title: Protective effect of neutralizing anti-IL-18α monoclonal antibody on a mouse model of acute graft-versus-host disease.
abstract: Graft-versus-host disease (GVHD) is a devastating complication of hematopoietic stem cell transplantation (HSCT), and is characterized by systemic inflammation and tissue damage in multiple organs, such as the liver and small intestine. Interleukin-18 (IL-18), an important pro-inflammatory cytokine, is elevated during the course of acute GVHD (aGVHD), and is associated with the severe clinical manifestations of the disease. The biological activity of IL-18 is based on its interaction with the IL-18 receptor (IL-18R) expressed in a variety of cells. The aim of this study was to assess whether blocking the interaction of IL-18 with IL-18R by the anti-IL‑18Rα antibody could attenuate the severity of aGVHD. We used a well-established mouse bone marrow transplantation (BMT) model (B6→BALB/c) to block the IL-18/IL-18R interaction by a neutralizing monoclonal antibody (mAb) against murine IL-18Rα. Administration of anti-IL-18Rα mAb had a significant protective effect on the clinical and pathologic manifestations of aGVHD, resulting in a markedly improved survival rate, modified inflammatory response and decreased tissue damage. Interfering with IL-18/IL-18R interaction affected levels of Th1, Th2 and Th17 subsets in the peripheral blood of the aGVHD animals. Additionally, it led to decreased tissue expression of IL-18 and apoptosis-associated molecules (Fas and FasL), and lower phosphorylation levels of p38MAPK in the liver and small intestine. These changes coincided with the decrease in cell apoptosis in aGVHD target organs. Thus, anti‑IL-18Rα therapy may, therefore, represent a new therapeutic interference approach for treating aGVHD.
authors.affiliation: Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou, Jiangsu 221004, P.R. China.
authors.forename: Xiaocui
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou, Jiangsu 221004, P.R. China.
authors.forename: Cuiping
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College; Key Laboratory of Bone Marrow Stem Cells; Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College; Key Laboratory of Bone Marrow Stem Cells; Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Pan
authors.affiliation: Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou, Jiangsu 221004, P.R. China.
authors.forename: Fanyun
authors.initials: F
authors.lastname: Kong
authors.affiliation: Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou, Jiangsu 221004, P.R. China.
authors.forename: Kuiyang
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Department of Pathogenic Biology and Immunology, Laboratory of Infection and Immunity, Xuzhou Medical College, Xuzhou, Jiangsu 221004, P.R. China.
authors.forename: Renxian
authors.initials: R
authors.lastname: Tang
authors.affiliation: Blood Diseases Institute, Xuzhou Medical College; Key Laboratory of Bone Marrow Stem Cells; Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China.
authors.forename: Lingyu
authors.initials: L
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D016019:Survival Analysis; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit