: The studies proposed herein will determine the molecular mechanisms, particularly the role of VEGFR-3, in corneal lymphangiogenesis, APC trafficking, and lymphatic drainage as they relate to corneal alloimmunity. VEGFR-3 is mainly expressed on lymphatics and our preliminary data have shown its increased expression on both lymphatics and APCs during inflammatory corneal neovascularization (NV). More importantly, APC trafficking to the draining lymph nodes (LN) after corneal transplantation, a critical component of inducing immunity to corneal grafts, is greatly reduced by an anti-VEGFR-3 strategy. We further propose to address the following issues: (i) the time course of the expressional changes of VEGFR-3 during corneal inflammation and its role in APC maturation; (ii) the functional effects of anti-VEGFR-3 strategies on allospecific delayed-type hypersensitivity (DTH) and graft survival; and (iii) the relationship between VEGFR-3 and other lymphatic factors, such as lymphatic vessel endothelial hyaluronan receptor (LYVE-1), Prox-1, and secondary lymphoid chemokine (SLC). We anticipate that these studies will reveal important molecular mechanisms that relate to vascular and lymphatic development in the cornea with corneal immunity. They will also provide knowledge necessary for manipulating the processes involved in corneal lymphangiogenesis and APC trafficking, with likely implications beyond transplant immunology alone. ? ?
| Chen, Lu; Huq, Syed; Gardner, Humphrey et al. (2007) Very late antigen 1 blockade markedly promotes survival of corneal allografts. Arch Ophthalmol 125:783-8 |
| Chen, Lu; Cursiefen, Claus; Barabino, Stefano et al. (2005) Novel expression and characterization of lymphatic vessel endothelial hyaluronate receptor 1 (LYVE-1) by conjunctival cells. Invest Ophthalmol Vis Sci 46:4536-40 |
