ROLE OF ANGIOGENESIS AND POTENTIAL OF ANTIANGIOGENESIS AS POSTTRANPLANT TREATMENT IN SMALL BOWEL TRANSPLANTATION

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We tried to clarify the role of angiogenesis in the process of acute allograft rejection and explore the potential of antiangiogenic therapy as novel posttransplant treatment in small bowel transplantation. To this end, we utilized a fully MHC mismatched murine small bowel transplantation model using microsurgical technique. C57BL/6 (H-2b) were used as donor and BALB/c (H-2d) as recipient. The graft were removed and examined on 7 day after transplantation. Histological evaluation revealed that massive cellular infitration as well as the severe tissue destruction were identified in rejecting small bowel grafts. Realtime PCR analysis indicated that VEGF and VEGF receptors were upregulated in the process of allograft rejection suggesting that VEGF-VEGFR interaction has some roles in alloimmune response. To clarify the underlying mechanisms, we further treated recipient mice with anti-VEGFR1 mAb and/or anti-VEGFR2 mAb. Although either VEGFR-1 or VEGFR-2 blockade didn't prolong allograft su … More rvival, the simultaneous blockade of both VEGFRs significantly prevented acute allograft rejection and prolonged allograft survival. Histological analysis also confirmed the protective effect of simultaneous blockade of VEGFRs on acute allograft rejection. These findings are suggestive that both VEGFR-1 and VEGFR-2 are functionally important and VEGF/VEGFR pathway play critical roles in alloimmune response. Furthermore, the effect was significantly associated with the downregulation of local cytokine and chemokine expressions. Our data demonstrates that VEGF may function in alloimmune response in vivo via two distinct major receptors : VEGFR-1 and VEGFR-2. Targeting VEGF-VEGFR pathway may represent a novel therapy for the protection of alloimmune response in clinical transplantation. Furthermore, to extend our study, we tested the function of VEGF and VEGFR in ischemia/reperfusion injury. Data also suggested that VEGF plays an important role in ischemia/reperfusion injury and blockade of VEGFRs significantly protected ischemic injury in the liver and the small intestine. These data suggested that targeting VEGF/VEGFR might represent a novel strategy in clinical transplantation. Less