Association of circulating interleukin (IL)-12-and IL-10-producing dendritic cells with time posttransplant, dose of immunosuppression, and plasma cytokines in renal-transplant recipients

Background. Interleukin (IL)-12-producing dendritic cells (IL-12(+)DC) polarize T helper (Th) differentiation toward Th1, whereas IL-10(+)DC induce Th differentiation toward Th2. We investigated DC and plasma cytokine patterns early and late after transplantation. Methods. Twenty-five hospitalized renal- transplant recipients without acute rejection or infection early (< 40 days) posttransplant, 32 symptom-free outpatients with long-term functioning transplants (2,762 +/- 2,423 days posttransplant), and 17 healthy controls were studied. The intracellular production of IL-12 and IL-10 in CD11c(+) CD83(+) CD40(+) DC was measured in freshly obtained whole blood using four-color fluorescence flow cytometry. In addition, plasma cytokine levels were investigated. Results. Early and late posttransplant patients had significantly lower proportions of IL-12(+)DC (early: P=0.001; late: P=0.034) and lower ratios of IL-12(+)/IL-10(+)DC (early: P=0.0001; late: P < 0.0001) than healthy controls. IL-10(+)DC (P=0.0004) and IL-12(+)DC (P=0.002) increased with time posttransplant in association with dose reductions of cyclosporine (IL-10(+)DC: P=0.003; IL-12(+)DC: P=0.005), methylprednisolone (IL-10(+)DC: P < 0.0001; IL-12(+)DC: P=0.001) and mycophenolate mofetil (IL-10(+)DC: P < 0.0001; IL-12(+)DC: P=0.004). Both IL-10(+)DC and IL-12(+)DC were associated with low plasma IL-10 (IL-10(+)DC: P=0.010; IL-12(+)DC: P=0.011) and high plasma IL-6 (IL-10(+)DC: P=0.001; IL-12(+)DC: P=0.009). IL-10(+)DC were also associated with high plasma levels of IL-3 (P=0.003), interferon (IFN)-gamma (P=0.014), and IL-2 (P=0.058). Conclusion. IL-10(+)DC and IL-12(+)DC in peripheral blood are associatedwith time after transplantation and dosage of immunosuppression. IL-10(+)DC dominate late posttransplant in the presence of Th1 plasma cytokines (high IFN-gamma and IL-2), high IL-3, and low IL-10. These findings could be a reflection of immunoregulatory processes favoring long-term allograft acceptance.