Function of the Vascular Endothelial Growth Factor Receptors Flt-1 and Flk-1/KDR in the Alloimmune Response In Vivo
| Autor: | Hiromichi Kanehiro, Yan Wu, David M. Briscoe, Kaoru Hamada, Naoya Ikeda, Satoru Akashi, Hisanori Kashizuka, Yukiyasu Kuzumoto, Daniel J. Hicklin, Yoshikazu Tsurui, Masayuki Sho, Yoshiyuki Nakajima, Takeo Nomi, Hitoshi Yoshiji |
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| Rok vydání: | 2005 |
| Předmět: |
Graft Rejection
Vascular Endothelial Growth Factor A Chemokine medicine.drug_class medicine.medical_treatment Biology Monoclonal antibody Proinflammatory cytokine Mice chemistry.chemical_compound medicine Animals Transplantation Homologous RNA Messenger Receptor Transplantation Vascular Endothelial Growth Factor Receptor-1 Kinase insert domain receptor Immunohistochemistry Vascular endothelial growth factor surgical procedures operative Cytokine chemistry Acute Disease embryonic structures Immunology cardiovascular system biology.protein Cytokines Chemokines |
| Zdroj: | Transplantation. 80:717-722 |
| ISSN: | 0041-1337 |
| DOI: | 10.1097/01.tp.0000173650.83320.b1 |
| Popis: | Background. We have recently reported that vascular endothelial growth factor (VEGF) functions as a proinflammatory cytokine to regulate the trafficking ofleukocytes 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-2 b ) into BALB/c (H-2 d ) 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. |
| Databáze: | OpenAIRE |
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