CD4+ CD25bright+ FoxP3+ T cells are potent regulators of T-cell reactivity, but their possible involvement in donor-specific nonresponsiveness after clinical kidney transplantation remains to be elucidated. We assessed the proliferative donor-reactivity in 33 kidney allograft recipients who were maintained on a combination of proliferation inhibitors (mycophenolate mofetil (MMF) or Azathioprine (Aza)) and prednisone, long (>5 years) after transplantation. Of the 33 patients, 8 still exhibited donor-reactivity, whereas 25 were classified as donor nonreactive patients. Within these 25 donor nonreactive patients, we assessed the involvement of CD4+ CD25bright+ regulatory T cells both by depleting them from the responder population as well as by reconstituting them to the CD25-/dim effector population. The absence of proliferation in these 25 patients, was abolished in 7 (28%) recipients upon depletion of the CD4 + CD25bright+ T cells. Reconstitution of these cells suppressed the donor-reactivity in a dose-dependent manner. Adding-back CD4 + CD25bright+ T cells inhibited the anti-third party response in all recipients, indicating that functional CD4+ CD25 bright+ T cells circulate despite more then 5 years of immunosuppressive treatment. Altogether, we conclude that in long-term immunosuppressed kidney allograft patients functional regulatory CD4+ CD25bright+ T cells circulate but that these cells mediate donor non reactivity only in a subset of patients.

Immunosuppression, Kidney transplantation, Regulatory T cells, Tolerance,
American Journal of Transplantation
Department of Internal Medicine

Veldhuis, J.H.L, Mol, W.M, Weimar, W, & Baan, C.C. (2006). CD4+ CD25bright+ regulatory T cells can mediate donor nonreactivity in long-term immunosuppressed kidney allograft patients. American Journal of Transplantation, 6(12), 2955–2964. doi:10.1111/j.1600-6143.2006.01566.x