title: Essential Role of Interleukin-12/23p40 in the Development of Graft-versus-Host Disease in Mice.
abstract: Graft-versus-host disease (GVHD), in both its acute (aGVHD) and chronic (cGVHD) forms, remains a major obstacle impeding successful allogeneic hematopoietic stem cell transplantation (allo-HSCT). T cells, in particular pathogenic T helper (Th) 1 and Th17 subsets, are a driving force for the induction of GVHD. IL-12 and IL-23 cytokines share a common p40 subunit and play a critical role in driving Th1 differentiation and in stabilizing the Th17 phenotype, respectively. In our current study, we hypothesized that p40 is an essential cytokine in the development of GVHD. By using p40-deficient mice, we found that both donor- and host-derived p40 contribute to the development of aGVHD. Neutralization of p40 with an anti-p40 mAb inhibited Th1- and Th17-polarization in vitro. Furthermore, anti-p40 treatment reduced aGVHD severity while preserving the graft-versus-leukemia (GVL) activity. Alleviation of aGVHD was associated with an increase of Th2 differentiation and a decrease of Th1 and Th17 effector T cells in the GVHD target organs. In addition, anti-p40 treatment attenuated the severity of sclerodermatous cGVHD. These results provide a strong rationale that blockade of p40 may represent a promising therapeutic strategy in preventing and treating aGVHD and cGVHD while sparing the GVL effect after allo-HSCT.
authors.affiliation: Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, China; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: David
authors.initials: D
authors.lastname: Bastian
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Steven
authors.initials: S
authors.lastname: Schutt
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Hung
authors.initials: H
authors.lastname: Nguyen
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Jianing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Jessica
authors.initials: J
authors.lastname: Heinrichs
authors.affiliation: Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, China; Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida.
authors.forename: Changqing
authors.initials: C
authors.lastname: Xia
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina; Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. Electronic address: yux@musc.edu.
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D002454:Cell Differentiation; D004195:Disease Models, Animal; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D020544:Graft vs Leukemia Effect; D006650:Histocompatibility Testing; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008212:Lymphocyte Depletion; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061251:Primary Cell Culture; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D057134:Antibodies, Neutralizing; D053762:Interleukin-12 Subunit p40
keywords: Antigen-presenting cells; Graft-versus-host disease; IL-12; IL-23; T cell differentiation; T cell migration; T cells; p40
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