Association of high anti-donor alloreactivity and low frequency of FoxP3-expressing cells prior to kidney transplantation with acute graft rejection.

Acute rejection (AR) is an important factor for the development of chronic allograft dysfunction following kidney Tx. Identification of patients who would benefit from closer clinical surveillance to allow individual tailoring of immunosuppression and hence reducing the rate of AR is highly desired. Aim of this study was to investigate the association of pre-transplant alloreactivity and frequency of regulatory T cells (T(regs) ) with AR following living-donor kidney Tx. Peripheral blood mononuclear cells were isolated from 40 patients prior to Tx. T-cell alloreactivity against donor and third-party antigen was assessed by proliferative responses in mixed lymphocyte culture and enzyme linked immunospot technique. Pre-transplant frequency of CD4(+) CD25(+) CD127(low) FoxP3(+) T(regs) was determined by flow cytometry. Experimental data were correlated with occurrence of AR. We found that patients with rejection-free (RF) post-Tx courses showed significantly lower pre-transplant alloreactivity to donor antigen compared to individuals with borderline findings (BL) or AR. For RF patients, the proliferative T-cell responses to third-party antigen were significantly higher than for stimulation with donor cells whereas lymphocytes of the AR group showed the inverse pattern. A significantly higher expression of FoxP3 within the CD4(+) CD25(+) CD127(low) subset for RF and BL compared to the AR group was observed. In conclusion, pre-transplant anti-donor alloreactivity and FoxP3 expression within the CD4(+) CD25(+) CD127(low) subpopulation might prove useful to further define the patient's risk for AR.

Impact of Basiliximab on regulatory T-cells early after kidney transplantation: down-regulation of CD25 by receptor modulation.

Monoclonal anti-CD25-antibodies are successfully applied in organ transplantation to reduce the incidence of acute graft rejection. However, targeting the CD25 molecule might not only affect activated T-cells but also regulatory T-cells (T(regs)) constitutively expressing the CD4(+)CD25(+)CD127(low)FoxP3(+) phenotype. In this study, we investigated the influence of the anti-CD25-antibody Basiliximab on the frequency of T(regs) early after kidney transplantation comparing individuals receiving/not receiving induction therapy (n = 14 and n = 7). Following Basiliximab administration, a distinct loss of CD4(+)CD25(high) T-cells was observed lasting for at least 6 weeks. This was not accompanied by a disappearance of the entire CD4(+)CD25(+)FoxP3(+) T(regs) but rather a decreased expression density of CD25 on the latter. In addition, a transient rise in CD4(+)CD25(-)FoxP3(+) T-cells was found which expressed the CD127(low) phenotype. Thus, a phenotypic shift of T(regs) from the CD25(+) to the CD25(-) compartment was suggested. This was supported by in vitro findings showing that the disappearance of CD4(+)CD25(high) cells in the presence of Basiliximab was due to down-regulation of CD25 expression meanwhile the suppressive function of these cells was maintained. In conclusion, Basiliximab therapy directly affects CD4(+)CD25(+)CD127(low)FoxP3(+) T(regs) but does not seem to be associated with functional consequences. Thus, it is unlikely that Basiliximab treatment negatively influences strategies involving T(regs) to promote tolerance after organ transplantation.