Vascular Endothelial Growth Factor-C Promotes Alloimmunity by Amplifying Antigen-Presenting Cell Maturation and Lymphangiogenesis

Abstract

Purpose. To investigate the role of anti–vascular endothelial growth factor (VEGF)-C therapy in corneal graft survival and concomitant suppression of hem- and lymph-angiogenesis. Methods. Corneal suture model in BALB/c mice was placed and immunohistochemical staining was performed with CD31/PECAM-1 and LYVE-1 to quantify the level of blood and lymphatic vessels. Corneal transplants were done in BALB/c mice from C57BL/6 mice donors; grafts were subsequently scored for opacity. VEGF-C was blocked in the angiogenesis and transplant model using neutralizing monoclonal anti-VEGF-C (VGX-100) by intraperitoneal injection. To determine the function of VEGF-C in maturation of antigen-presenting cells (APCs), bone marrow–derived dendritic cells were generated and matured in the presence or absence of VEGF-C. Results. VEGF-C expression was demonstrated to be markedly upregulated in corneal graft rejection. VEGF-C blockade, through administration of a VEGF-C blocking monoclonal antibody, suppresses corneal angiogenic responses, inhibits trafficking and maturation of APCs, and significantly improves allotransplant survival. Conclusions. These data suggest VEGF-C as a potentially important target in corneal transplant pharmacotherapy and immunobiology.