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Maryam Tahvildari, Masahiro Omoto, Yihe Chen, Sunil K Chauhan, Reza Dana; In Vivo Expansion of Regulatory T Cells Reduces Corneal Inflammation in High Risk Corneal Transplantation. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3217.
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© ARVO (1962-2015); The Authors (2016-present)
Decreased numbers of functional regulatory T cells (Treg) in high risk (HR) corneal transplantation has been suggested to contribute to corneal allograft rejection. In this study, we investigated whether Treg expansion through low dose interleukin-2 (IL-2) reduces graft leukocyte infiltration in HR corneal allografts.
Corneal sutures were placed on the host corneas two weeks before transplantation to induce inflamed HR graft beds. BALB/c (H-2d) mice were used as recipients and C57BL/6 (H-2b) mice served as donors. Graft recipients received 3 intraperitoneal injections (once a day) of IL-2 (1μg/20g body weight in 100µl of saline) before transplantation. Saline injected mice with either inflamed (HR) or uninflamed low risk (LR) corneas were used as controls. Injections were continued twice a week until two weeks after transplantation when corneas and ipsilateral cervical lymph nodes (LN) were harvested. Flow cytometry analysis was used to study leukocyte infiltration of the grafts, as well as Treg frequencies and function in draining LNs.
Corneal allografts demonstrated significantly decreased frequencies of CD45+ cells (leukocytes) in HR IL-2 treated hosts (7.9%) compared to either HR controls (13.1%, p=0.036) or LR controls (11.04%, p=0.005). CD4+ T cells constituted 1.4% of graft cells in the HR IL-2-treated group vs. HR controls (2.7%, p= 0.003) and LR controls (1.8%, p=0.045). Draining LNs showed increased frequencies of CD4+CD25+Foxp3+ Tregs in HR IL-2-treated hosts (14.91%±0.4) compared to both HR (13.42%±0.5) and LR (14.47%±0.2) controls. To assess Treg suppressive function, CTLA-4+ cell frequencies and CTLA-4 expression levels (mean fluorescent intensity, MFI) were studied among Foxp3+ Tregs. Frequencies of CTLA-4+Foxp3+ Tregs were higher in the HR IL-2 treated group (27.2%) compared to HR controls (24.3%, p=0.004) and LR controls (24.5%, p=0.027). A similar increase was observed for CTLA-4 MFI: 225±2.6 in the HR IL-2 treated group vs. 206±5.2 in HR controls and 210±6.5 in LR controls.
Low dose IL-2 treatment reduces corneal inflammation in HR corneal transplantation below the levels observed in LR transplants, while increasing Treg numbers and their function. These findings suggest that Treg targeted therapies may decrease corneal rejection rates in high risk corneal transplantation.
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