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Nancy J. Reyes, Peter W. Chen, Jerry Y. Niederkorn; Allergic Conjunctivitis Exacerbates Corneal Allograft Rejection by Rendering Effector Cells Resistant to T Regulatory Cell-mediated Suppression. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2370.
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To elucidate the role of allergic conjunctivitis in the exacerbation of corneal allograft rejection.
Wild-type (WT) BALB/c and IL-4R-/- mice were given orthotopic C57BL/6 (B6) corneal allografts. Allergic conjunctivitis (AC) was induced in WT BALB/c and IL-4R-/- mice using short ragweed (SRW). Early phase responses of AC were evaluated clinically and late phase responses by histopathology. Cytokine profiles were evaluated by ELISA. CD4+CD25+ T regulatory cells (Tregs) were isolated from BALB/c hosts with clear corneal allografts at day 21 and were co-cultured with anti-CD3-stimulated CD4+ T cells from naïve mice in the presence of recombinant IL-4 (rIL-4), rIL-5, or rIL-13. Treg-mediated suppression of CD4+ T cell proliferation was measured in vitro. Treg activity was also measured in vivo using a local adoptive transfer (LAT) of delayed-type hypersensitivity (DTH) assay in which sensitized CD4+ effector cells were co-injected with Tregs.
CD4+ T cells from SRW sensitized mice produced IL-4, IL-5, and IL-13 in vitro. In vitro and in vivo assays showed that IL-4, but not IL-5 or IL-13, prevented Treg-mediated suppression, both in vitro and in vivo. Both the clinical and histopathological features of AC were the same in SRW-sensitized IL-4R-/- mice and WT mice. However, SRW-sensitized IL-4R-/- mice displayed the same 50% graft survival as non-allergic WT mice. Restoration of graft survival in SRW-sensitized allergic WT mice also occurred if the allergic mice were isolated from SRW pollen for 14 days prior to receiving corneal allografts.
In allergic conjunctivitis, IL-4, but not IL-5 or IL-13, is the key cytokine involved in rendering effector T cells resistant to Treg suppression, which in turn leads to exacerbation of corneal allograft rejection. Effector T cells from IL-4R-/- mice cannot respond to IL-4 and as a result are amenable to Treg suppression, even in hosts with ongoing AC. Immune privilege of corneal allografts can also be restored in allergic hosts by preventing their exposure to allergen, which eliminates IL-4 production. It is possible that blocking IL-4 with anti-IL-4 antibody may also restore immune privilege of corneal allografts in hosts with allergic conjunctivitis.
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