Immunological Monitoring of Renal Transplant Recipients to Predict Acute Allograft Rejection Following the Discontinuation of Tacrolimus

Abstract

BackgroundTransplant patients would benefit from reduction of immunosuppression providing that graft rejection is prevented. We have evaluated a number of immunological markers in blood of patients in whom tacrolimus was withdrawn after renal transplantation. The alloreactive precursor frequency of CD4+ and CD8+ T cells, the frequency of T cell subsets and the functional capacity of CD4+CD25+FoxP3+ regulatory T cells (Treg) were analyzed before transplantation and before tacrolimus reduction. In a case-control design, the results were compared between patients with (n = 15) and without (n = 28) acute rejection after tacrolimus withdrawal.Principal FindingsPrior to tacrolimus reduction, the ratio between memory CD8+ T cells and Treg was higher in rejectors compared to non-rejectors. Rejectors also had a higher ratio between memory CD4+ T cells and Treg, and ratios <20 were only observed in non-rejectors. Between the time of transplantation and the start of tacrolimus withdrawal, an increase in naive T cell frequencies and a reciprocal decrease of effector T cell percentages was observed in rejectors. The proportion of Treg within the CD4+ T cells decreased after transplantation, but anti-donor regulatory capacity of Treg remained unaltered in rejectors and non-rejectors.ConclusionsImmunological monitoring revealed an association between acute rejection following the withdrawal of tacrolimus and 1) the ratio of memory T cells and Treg prior to the start of tacrolimus reduction, and 2) changes in the distribution of naive, effector and memory T cells over time. Combination of these two biomarkers allowed highly specific identification of patients in whom immunosuppression could be safely reduced.

Increased CD64 expression on polymorphonuclear neutrophils indicates infectious complications following solid organ transplantation

“…This is consistent to other studies' results (71,72). A combination of immunologic parameters may be useful.…”

CD4+CD25+Foxp3+IFNγ+ Treg are immunosuppressive in vitro and increase with intensity of the alloresponse in pretransplant MLC

“…In some patients, immunosuppressive drugs effectively block the alloresponse and enable the establishment of a functional balance of alloreactive effector cells with IFNγ + iTreg, eventually leading to graft acceptance [12]. In other patients, for reasons unknown, immunosuppressive drugs effectively block iTreg induction which results in disappearance of this subset in the circulation [26][27][28][29]. Whether the balance tips to one side or the other depends on the individual patient's response to the administered immunosuppressive drugs and the cytokine milieu in the microenvironment of cells that are involved in the alloresponse [30][31][32][33].…”

Biomarkers to assess donor-reactive T-cell responses in kidney transplant patients

“…Furthermore, contradictory data has been reported. No differences were found between rejectors and non-rejectors when monitoring precursor frequencies of CD4+ and CD8+ T-cells in a group of 43 kidney transplant patients determined by CFSE-labeling(80).…”