Antigen specific, CD8+, cytolytic T lymphocytes (CTLs) are important mediators of resistance in several human infections and most likely in malignancies. Therefore, immunotherapies that stimulate this arm of the immune response could be essential for effective host immunity. However, the cellular requirements for eliciting specific and potent CTLs from human lymphocytes are not well defined, even in tissue culture where repetitive stimulation with antigen and exogenous cytokines are necessary. We have identified dendritic cells as an effective vehicle for generating human antigen specific CD8+ CTLs in the influenza virus system. Our goals are to dissect the antigen presenting function of dendritic cells to comprehend how potent CTLs are generated and to define new strategies for inducing CTL responses. Four observations make the pursuit of a dendritic cell strategy promising. (1) Strong CD8+ proliferative and cytolytic responses are generated from T cells of primed donors by influenza virus infected dendritic cells within 7 days of culture; (2) neither CD4+ helper T cells nor exogenous cytokines are required; (3) nonreplicating or inactivated forms of influenza virus are effective; (4) antigen pulsed dendritic cells induce CD8+ CTL responses in vivo in animal models. Advantage will be taken of new developments wherein large numbers of potent mature dendritic cells can be generated from few precursors in blood. Optimal approaches and mechanisms for charging dendritic cell class I molecules with antigens will be determined. Inactivated forms of influenza virus and MHC restricted peptides will each be evaluated. The contribution of key cytokines (IL-12, IL-15) will also be determined. The results will be extended to the HIV-1 and melanoma systems where CTLs are considered to play a crucial protective role, and both primary and recall responses can be studied. Finally, mouse models will be established where the efficacy of antigen charged dendritic cells to induce CTL responses in situ can be directly evaluated. The data should lead to the development of new strategies for vaccination and therapy of infection and malignancies in man.
Showing the most recent 10 out of 20 publications
