Contrasting effects of myeloid dendritic cells transduced with an adenoviral vector encoding interleukin-10 on organ allograft and tumour rejection

Mouse bone marrow-derived myeloid dendritic cells (DC) propagated in granul ocyte-macrophage colony-stimulating factor and transforming growth factor-b eta(1) (TGF-beta(1)) (so-called 'TGF-beta DC') are phenotypically immature, and prolong allograft survival. Interleukin-10 (IL-10) has been shown to i nhibit the maturation of DC by down-regulating surface major histocompatibi lity complex (MHC) class II, co-stimulatory and adhesion molecule expressio n. Genetic engineering of TGF-beta DC to overexpress IL-10 might enhance th eir tolerogenic potential. In this study, adenoviral (Ad) vectors encoding the mouse IL-10 gene were transduced into B10 (H2(b)) TGF-beta DC. Transduc tion with Ad-IL-10 at a multiplicity of infection (MOI) of 50-100 resulted in a modest reduction in the incidence of DC expressing surface MHC class I I, CD40, CD80 and CD86. Paradoxically, Ad-IL-10 transduction enhanced the a llostimulatory activity of DC in mixed leucocyte reactions and cytotoxic T lymphocyte assays, and increased their natural killer cell stimulatory acti vity. Systemic injection of normal C3H recipients with Ad-IL-10-transduced B10-DC 7 days before organ transplantation, exacerbated heart graft rejecti on and augmented circulating anti-donor alloantibody titres. Contrasting ef fects were observed in relation to tumour growth. All mice preimmunized wit h Ad-IL-10-transduced, tumour antigen (B16F10)-pulsed DC developed palpable tumours, associated with significant inhibition of splenic anti-tumour cyt otoxic T lymphocyte generation. Animals pretreated with control Ad-LacZ-tra nsduced, B16F10-pulsed DC however, remained tumour free. These findings are consistent with the multifunctional immunomodulatory properties of mammali an IL-10.