Immunotherapy For Invasive Pulmonary Aspergillosis With Dendritic Cells Transduced With An Adenovirus Vector Encoding Interleukin-12

Invasive pulmonary aspergillosis is a common and devastating complication of immunosuppression. Over the past 2 decades, its incidence has increased dramatically along with an increase in the number of imrnunocompromised hosts. Dendritic cells (DCs), the most potent antigen-presenting cells (APC), play major roles in host defense against aspergillus fumigatus (Af) as they behave as both sentinel for innate immune recognition and initiator for protective immunity. Respiratory tract DC can internalize and then transport conidia and hyphae of Af from the airways to the draining lymph nodes and spleens. DCs ingest fungi, then secrete IL-12 and initiate fungus-specific immune response. As a key link between the innate and cell-mediated Ag-specific immune responses, IL-12 can induce IFN- Y production from NK cells and T lymphocytes, and enhance proliferation of Ag-specific T cells. The focus of our study is to assess a new paradigm in the development of a vaccine to protect against aspergillus infection, using DCs engineered to secrete IL-12 as the immunizing biologic agent. Our study showed that: 1. DCs, with typical morphology and activity, can be gotten through culturing the bone marrow cells of mice in vitro. These DCs engulf aspergillus conidia through coiling phagocytosis and then mature. 2. Transfection of DCs with adenovirus encoding the whole cDNA of IL-12 did not affect their morphology and capacity to engulf conidia. The transduced DC produced IL-12 in vitro, with a mean concentration of 1110 pg/ml from 106 cells in 24 h. The secreted IL-12 was biologically active to induce the production of IFN- Y from spleen cells. 3. Adoptive transfer of DCs pulsed ex vivo with heat-inactivated Af (HAF)to naive mice induced the Ag-specific production of IFN-Y, the transduced Af-pulsed DCs augmented this immune response further. Animals receiving HAF-pulsed DCs had lower fungal burdens, a more than threefold higher survival rate at day 3. This protection was associated with a pronounced enhancement in the aspergillus-specific IFN- Y response. IL-12-engineered DCs could augment this protection strikingly as judged by a higher survival and that almost no aspergillus could be detected in the lung of mice that had received IL-12-transduced HAF-pulsed DCs. Our findings offer encouragement and additional rationale for the development of a DC-based vaccine against aspergillus and perhaps other infectious diseases.