Genetic engineering of dendritic cells to fight viruses
Dendritic cells (DCs) were discovered in 1973 by Steinman and Cohn as rare cells with dendrite-like protrusions that had the ability to initiate innate and adaptive immune responses. The cells, now known as the “professional antigen presenting cells” of the immune system, present peptide antigens on class I and II MHC proteins to CD4 and CD8 T cells, alerting them to the presence of viral and bacterial pathogens. DCs activate T cells through the T cell receptor and by engaging CD80 and CD86. Because of their potent ability to prime T cells, DCs have been used therapeutically in “DC vaccines” to induce T cell immune responses against pathogens and tumors. A patient’s DCs are cultured in vitro with antigen and then reinfused. The DCs home to lymphoid organs where they activate antigen-specific T cells. The approach has been used to stimulate anti-tumor cytolytic T lymphocytes.
We are developing second generation DC vaccines both against HIV and cancer. We test the HIV DC vaccines in the bone marrow/liver/thymus humanized mouse model. These mice have a functional human immune system that responds to HIV-1 infection and supports replication of the virus. We engineer DCs in culture using lentiviral vectors that express HIV or tumor antigen, allowing for antigen presentation that is much longer-lived and more potent than conventional methods. The cancer vaccines we are developing are tested using mouse melanoma and pancreatic cancer models.