GENERATION OF TOLEROGENIC DENDRITIC CELLS BY TREATMENT WITH MITOMYCIN C: INHIBITION OF ALLOGENEIC T-CELL RESPONSE IS MEDIATED BY DOWNREGULATION OF ICAM-1, CD80, AND CD86

Abstract

BACKGROUND: Deliberately generated tolerogenic dendritic cells (DC) might be a useful tool for induction of donor-specific tolerance in transplantation. In this article, the authors study the effect of mitomycin C (MMC)-treated DC on rat T cells and delineate the mechanism of their conversion into tolerogenic cells. METHODS: The influence of MMC treatment on the capacity of DC to activate allogeneic T cells was tested in vitro, and the expression of cell surface molecules was studied by flow cytometry. RESULTS: MMC-treated DC lose their allostimulatory capacity, and this cannot be attributed to cell death or release of MMC. Interestingly, suppressed T cells cannot be restimulated, indicating that MMC-treated DC induce tolerance. MMC treatment selectively decreases adhesion (intercellular adhesion molecule [ICAM]-1) and co-stimulatory (CD80, CD86) molecules. Functional blocking of these molecules with specific antibodies confers to DC the same T-cell-suppressive properties as treatment with MMC. CONCLUSIONS: MMC treatment converts rat DC into tolerogenic cells. This mechanism is mediated by decrease of ICAM-1, CD80, and CD86.