The role of IL-10 in the liver tolerance effect

• Introduction and aim: A liver graft is less prone to induce rejection compared to a renal graft and previous findings suggest that an auxiliary liver transplantation a few hours before a renal transplantation improves kidney graft survival in highly sensitized patients. Dendritic cells (DC) are important initiators of rejection. During transplantation DC within the allograft become activated and migrate to secondary lymphoid organs where they activate NK cells and alloreactive T cell. The aim of this study was to investigate the role of DC maturation in the liver mediated acceptance of a renal graft. Methods: Real-time PCR was used to compare changes in graft gene expression of IFN-γ, TNF-α, IL-1β and IL-10 in the liver and kidney in patients undergoing combined auxiliary liver-kidney transplantation (n=8). These are inflammatory mediators known to participate in transplantation-induced DC activation. Presence of interleukin (IL) 10 and 12 was measured in peripheral blood in these patients. Monocyte-derived DCs was matured with a cytokine-cocktail consisting of IFN-γ, TNF-α and IL-1β +/- IL-10. The effect of these cytokines on DC secretion of chemokines MIG, IP-10 and I-TAC was investigated with ELISA. Results: The DC-activation-associated inflammatory mediators TNF-α, IL-1β and IFN-γ were similarly upregulated in both liver and kidney grafts after reperfusion. While no reperfusion-dependent mRNA increase for IL-10 was found in transplated grafts, serial measurement of cytokine levels in peripheral blood revealed that IL-10 levels increased 60-fold in serum shortly (within 1 h) after liver, but before kidney, reperfusion and returned to pre-transplant levels at day 2 post-transplantation (n=3). No significant changes were seen in IL-12 levels. DCs matured with a cocktail consisting of IFN-γ, TNF-α and IL-1β demonstrated a strong production of CXCR3-ligands (MIG 280 ng/ml, IP-10 19 ng/ml, I-TAC 619 pg/ml) which was sustained even after removal of the cytokine-cocktail. These chemokines are indispensable for DC-mediated recruitment of blood NK cells into secondary lymphoid organs and their subsequent boosting of TH1-deviated alloresponses. Addition of IL-10 during DC maturation significantly decreased the production of all three CXCR3-ligands (MIG -33%, IP-10 -25%, I-TAC -67%). Conclusions: These findings indicate that IL-10 is selectively and rapidly released during liver transplantation, probably due to accumulation during the ischehmia period. This release may potentially inhibit a TH1-deviating crosstalk between donor DC and recipient NK cells, suggesting a role for IL-10 in the liver-mediated acceptance of a renal graft in highly sensitized patients.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kirurgi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Surgery (hsv//eng)

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