title: Blockade of NKG2D synergized with CTLA4-Ig in promoting long-term graft survival in murine models of cardiac transplantation.
abstract: BACKGROUND
  Blockade of B7-CD28 interaction with CTLA4-Ig could prolong allograft survival in cardiac transplantation. NKG2D is an activating or coactivating receptor on NK cells, γδ T, and CD8 T cells and played an important role in transplant immunity.
  
  
  METHODS
  C57BL/6 (wild type and γδ or interleukin (IL)-17) mice were transplanted with allogeneic BALB/c hearts and treated with CTLA4-Ig alone or in combination with anti-NKG2D monoclonal antibodies. The survival of grafts was monitored daily by abdominal palpation until the complete cessation of cardiac contractility.
  
  
  RESULTS
  We found that wild type recipient treated with anti-NKG2D monoclonal antibodies plus CTLA4-Ig showed significantly prolonged survival cardiac allograft (>90 days, P<0.001). These in vivo results in combined therapy group correlated with low expression of interferon-γ whereas increased expression of IL-4 and alternatively activated macrophage markers. Furthermore, with blockade of NKG2D, the number of IL-17-producing γδ T cells was significantly reduced, which was demonstrated as the main source of IL-17 production. And in our γδ and IL-17 murine cardiac transplantation models, we found that γδ or IL-17 deficiency could significantly prolong cardiac allograft survival.
  
  
  CONCLUSIONS
  Blockade of NKG2D is effective in synergizing with CTLA4-Ig to promote long-term cardiac allograft survival in mice, and this effect is associated with decreased infiltration of IL-17-producing γδ T cells.
authors.affiliation: Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. lijun00207@163.com
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Hongfei
authors.initials: H
authors.lastname: Zhu
authors.forename: Sihua
authors.initials: S
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.forename: Chenggui
authors.initials: C
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.forename: Jiahong
authors.initials: J
authors.lastname: Xia
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D060908:CTLA-4 Antigen / Q000187:drug effects* / Q000276:immunology*; D002465:Cell Movement; D006085:Graft Survival / Q000276:immunology* / Q000502:physiology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D007074:Immunoglobulin G / Q000276:immunology; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D023421:Models, Animal; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000187:drug effects* / Q000276:immunology*; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D007074:Immunoglobulin G; D020381:Interleukin-17; C527086:Klrk1 protein, mouse; D015778:Minor Histocompatibility Antigens; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490521:Rae1 protein, mouse; D016692:Receptors, Antigen, T-Cell, gamma-delta; C114735:minor H antigen H60