Characterization of Rabbit Antithymocyte Globulins-Induced CD25+ Regulatory T Cells From Cells of Patients With End-Stage Renal Disease

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Background.Rabbit antithymocyte globulins (rATGs) are known to convert CD4+CD25FoxP3 T cells from healthy individuals to CD4+CD25+FoxP3+ T cells. In this study, we investigated the effect of rATG on the induction of regulatory T cells (Tregs) from blood cells of patients with end-stage renal disease who are candidates for transplantation and rATG-induction therapy. The induced Tregs were analyzed and compared with naturally occurring CD4+CD25+FoxP3+T cells.Methods.The CD25 T cells of pretransplant patients (n=7) and healthy controls (n=4) were stimulated with rATG or control rabbit immunoglobulins for 24 hr. The phenotype of induced Tregs was examined by flow cytometry, and their function was studied in the conventional suppression assay. Further characterization was performed by mRNA analyses.Results.After 24 hr, the percentage of CD4+CD25+FoxP3+CD127−/low T cells and CD8+CD25+FoxP3CD127+ T cells became higher in the rATG-treated samples compared with the rabbit immunoglobulin-treated samples (P<0.01). The rATG-induced CD25+T cells, whether CD4+ or CD8+ inhibited the allogeneic responses of CD25−/dim effector T cells as vigorously as natural CD25+T cells. However, the proportion of FoxP3+ within the top 2% rATG-induced CD4+CD25+T-cells was lower than within the natural CD4+CD25+T-cells (11%±2% vs. 95%±5%, P<0.01). The mRNA-expression levels of interleukin-27, interleukin-10, interferon-γ, perforin, and granzyme B were markedly higher compared with natural CD25+T-cells (all P=0.03), whereas CTLA4 (P=0.03), transforming growth factor-β (P=0.02), and RORγt (P=0.04) were lower.Conclusion.rATG allows the induction of Tregs from patient peripheral blood mononuclear cell in vitro. In comparison with natural Tregs, the rATG-induced Tregs are phenotypically distinct but have similar regulatory activities. rATG may beneficially contribute to the mechanisms that control alloreactivity.

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