All Roads Lead to T Regulatory Cells (2010)

The article by Iwase et al. (1) from the current issue highlights the importance of T regulatory cells (Tregs) in the clinical transplantology. Thorough study with almost 300 recipients performed in Nagoya University School of Medicine was a quest for molecular signature of tolerance after renal transplantation. The authors went through a series of genes reported to be associated with tolerance and found that the expression of FoxP3, the best known marker of Tregs, correlates the most, far more than other genes, with the long-term clinical outcome in kidney allograft recipients. Immunosuppressive potential of CD4+CD25+ Tregs have attracted a lot of interest for the past 15 years. Simple Pubmed search for “Foxp3 and transplantation” gives impressive almost 1000 records, with many of them performed in a human setting. The study from this issue (1) comes to light together with two important clinical articles focused exclusively on the tolerance after kidney transplantation. The efforts of European (2) and North American (3) networks of transplant researchers published only recently led in a great proportion to conclusions similar to those presented by the Nagoya's group: there is a tight connection between good clinical outcome of the transplantation and high level of FoxP3-positive Tregs. Both European and American networks found the highest level of FoxP3 in unique but extremely valuable groups of transplant patients. The most interesting were tolerant allograft kidney recipients who ceased maintenance immunosuppression and yet did not develop rejection. The second intriguing group with high level of FoxP3 consisted of recipients whose long-term immunosuppression was reduced to less than 10 mg/d of prednisone equivalent only. Although different in design, all studies cited in this commentary give similar perspective that may add to the current diagnostics in transplantation. It seems that simple test from peripheral blood assessing Tregs signature, such as the expression of FoxP3, might be used to screen the recipients and predict with high probability worsening function of the transplanted kidney long before clinical signs of rejection are found. As that the activities preventing the rejection could be performed before the damage to the allograft occurred. The link between FoxP3 and chronic changes is of special importance because chronic rejection is still a problem in kidney transplantation. Even more tempting would be a perspective of safe individualized weaning of maintenance immunosuppression adjusted to the activity of donor-specific Tregs in particular recipients. Indeed, “Treg MLR” functional test for the assessment of the level of donor-specific Tregs in kidney recipients have been proposed for this purpose in the Transplantation journal last year (4). The last but not the least would be a perspective of active immunomodulation by mimicking the function of Tregs or simply increasing the level of these cells in kidney recipients. The simplest way to achieve this goal is the use of drugs known to increase the level of Tregs such as rapamycin or depletion antibodies in the induction phase around the transplantation. Nevertheless, few more efficient approaches that translate directly basic studies on Tregs into the clinic have been introduced recently. BENEFIT study proved that maintenance immunosuppression with belatacept, fusion protein CTLA-4-Ig mimicking the activity of the major suppressive receptor of Tregs, is at least as good as suppression with calcineurin inhibitors (5). Another translational approach, success of which was because of Tregs, was the creation of tolerant lymphohematopoietic chimeras in which kidney allotransplant was preceded by infusion of hematopoietic stem cells from the prospective donor. Operationally tolerant chimera recipients, whose maintenance immunosuppression was withdrawn, were characterized by intragraft levels of FoxP3 several times higher than those in other groups of kidney recipients (6). Finally, current technology paved the way for large-scale production of human Tregs, which can be transferred to the recipients to withdraw immunosuppression afterward (7). Many, if not all, attempts to translate research on Tregs into practice will finally find a place in the clinic. Articles published recently, including this from the current issue (1), clearly indicate that kidney transplantation is in a forefront of these efforts.