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).


CONCLUSIONS
IL-10+DC and IL-12+DC in peripheral blood are associated with 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.
Daniel
Volker
V
Institute of Immunology, Department of Transplantation Immunology, University of Heidelberg, S-69120 Heidelberg, Germany. Volker.Daniel@med.uni-heidelberg.de
Naujokat
Cord
C
Sadeghi
Mahmoud
M
Wiesel
Manfred
M
Hergesell
Olaf
O
Opelz
Gerhard
G
D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood*; D003713:Dendritic Cells / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016753:Interleukin-10 / Q000097:blood*; D018664:Interleukin-12 / Q000097:blood*; D016030:Kidney Transplantation / Q000276:immunology*; D008775:Methylprednisolone / Q000627:therapeutic use; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011184:Postoperative Period; D012016:Reference Values; D013997:Time Factors
D016207:Cytokines; D007166:Immunosuppressive Agents; D016753:Interleukin-10; D018664:Interleukin-12; D016572:Cyclosporine; D003404:Creatinine; D009173:Mycophenolic Acid; D008775:Methylprednisolone