Down-regulated donor-specific T-cell reactivity during successful tapering of immunosuppression after kidney transplantation

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Abstract
Stable cadaveric renal transplant patients were routinely converted from cyclosporin A (CsA) to either azathioprine (AZA) or mycophenolate mofetil (MMF) 1 year after transplantation to reduce the side effects of long‐term immunosuppressive therapy. Thereafter, the AZA and MMF dose was gradually tapered to 50% at 2 years after transplantation. We questioned whether a reduction of immunosuppressive treatment results in a rise of donor‐specific T‐cell reactivity. Before transplantation (no immunosuppression), 1 year (high dose immunosuppression) and 2 years (low dose immunosuppression) after transplantation, the T‐cell reactivity of peripheral blood mononuclear cells (PBMC) against donor and third‐party spleen cells was tested in mixed lymphocyte cultures (MLC) and against tetanus toxoid (TET) to test the general immune response. We also measured the frequency of donor and third‐party reactive helper (HTLpf) and cytotoxic (CTLpf) T‐lymphocyte precursors in a limiting dilution assay. Donor‐specific responses, calculated by relative responses (RR = donor/third‐party reactivity), were determined. Comparing responses after transplantation during high dose immunosuppression with responses before transplantation (no immmunosuppression), the donor‐specific MLC‐RR (P = 0·04), HTLp‐RR (P = 0·04) and CTLp‐RR (P = 0·09) decreased, while the TET‐reactivity did not change. Comparing the responses during low dose with high dose immunosuppression, no donor‐ specific differences were found in the MLC‐RR, HTLp‐RR and CTLp‐RR, although TET‐reactivity increased considerably (P = 0·0005). We observed a reduction in donor‐specific T‐cell reactivity in stable patients after renal transplantation during in vivo high dose immunosuppression. Tapering of the immunosuppressive load had no rebound effect on the donor‐specific reactivity, while it allowed recovery of the response to nominal antigens.

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