Immunosuppression

The rejection reaction after organ transplantation is mediated by T lymphocytes and NK cells, among others. After recognition of an allogeneic target cell through the binding of various receptors to specific ligands, a signaling cascade is triggered in these effector cells, which leads to the activation of these effector cells via a phosphorylation chain and the influx of calcium (Ca++). This leads to a series of effector functions, including cytotoxicity, i.e. the release of cytotoxic molecules through degranulation, as well as the expression of cytokines and chemokines. Some immunosuppressive drugs now target this Ca-mediated signal transduction, whereby the mechanisms of calcineurin inhibitors, CNI, such as cyclosporin A (CsA) and tacrolimus (FK506) are best studied for T cells, followed by mTOR inhibitors such as rapamycin or everolimus. The suppressive effect is achieved by these drugs binding to the calcineurin/FKBP12 complex and blocking the dephosphorylation of the NFAT transcription factor NFAT and thus its translocation into the nucleus, thereby stopping NFAT-dependent gene expression of target genes such as pro-inflammatory cytokines like IL-2 and IFN-g.

The systemic influence of immunosuppressive drugs on the composition of lymphocytes in the peripheral blood is being investigated in various cohorts, including kidney transplant patients. It was clearly shown that the number of CD8+CD3+ T cells was significantly reduced in patients receiving CsA-mediated immunosuppression compared to healthy volunteers and patients with Tac/sirolimus-mediated (T/S) immunosuppression (Fig. 2). In addition, B cells and NK cells also showed reduced representation in peripheral blood in immunosuppressed kidney recipients. Our current work on the differences in the mode of action of CNI versus mTOR inhibitors specifically on NK cells has also shown that CNI, but not mTOR inhibitors, almost completely suppress NK cell activation, both at the receptor level and at the level of NFAT-induced gene expression.

An important long-term goal of our research activities in the field of immunosuppression is to determine the individual immune status of patients after organ or stem cell transplantation or tumour patients as precisely as possible and thus to be able to optimize therapeutic intervention - in the sense of "precision medicine", which uses the fundamental immunological principles for the optimization of patient treatment.