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Maryam Tahvildari, Parisa Emami-Naeini, Yihe Chen, Masahiro Omoto, Jing Hua, Sunil Chauhan, Reza Dana; In Vivo Administration of Interleukin-2 Increases Corneal Allograft Survival through Expansion of CD4+CD25+ T Regulatory Cells. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2061.
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T regulatory cells (Tregs) have a major role in inhibiting growth and differentiation of activated T cells following alloantigen stimulation, and it has been found that interleukin-2 (IL-2) is crucial in the generation and maintenance of these cells. In this study of murine corneal transplantation, we aimed to investigate the effect of systemic administration of IL-2 on corneal allograft survival.
Corneal transplantation was performed on 8-10 week-old male BALB/c (H-2d) mice using C57BL/6 (H-2b) mice as donors. Prior to surgery, recipient mice received 3 intraperitoneal injections (once a day) of either IL-2 (1µg/20 g body weight, in 100µl phosphate buffer saline [PBS]) or PBS alone (as control). Injections were continued once daily for one week after surgery followed by twice a week for another 4 weeks. Allografts were evaluated up to 5 weeks post-transplantation and were scored using the standard opacity grading system (from 0 to +5). Frequencies of CD4+CD25+Foxp3+ Tregs in the draining lymph nodes were evaluated by flow cytometry on the day of transplantation (day 0), one week (day 7) and two weeks (day 14) afterwards. In addition, the suppressive function of CD4+CD25+ Tregs derived from draining lymph nodes of recipient mice was evaluated one week after transplantation.
Of the six corneas transplanted in each group, 66.6% in the IL-2 treated group remained clear up to 5 weeks after surgery compared to 33.3% in the control group; moreover, IL-2 treatment delayed the incidence of graft rejection with mean rejection time of 32±1.4 days (mean±SD) for the IL-2 treated vs. 19.5±7.7 days for the control group. Flow cytometric analysis showed significant increases in the frequencies of CD4+CD25+Foxp3+ Tregs in the draining lymph nodes of recipient mice in the IL-2 treated group compared to the control group at day 0 (14.54% vs. 10.25%, p=0.014), day 7 (14.77% vs. 11.73%, p=0.009) and day 14 (16.15% vs. 12.41%, p=0.0007). Treg suppression assay revealed 16.05% increased suppression of effector T cells in the IL-2 treated group compared to the control group one week after transplantation (p=0.01).
According to our results, systemic administration of IL-2 is capable of enhancing the frequencies and suppressive function of CD4+CD25+Foxp3+ Tregs, and increases corneal allograft survival.
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