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J. Hori, M. C. Wang, H. Taniguchi, Y. Kitahara, H. Takahashi, M. Oshima, S. Sakaguchi, M. Azuma; Role of Glucocorticoid-Induced TNF Receptor Ligand in Immune Privilege of Corneal Allografts. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3627.
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The pathway between glucocorticoid-induced TNF receptor family-related protein (GITR) and its ligand (GITRL) has been shown to control the function of regulatory T cells (Treg). To investigate the role of this pathway in ocular immune privilege, we used in vivo experimental models including anterior chamber-associated immune deviation (ACAID) and acceptance of corneal allografts.
Normal corneas of C57BL/6 mice were orthotopically transplanted into normal eyes of BALB/c mice, and graft survival was assessed. In a separate experiment, BALB/c mice received anterior chamber injection of C57BL/6 splenocytes 2 weeks prior to subcutaneous immunization. Induction of allo-specific ACAID was assessed by ear challenge with C57BL/6 splenocytes at 1 week after immunization. Recipients were intraperitoneally administrated agonistic anti-GITR (DTA-1) or antagonistic anti-GITRL (MIH44) monoclonal antibodies (mAb), or control IgG, for 8 weeks after corneal grafting, and for 3 weeks after AC injection. Expressions of GITRL, GITR, and Treg-specific transcription factor Foxp3 in normal and graft-bearing eyes were assessed immunohistochemically by confocal microscopy.
GITRL was expressed constitutively in the corneal endothelium, iris-ciliary body and retinal pigment epithelium. Treatment with DTA-1 or MIH44 did not affect allo-specific ACAID, but led to accelerated corneal allograft rejection. GITRL-expressing corneal allografts were infiltrated with Foxp3(+)GITR(+)CD4(+)T-cells, during which allograft acceptance occurred. In contrast, blockade of GITRL led to infiltration of a number of Foxp3(-)GITR(+)CD4(+)T-cells into allografts, leading to allograft rejection.
T-cell stimulation through GITR by agonistic mAb enhances effector T-cell responses against corneal allografts. On the contrary, GITRL expressed on corneal endothelium plays a role in the acceptance of corneal allografts, via Treg-mediated suppression within the cornea.
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