Generation of Donor-Specific Regulatory T-Cell Function in Kidney Transplant Patients
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Background. In the search for mechanisms that can induce and maintain transplant tolerance, donor-specific CD4(+)CD25(bright) (+)Foxp3(+) regulatory T cells have been frequently mentioned. However, it remains to be demonstrated, whether these cells are generated after clinical transplantation. Methods. We prospectively analyzed the phenotype and function of peripheral regulatory CD4(+)CD25(bright+) T cells of 79 patients before, 3, 6, and 12 months after kidney transplantation. The immune regulatory capacities of CD4(+)CD25(bright+) T cells were assessed by their depletion from peripheral blood mononuclear cells and in co-culture with CD25(neg/dim) responder T-cells in the mixed lymphocyte reactions. Results. In the first year after transplantation, the number and proportion of CD4(+)CD25(bright+) T cells significantly decreased (P<0.05 and P<0.001, respectively). In the mixed lymphocyte reactions, we observed donor-specific hypo-responsiveness in the presence of significantly increased proliferation to third and fourth Party-Ag, (P<0.001 and P<0.05, respectively). Furthermore, functional analysis of CD25(bright+) cells showed that the effect of depletion of these cells from peripheral blood mononuclear cells, and their suppressive capacities in co-culture with donor-Ag stimulated CD25(neg/dim) responder T-cells (1:10 ratio) significantly improved (P<0.01 and P<0.001, respectively). Moreover, the difference between the stimulation with donor-Ag and third Party-Ag became apparent at 6 months after transplantation. Conclusions. These findings demonstrate that donor-specific CD4(+)CD25(bright+) regulatory T-cell function is generated in fully immunosuppressed renal recipients in the first year after transplantation.