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Jing Hua, William Stevenson, Thomas Dohlman, Hyun Soo Lee, Zahra Sadrai, Ilya Leskov, Daniel Saban, Sunil Chauhan, Reza Dana; Dysfunctional Regulatory T cells in Dry Eye Disease Exacerbate Corneal Allograft Rejection. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4127.
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Anecdotal clinical observations suggest that dry eye disease (DED) undermines corneal graft survival. However, the underlying mechanisms are not well understood. This study investigated the survival rate and the adaptive immune response following corneal allotransplantation in DED host mice.
DED was induced in 10 female Balb/c mice using the controlled environment chamber with subcutaneous scopolamine injection over two weeks. C57Bl/6 donor corneas were then grafted onto Balb/c mice with DED. Ten normal Balb/c mice residing in room air (RA) underwent corneal transplantation and served as controls. Two other groups of DED hosts underwent adoptive transfer of naïve Balb/c CD4+CD25+ regulatory T cells (Treg) or CD4+CD25- effector T cells as control one day before allotransplantation. Cells from 3 mice of each DED, RA and naïve control group were analyzed using the T cell proliferation assay, flow cytometry (FACS), and quantitative real time PCR.
Kaplan-Meier survival curves indicated that significantly fewer corneal grafts survived in DED mice (22.2%, n=9) after eight weeks, compared to RA controls (50%, n=10, p<0.01). The earliest graft rejection appeared at 10 days after the transplantation in DED recipients, and at three weeks in controls. Treg from draining lymph nodes of DED hosts showed significantly lower suppression in the T cell proliferation assay (2.6±9.6% in DED, 43.9±2.9% in RA, and 85.1±0.3% in naïve control, n=3, ANOVA). Although the frequencies of CD4+CD25+Foxp3+ Treg were comparable between all groups in FACS analyses, the DED host group exhibited significantly lower Foxp3 expression via qPCR (0.6- in DED, 0.7-fold in RA, normalized to naïve controls, n=3, ANOVA). Adoptive transfer of naïve Balb/c CD4+CD25+ Treg to DED hosts significantly delayed graft rejection (median survival of 56 days in transferred, compared to 17.5 days in controls), and improved the graft survival rate to 44.4% (n=9) by 8 weeks, compared to 10% in the CD4+CD25--transferred control group (n=10).
Our data suggest that dysfunction of the Treg apparatus may be the key mechanism underlying the exacerbation of corneal allograft rejection in DED hosts.
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