Contrasting effects of myeloid dendritic cells transduced with an adenoviral vector encoding interleukin‐10 on organ allograft and tumour rejection
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SummaryMouse bone marrow‐derived myeloid dendritic cells (DC) propagated in granulocyte–macrophage colony‐stimulating factor and transforming growth factor‐β1 (TGF‐β1) (so‐called ‘TGF‐β DC’) are phenotypically immature, and prolong allograft survival. Interleukin‐10 (IL‐10) has been shown to inhibit the maturation of DC by down‐regulating surface major histocompatibility complex (MHC) class II, co‐stimulatory and adhesion molecule expression. Genetic engineering of TGF‐β DC to overexpress IL‐10 might enhance their tolerogenic potential. In this study, adenoviral (Ad) vectors encoding the mouse IL‐10 gene were transduced into B10 (H2b) TGF‐β DC. Transduction 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 II, CD40, CD80 and CD86. Paradoxically, Ad‐IL‐10 transduction enhanced the allostimulatory activity of DC in mixed leucocyte reactions and cytotoxic T lymphocyte assays, and increased their natural killer cell stimulatory activity. Systemic injection of normal C3H recipients with Ad‐IL‐10‐transduced B10‐DC 7 days before organ transplantation, exacerbated heart graft rejection and augmented circulating anti‐donor alloantibody titres. Contrasting effects were observed in relation to tumour growth. All mice preimmunized with Ad‐IL‐10‐transduced, tumour antigen (B16F10)‐pulsed DC developed palpable tumours, associated with significant inhibition of splenic anti‐tumour cytotoxic T lymphocyte generation. Animals pretreated with control Ad‐LacZ‐transduced, B16F10‐pulsed DC however, remained tumour free. These findings are consistent with the multifunctional immunomodulatory properties of mammalian IL‐10.
