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  • 2020–2021 BCSC Basic and Clinical Science Course™

    Go to Academy Store Learn more and Purchase.

    8 External Disease and Cornea

    Chapter 11: Diagnosis and Management of Immune-Related Disorders of the External Eye

    Corneal Transplant Rejection

    The cornea was the first successfully transplanted solid tissue. After other tissues had been transplanted, it was observed that corneas were rejected less frequently than other transplanted tissues. The concept that the cornea was a site of “immunologic privilege” and that corneal grafts were somehow protected from immunologic destruction subsequently emerged. Early immunologists attributed ocular immune privilege to “immunologic ignorance” due to the absence of lymphatics draining the anterior segment. It was later recognized that corneal grafts are not different from other tissue grafts and that the allogeneic cells of the transplant elicit an immune response, but the response is aberrant. There is a profound antigen-specific suppression of cell-mediated immunity, especially T-cell–mediated inflammation, such as delayed hypersensitivity and a concomitant induction of antibody responses.

    Tolerance of a corneal graft is recognized as an active process, based on several features:

    • absence of blood and lymphatic channels in the graft and its bed

    • absence of MHC class II+ APCs in the graft

    • reduced expression of MHC-encoded alloantigens on graft cells replaced with minor peptides (nonclassical MHC-Ib molecules) to avoid lysis by natural killer cells

    • expression of T-cell–deleting CD95 ligand (Fas ligand, or FasL) on endothelium, which can induce apoptosis in killer T cells

    • immunosuppressive microenvironment of the aqueous humor, including transforming growth factor β2, α-melanocyte-stimulating hormone, vasoactive intestinal peptide, and calcitonin gene–related peptide

    • anterior chamber–associated immune deviation (ACAID) involving the development of suppressor T cells (ACAID is a downregulation of delayed-type cellular immunity. Antigens released into the aqueous humor are, presumably, recognized by dendritic cells of the iris and ciliary body. These APCs can then enter venous circulation and induce regulatory T cells in the spleen, bypassing the lymphatic system.)

    For an immune response to occur, an antigenic substance is introduced and “recognized” (afferent arm; sensitization), resulting in the synthesis of specific antibody molecules and the appearance of effector lymphocytes that react specifically with the immunizing antigen (efferent arm; rejection). Although antibodies to foreign tissues are formed during graft rejection, they are not believed to be important in the usual type of allograft rejection. Rather, extensive evidence indicates that allograft rejection is associated with cellular immune mechanisms. Such T-lymphocyte–mediated responses are delayed hypersensitivity reactions. Other mechanisms are also probably involved. For the endothelial cells to be rejected, they must express MHC class II antigens.

    See also the discussion of clinical signs of corneal transplant rejection in Chapter 15 of this volume. BCSC Section 9, Uveitis and Ocular Inflammation, discusses and illustrates the principles of immunology in greater detail.

    Angiogenesis and Lymphangiogenesis in the Cornea

    Though not normally present in the cornea, blood vessels 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. 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.

    Targeting angiogenesis in order to modulate immune responses after corneal transplant has been the primary area of interest for many researchers. Treatment of corneal neovascularization after corneal transplant may limit both the afferent and efferent arms of alloimmunity and thus reduce the tendency toward inflammatory reactions, which can jeopardize graft survival. VEGF inhibitors, including ranibizumab, bevacizumab, and aflibercept, are used to treat neovascular age-related macular degeneration. The efficacy of these antiangiogenic therapies, which are administered topically and subconjunctivally after transplantation, has been demonstrated. Novel antiangiogenic “t” molecules, which target the intracellular pathways of angiogenesis (small interfering RNA, antisense oligonucleotides), have been reported to provide a promising alternative.

    VEGF-C induces lymphangiogenesis in various animal models. Lymphatics transport APCs to regional lymphoid tissue, where the APCs initiate the T-cell response. The growth of new lymphatic vessels thus facilitates access of donor and host APCs and antigenic material to regional lymph nodes, accelerating sensitization to graft antigens. Recently, the targeting of lymphangiogenesis has also become a focused area of research. There is evidence that blocking lymphatic vessels may play a key role in the prevention and treatment of corneal graft rejection.

    Abudou M, Wu T, Evans JR, Chen X. Immunosuppressants for the prophylaxis of corneal graft rejection after penetrating keratoplasty. Cochrane Database Syst Rev. 2015;(8):CD007603. Epub 2015 Aug 27.

    Albuquerque RJC, Hayashi T, Cho WG, et al. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med. 2009;15(9):1023–1030.

    Bachmann B, Taylor RS, Cursiefen C. Corneal neovascularization as a risk factor for graft failure and rejection after keratoplasty: an evidence-based meta-analysis. Ophthalmology. 2010;117(7):1300–1305.e7.

    Benayoun Y, Petellat F, Leclerc O, et al. Current treatments for corneal neovascularization. J Fr Ophtalmol. 2015;38(10):996–1008.

    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.

    Maruyama K, Ii M, Cursiefen C, et al. Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest. 2005;115(9):2363–2372.

    Skobe M, Dana R. Blocking the path of lymphatic vessels. Nat Med. 2009;15(9):993–994.

    Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.

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