Molecular regulation of lymphangiogenesis in corneal alloimmunity

University Of California Berkeley, Berkeley CA

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Abstract

DESCRIPTION (provided by applicant): Lymphatic research represents an explosive field of new discovery owning to the recent identification of several lymphatic specific markers. The cornea provides an ideal tissue for lymphatic studies due to its accessible location, transparent nature, and lymphatic-free and -inducible character. Additionally, corneal transplantation offers an excellent model for lymphatic research because it allows for (i) functional lymphatic cell trafficking studies;and (ii) identification of cellular contributions (donor or recipient source) to the process of lymphangiogenesis (LG). Studies on corneal LG bear direct applications to high risk (HR) transplantation where grafting is performed on lymphatic-rich host beds and the rejection rate can be as high as 90%, a category that many patients blind from corneal diseases fall into after inflammatory, infectious, traumatic, or toxic insults. In this setting, the trafficking of antigen presenting cells (ARC) afforded by lymphatics is greatly enhanced. To date, there is no effective management for this situation. My long-term goal is to elucidate the molecular mechanisms of LG using in vitro and corneal models, a necessary prerequisite to the development of new therapeutic protocols. My hypothesis is that corneal LG can be manipulated through specific lymphatic factors or cell populations (such as the macrophages), and combined blockade of several factors optimizes the outcomes of HR graft survival. This hypothesis is based on my preliminary data that 1) vascular endothelial growth factor receptor-3 (VEGFR-3) is expressed on both APCs and newly developed lymphatics, and its blockade leads to improved graft survival in uninflamed beds;2) a1 integrin (very late antigen-1, VLA-1) deficiency leads to diminished corneal LG, and universal graft survival in uninflamed beds;and 3) lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) is expressed on normal conjunctival cells of macrophage lineage and these cells may supply functional corneal LG during inflammation. The specific aims of this proposal are to: 1) define the role of VEGFR-3. I will study the role of VEGFR-3 in both development and maintenance of LG, and modifications of HR host beds and graft survival at both early and late stages;2) determine the role of VLA-1.1 will identify the expressional patterns of VLA-1 during corneal inflammation, and the role of VLA-1 in lymphatic endothelial cell functions in vitro, and corneal LG, lymphatic trafficking, modifications of HR host beds and graft survival in vivo;and 3) investigate the interaction between VEGFR-3, VLA-1 and LYVE-1.1 will investigate the role of conjunctival macrophages in corneal LG, the interplay between these three factors, and the effect of the concurrent blockade on modifications of HR host beds and graft survival. Research on corneal LG will have broader clinical implications beyond the treatment of ocular diseases alone, since lymphatic dysfunctions have been found in a diverse array of diseases including cancer metastasis, lymphedema, diabetics, arthritis, and AIDS, among many others.