[Regulatory T cells in kidney transplant recipients]. / Cellule T-regolatorie nel trapianto di rene.

Immunosuppressive drugs are essential for the prevention of acute transplant rejection but some may not promote long-term tolerance. Tolerance to self-antigens is ensured naturally by several mechanisms; one major mechanism depends on the activity of regulatory T lymphocytes (Treg), particularly CD4+CD25+ T cells. The transcription factor forkhead box protein 3 (Foxp3) has been identified as a molecular marker for Treg cells. The direct effects of immunosuppressive drugs on CD4+CD25+ cells are uncertain. In the clinical setting, basiliximab used in the induction phase of immunosuppression effectively reduced the number of acute rejection episodes. We studied the effects of the most widely used immunosuppressive induction regimens including cyclosporine, mycophenolate mofetil, steroids, and anti-CD25 monoclonal antibody (basiliximab) on the capacity to regulate human Treg in vivo. Twenty first cadaveric kidney transplant recipients (14 men, 6 women) were enrolled in the study. Blood samples were collected before kidney transplant and after one month. Blood sampling was done immediately before the administration of immunosuppressive therapy after an overnight fast. None of the transplant recipients presented laboratory or clinical signs of infection or acute rejection. The number and percentage of CD4+CD25+ and Foxp3+ T cells were determined by fluorescence activated cell sorter (FACS) analysis. Our results showed absence of both CD4+CD25+ and CD4+CD25+ Foxp3+ T cells one month after transplant. Peripheral CD4+CD25-Foxp3+ T cells significantly decreased after transplant but did not disappear. These preliminary data suggest that immunosuppressive induction therapy with basiliximab completely suppresses CD4+CD25+ regulatory cells and significantly reduces the total number of Foxp3+ lymphocytes.

The effect of sirolimus- or cyclosporine-based immunosuppression effects on T-cell subsets in vivo.

While sirolimus (SRL) is thought to be a non-nephrotoxic agent, cyclosporine A (CsA) toxicity is a serious problem in kidney transplantation. We compared the effects of the two drugs on T-helper (Th) subsets in kidney transplant patients. We examined 24 first cadaver kidney recipients equally randomized to receive SRL/mycophenolate mofetil (MMF)/methylprednisolone (MP), or cyclosporine with either MMF or MP. The Th1 and Th2 subsets in peripheral blood were separated based on their production of interferon-gamma (INFgamma) or interleukin (IL)-4/IL-5. The lymphocytes were stimulated with phytohemoagglutinin or with allogenic CD3-depeted and irradiated antigen-presenting cells. Furthermore, the conversion potential of Th0 to Th1 was determined by measuring IL-12 and IL-18 levels after lipopolysaccharide challenge. When peripheral blood lymphocytes taken from SRL-treated patients were stimulated by phytohemoagglutinin, there were significantly lower INFgamma-producing cells compared with the lymphocytes taken from patients treated with CsA. The number of IL-4/IL-5-producing cells did not differ among the patient groups. Release of IL-12 but not IL-18 from peripheral lymphocytes following treatment with lipopolysaccharide was significantly lower in the SRL-treated patients. These results show that compared with CsA, SRL caused a significant decrease in the Th1 lymphocyte subset associated with a significant reduction of IL-12 release.

Influence of methylprednisolone on plasma homocysteine levels in cadaveric renal transplant recipients.

The aim of the present study was to investigate plasma homocysteine levels in renal transplant recipients in the course of steroid-based or steroid-free immunosuppression. Data from 32 patients were retrospectively analyzed according to the steroid immunosuppressive regimen. The 20 recipients on methylprednisolone (MP) plus cyclosporine (CyA) or tacrolimus (TRL) (n = 20) showed similar creatinine levels when compared with those on calcineurin inhibitors plus mycophenolate mofetil (MMF; n = 12), (1.6 +/- 1.5 vs 1.6 +/- 0.4 mg/dL; P = NS) but significantly higher total plasma homocysteine (tHcy) levels (28.5 +/- 12.5 vs 16.3 +/- 5.5 micromol/L; P < .05). No differences of tHcy levels have been observed when patients were analyzed according to CyA- or TRL-based immunosuppression regardless of MP or MMF associations. Our data suggest that recipients, particularly those on steroid-based immunosuppression, should receive homocysteine-lowering treatment early after transplantation.