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Takenori Inomata, Jing Hua, Masahiro Omoto, Qiang Zhang, Reza Dana; Impaired Peripheral Induction of Regulatory T Cells in High-Risk Corneal Transplantation. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3221.
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To evaluate peripheral induction of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in regional lymph nodes (LNs) following corneal allograft transplantation in high-risk (HR) vs. low-risk (LR) conditions.
Orthotopic corneal transplantation was carried out in 8-week old mice by grafting C57BL/6 donor corneas to BALB/c recipients. To induce host HR conditions we placed three stromal sutures into the recipient corneas two weeks prior to surgery. T cell subsets in the ipsilateral LNs of HR and LR BALB/c mice were analyzed before and 14 days after grafting using flow cytometry. According to previous studies, we identified peripherally induced Tregs as Nrp-1 (Neuropilin 1)-CD4+CD25+Foxp3+. In addition, we analyzed the expression of inhibitory molecules CTLA-4 and PDL-1 in Treg subsets using flow cytometry and Treg function in vitro using a suppression assay.
Before transplantation, the frequency of Nrp-1- Tregs in HR hosts was 13% higher than that in LR hosts ( p<0.01). In contrast, by 14 days after transplantation HR recipients showed a 11% reduction in the frequency of Nrp-1- Tregs compared to LR recipients (p<0.01). CTLA-4 and PDL-1 had lower expression levels in Nrp-1- Tregs of HR recipients compared to LR recipients at day 14 (CTLA-4: LR 665 vs. HR 618, p=0.0380, PDL-1: LR 1512, HR 1353, p=0.0459). In addition, Tregs from HR hosts showed a significantly reduced suppressive function compared to Tregs from LR hosts at day 14 (LR 51% vs. HR 39%, p=0.0051, n=3).
High-risk (e.g. intense inflammatory) conditions in the host impair the peripheral induction of Tregs following corneal transplantation, and reduce the expression of inhibitory molecules and suppressive function of Tregs. Our results suggest that impaired Treg induction or Treg dysfunction may be responsible for the loss of corneal graft tolerance in HR conditions.
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