Exhaustive depletion of graft resident dendritic cells: marginally delayed rejection but strong alteration of graft infiltration.

Abstract

BACKGROUND: Donor dendritic cells (DDC) are believed to sustain direct recognition leading to acute allograft rejection. However, DDC are also required for tolerance induction in various models. METHODS: We studied the effect of DDC depletion on major histocompatibility complex (MHC) mismatched rat heart allografts in a strain combination characterized by a DDC-dependant tolerance induction. Grafts were depleted of DDC either by pretreating donors with cyclophosphamide (CyP) or by being parked in an intermediate recipient treated with cyclosporine A (CsA). RESULTS: CyP depleted 95% of resident DC and no specific donor MHC class II staining was observed in parked grafts. Parked grafts survived significantly but only moderately longer than untreated grafts (10.8+/-1.9 days vs. 6.5+/-0.5 days; P<0.05). Compared to unmodified grafts, on day 5 after transplantation, the magnitude of the graft infiltrate was dramatically decreased in DDC-depleted grafts, with IgG deposition within the grafts at the time of rejection. In parallel, the cytokine transcript levels were also lower in these grafts on day 5, but reached levels similar to those of unmodified grafts by day 7, indicating a delayed pattern of rejection. CONCLUSIONS: Taken collectively, these data suggest that DDC depletion has a greater effect on the capacity of tolerance induction than the rejection process.