Dendritic cell (DC)-based anti-infective strategies: DCs engineered to secrete IL-12 are a potent vaccine in a murine model of an intracellular infection

Infections with intracellular pathogens such as Leishmania donovani and Myc obacterium tuberculosis pose serious health problems worldwide. Effective v accines for these pathogens are not available. Furthermore, despite optimal therapy, disease progression is often seen with several intracellular infe ctions. For these reasons, we initiated studies to develop novel anti-infec tive vaccine and treatment strategies that couple the potent Ag-presenting capacity of dendritic cells (DC) with paracrine delivery of potent anti-inf ective cytokines such as IL-12 to local immune response sites. We tested th is strategy in a murine model of visceral leishmaniasis, Adoptive transfer of DCs pulsed ex vivo with soluble L. donovani Ags (SLDA) to naive mice ind uced the Ag-specific production of IFN-gamma, and increased the percentage of activation markers on spleen lymphocytes. SLDA-pulsed DCs engineered by retroviral gene transfer techniques to secrete high levels of biologically active murine IL-12 augmented this immune response further. In several diff erent vaccination and immunotherapy protocols, compared with sham-treated m ice, animals receiving SLDA-pulsed DCs either before or following infection had 1-3 log lower parasite burdens, and this protection was associated wit h a pronounced enhancement in the parasite-specific IFN-gamma response, The augmentation of this protection by IL-12-engineered DCs was striking. Firs t, live parasites were not detected in the liver of mice vaccinated with IL -12-transduced, SLDA-pulsed DCs, Second, this parasitological response was associated with a nearly normal liver histology, In contrast, parasites and granulomas were found in mice vaccinated with SLDA-pulsed, nontransduced D Cs. Collectively, these studies provide the rationale for the development o f potent DC-based immunotherapies.