVHD, which was shown by the onset time of aGVHD, body weight, clinical aGVHD scores, pathology aGVHD scores, and survival. Inhibition of Notch signaling pathway by DAPT ex vivo only reduced pathology aGVHD scores in the liver and intestine and had no impact on the onset time and clinical aGVHD scores. We investigated the possible mechanism by analyzing the phenotype of host APCs and donor-derived T cells. Notch signaling pathway had a broad effect on both host APCs and donor-derived T cells. The expressions of CD11c, CD40, and CD86 as the markers of activated dendritic cells (DCs) were decreased. The proliferative response of CD8+ T cell decreased, while CD4+Notch-deprived T cells had preserved expansion with increased expressions of CD25 and Foxp3 as markers of regulatory T cells (Tregs). In conclusion, Notch inhibition may minimize aGVHD by decreasing proliferation and activation of DCs and CD8+T cells while preserving Tregs expansion.
authors: Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, China.|Institute of Hematology, Jinan University, Guangzhou, China.|Department of Hematology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510230, China.
authors: Xiaodan
authors: X
authors: Luo
authors: Department of Hematology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510230, China.
authors: Lihua
authors: L
authors: Xu
authors: Department of Hematology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, China.|Institute of Hematology, Jinan University, Guangzhou, China.
authors: Yangqiu
authors: Y
authors: Li
authors: Department of Hematology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510230, China. tanhuo.2008@163.com.
authors: Huo
authors: H
authors: Tan
mesh_terms: D000208:Acute Disease; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology*; D016026:Bone Marrow Transplantation; D003959:Diamines / Q000494:pharmacology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D006649:Histocompatibility Antigens / Q000378:metabolism; D006650:Histocompatibility Testing; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C000612000:24-diamino-5-phenylthiazole; D003959:Diamines; D006649:Histocompatibility Antigens; D051880:Receptors, Notch; D013844:Thiazoles
keywords: Antigen-presenting cell; Graft-versus-host disease; Notch; Signaling; T cell