Genetic engineering of dendritic cells to fight viruses

Dendritic cells (DCs) were discovered in 1973 by Steinman and Cohn as rare cells in the mouse spleen with dendrite-like protrusions that had the ability to initiate innate and adaptive immune responses.  The cells are now known as the “professional antigen presenting cells” of the immune system.  In small numbers, DCs alert CD4 and CD8 T cells to the presence of viral or bacterial pathogens by presenting peptide antigens on class I and II MHC proteins to the T cell receptor on antigen-specific T cells.  They activate responding T cells through the TCR and by engaging the coreceptors CD80 and CD86.  These properties of DCs provide an opportunity to use them therapeutically in “DC vaccines” as a means to induce T cell immune responses against a specific pathogen or against tumor antigens.  In this approach, a patient’s DCs are incubated with antigen in vitro and then reinfused, such that they can activate antigen-specific T cells.  This approach has been used to stimulate anti-tumor T cytolytic T cells that target tumor cells for destruction.  We are generating second generation DC vaccines that act against HIV or cancer.  We are testing anti-HIV DC vaccines in humanized mice models.  HIV can replicate in these mice and deplete their human T cells and the mice develop an antiviral human T cell response. 

We are also developing the approach for cancer using mouse models for melanoma and pancreatic cancer.  We engineer the DCs in culture using lentiviral vectors that express HIV or tumor antigen.  The vectors coexpress immunostimulatory genes such as CD40L, a potent activator of DCs.  We are working to understand how DCs function in the immune response against viruses and cancer and to understand how we can best engineer them to stimulate therapeutic immune responses.  This involves understanding where they home to upon injection and the cytokines that they express.