title: Function of the vascular endothelial growth factor receptors Flt-1 and Flk-1/KDR in the alloimmune response in vivo.
abstract: BACKGROUND
  We have recently reported that vascular endothelial growth factor (VEGF) functions as a proinflammatory cytokine to regulate the trafficking of leukocytes into allografts in the early posttransplant period. VEGF binds two major VEGF receptors: VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR). Here, we wished to investigate the expression and function of VEGF receptors in the process of acute allograft rejection in vivo.
  
  
  METHODS
  We performed fully MHC-mismatched C57BL/6 (H-2b) into BALB/c (H-2d) vascularized heterotopic murine cardiac transplants and we examined the expression of VEGF and VEGF receptors by immunohistochemistry during acute allograft rejection. Next, we treated mice with specific neutralizing monoclonal antibodies against murine VEGFR-1 and VEGFR-2 and examined their effect on the development of acute allograft rejection by histology and by analysis of graft survival. The intragraft expression of cytokines and chemokines were also evaluated by quantitative real-time PCR analysis.
  
  
  RESULTS
  The expression of VEGF, VEGFR-1 and VEGFR-2 were significantly up-regulated during allograft rejection as compared to isografts. Administration of either anti-VEGFR-1 or anti-VEGFR-2 alone failed to inhibit allograft rejection. However, coadministration of both antibodies together inhibited leukocyte infiltration of allografts and prolonged allograft survival. Furthermore, the effect of VEGFR blockade was associated with the downregulation of intragraft cytokine and chemokine expression.
  
  
  CONCLUSIONS
  Our data suggest that VEGF-VEGFR interactions function in the alloimmune response in vivo. Targeting VEGFRs may represent a novel therapy to protect allografts following clinical transplantation.
authors.affiliation: Department of Surgery, Nara Medical University, Nara, Japan. m-sho@naramed-u.ac.jp
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sho
authors.forename: Satoru
authors.initials: S
authors.lastname: Akashi
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kanehiro
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hamada
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kashizuka
authors.forename: Naoya
authors.initials: N
authors.lastname: Ikeda
authors.forename: Takeo
authors.initials: T
authors.lastname: Nomi
authors.forename: Yukiyasu
authors.initials: Y
authors.lastname: Kuzumoto
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tsurui
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: David M
authors.initials: DM
authors.lastname: Briscoe
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nakajima
mesh_terms: D000208:Acute Disease; D000818:Animals; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology*; D007150:Immunohistochemistry; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D014184:Transplantation, Homologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000276:immunology* / Q000378:metabolism*
chemical_list: D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1