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Jerry Y Niederkorn, Kathryn Joy Paunicka, jessamee Mellon, joseph R brown; Second corneal allografts ablate T regulatory cells that are induced by first corneal allografts and produce a permanent loss of immune privilege in both eyes. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4874.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the mechanism whereby an initial penetrating keratoplasty (PK) abolishes immune privilege of subsequent corneal allografts
Corneas from C57BL/6 donors were grafted orthotopically to BALB/c mice. A 2.0 mm trephine was used to make shallow circumferential incisions in left eyes prior to applying corneal allografts to right eyes. T regulatory cell (Treg) activity was measured in vivo using a local adoptive transfer (LAT) of DTH assay. Tregs were also assessed by flow cytometry.
C57BL/6 corneal allografts underwent rejection in 50% of naïve BALB/c hosts. However, PK to one eye abolished immune privilege and resulted in 100% graft rejection in the contralateral, unmanipulated eye, even when the first corneal graft was syngeneic and did not evoke an immune response. This effect could be mimicked with either 360° or 180° corneal incisions, which induced rejection of 90-100% corneal grafts transplanted to the opposite eye, even 100 days after the initial corneal incision. PK induced a 300-fold increase in substance (SP) production in both eyes. Intravenous injection of 1.0 pg of SP abolished immune privilege of corneal allografts (>90% rejection), which persisted for ≥100 days. Placing shallow 360° corneal incisions in one eye also induced the immune rejection of long-standing (>60 days) corneal allografts in the opposite eye. The surgery-induced loss of immune privilege coincided with a steep down-regulation in GITR expression on CD4+CD25+ T regulatory cells (Tregs) but had no effect on Treg expression of CTLA-1, Foxp3, or TGF-β on corneal allograft- induced Tregs.
First time C57BL/6 corneal transplants enjoy a 50% acceptance rate in naïve BALB/c mice. However, circular corneal incisions used in preparation for a second PK disable disable T regs by down-regulating GITR expression. The ablation of T reg function induced by second PK also abolishes the immune privilege of long-standing corneal allografts in the opposite eye and leads to immune rejection of previously healthy corneal transplants.
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