title: Anti-interleukin-12/23p40 antibody attenuates chronic rejection of cardiac allografts partly via inhibition γδT cells.
abstract: In our previous study, we showed that treatment with an anti-interleukin (IL)-12/23p40 antibody inhibits acute cardiac allograft rejection via inhibiting production of interferon (IFN)-γ and IL-17a. However, the impact of this antagonistic anti-p40 antibody on chronic cardiac rejection was unclear. Hearts of B6.C-H2bm12/KhEg mice were transplanted into major histocompatibility complex (MHC) class II-mismatched C57Bl/6J mice (wild-type, γδTCR (-/-)  and IL-17(-/-) ), which is an established murine model of chronic allograft rejection without immunosuppression. The mice were treated with control immunoglobulin (Ig)G or 200 µg anti-p40 monoclonal antibody on post-operative days, respectively. Abdominal palpation and echocardiography were used to monitor graft survival. The mice administered with anti-p40 antibody showed a significant promotion in graft survival (median survival time >100 days), and histological analyses revealed that cardiac allograft rejection was attenuated. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunofluorescence analyses demonstrated that anti-p40 antibody down-regulated the level of ingraft cytokine and chemokine expression (IL-6, IFN-γ, IL-17a, CCL2 and CCL20). Flow cytometry analyses showed that γδ T cells are an important ingraft source of IFN-γ and IL-17a and inhibit the production of inflammation cytokine by anti-p40 antibody. Compared with the wild-type group, the graft survival time in the γδ T cell receptor(-/-)  and IL-17(-/-)  mice was prolonged significantly. Therefore we propose that, in the chronic allograft rejection model, treatment with anti-p40 antibody prolongs graft survival possibly by reducing the amount of reactive inflammatory cells, especially γδ T cells.
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan Institute of Cardiovascular Surgery, Xijing Hospital, The 4th Military Medical University, Xi'an, Shaanxi Province Department of Cardiovascular Surgery, Fu Wai Hospital, Beijing, China.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: A
authors.initials: A
authors.lastname: Xie
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: P
authors.initials: P
authors.lastname: Ye
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Rui
authors.forename: J
authors.initials: J
authors.lastname: Xia
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation; D007371:Interferon-gamma / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40 / Q000037:antagonists & inhibitors* / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis*; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D018925:Chemokines; D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma