immune unresponsiveness or even immunologic tolerance.

Niederkorn JY. Cornea: window to ocular immunology. Curr Immunol Rev. 2011;7(3):328–335.

Stern ME, Schaumburg CS, Dana R, Calonge M, Niederkorn JY, Pflugfelder SC. Autoimmunity at the ocular surface: pathogenesis and regulation. Mucosal Immunol. 2010;3(5):425–442.

Angiogenesis and Lymphangiogenesis in the Cornea

Though not normally present in the cornea, blood and lymphatic vessels may extend into the cornea —as sprouts of the vascular endothelium from the limbal tissue—after inflammatory, infectious, traumatic, chemical, or toxic insults. The cellular and molecular mechanisms of corneal angiogenesis and lymphangiogenesis are not completely understood. Inflammatory cells infiltrate tissue at local sites of vascular remodeling, where they secrete proangiogenic factors and metalloproteinases. Vascular endothelial growth factor (VEGF) is upregulated in inflamed and vascularized corneas in humans and in animal models. VEGF-A and fibroblast growth factor 2 (FGF-2) induce lymphangiogenesis in corneas of C57BL/6 mice. VEGF-C also induces lymphangiogenesis in various animal models and, under certain conditions, angiogenesis in both humans and animal models. Lymphangiogenesis is thought to be secondary to angiogenesis, suggesting common molecular and cellular origins for the 2 processes.

Vascularization of the cornea increases the risk of immune rejection after corneal transplantation, leading to a rate of graft rejection greater than 50%. This may occur even when a strict regimen of topical and systemic immunosuppressive agents is used. In fact, stratification of risk factors for immunologic rejection in penetrating keratoplasty has identified recipient vascularization as a critical proximal cause of earlier and more fulminant rejection episodes. Lymphatic neovessels may grow in parallel with the blood vessels; this facilitates access of donor and host APCs and antigenic material to regional lymph nodes, accelerating sensitization to graft antigens.

Therefore, targeting angiogenesis in order to modulate immune responses after corneal transplantation has been the primary area of interest for many researchers. Treatment of corneal neovascularization after corneal transplantation may limit both the afferent (sensitization) and efferent (rejection) arms of alloimmunity and thus reduce the tendency toward inflammatory reactions, which can jeopardize graft survival. VEGF inhibitors, including pegaptanib sodium, ranibizumab, and bevacizumab, are used to treat neovascular age-related macular degeneration. Recently, there has been increasing interest in using topical and subconjunctival anti-VEGF to treat corneal neovascularization.

Bourghardt Peebo B, Fagerholm P, Traneus-Röckert C, Lagali N. Time-lapse in vivo imaging of corneal angiogenesis: the role of inflammatory cells in capillary sprouting. Invest Ophthalmol Vis Sci. 2011;52(6):3060–3068.

Dastjerdi MH, Saban DR, Okanobo A, et al. Effects of topical and subconjunctival bevacizumab in high-risk corneal transplant survival. Invest Ophthalmol Vis Sci. 2010;51(5):2411–2417.

Ecoiffier T, Yuen D, Chen L. Differential distribution of blood and lymphatic vessels in the murine cornea. Invest Ophthalmol Vis Sci. 2010;51(5):2436–2440.

Tissue-Specific Patterns of Immune-Mediated Ocular Disease

Conjunctiva

The conjunctiva is part of the mucosa-associated lymphoid tissue (MALT), which involves a variety of mucosal tissues in the body, including the lacrimal gland. Humoral immunity in the conjunctiva