T-Regulatory Cells—What Relationship With Immunosuppressive Agents?

The immune system maintains self-tolerance through the interplay of several mechanisms. One of the key mechanisms is the suppression of effector cells through regulatory T cells (Tregs). Recent progress has allowed the identification, analysis, and experimental manipulation of various subpopulations of Tregs. Several major issues regarding Tregs have emerged in relation to organ transplantation, including the questions of whether immunosuppressive drugs influence Tregs and whether Tregs can be used therapeutically to achieve graft acceptance or even tolerance.Although none of the available immunosuppressive drugs have been specifically designed to influence Tregs, they nevertheless do so through various pathways. Notably, current evidence suggests that rapamycin has a favorable effect on Tregs in organ transplant recipients, whereas calcineurin inhibitors (CNI) have markedly negative effects on Tregs.The idea of inducing tolerance through the therapeutic administration of Tregs has received much attention in recent years. To obtain sufficient numbers of recipient-derived Tregs, various strategies are being investigated to expand sorted Treg populations. Rapamycin has been found to significantly promote the in vitro expansion of murine and human Tregs; it may thereby help to generate clinically relevant quantities of Tregs. However, no data have yet been published that would demonstrate that the therapeutic use of Tregs induces transplantation tolerance across full major histocompatibility complex barriers in immunocompetent mice displaying a polyclonal T-cell repertoire.