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180 Dying to Produce a Lively HIV Vaccine: HIV DNA Vaccines Improving Antigen Delivery to Dendritic Cells through Apoptosis in Vivo Results in Improved Cellular Immunity
M. A. Chattergoon, J. J. Kim, J.-S. Yang, J. I. Sin, S. Kudchodkar, and D. B. Weiner*
Univ. of Pennsylvania Sch. of Med. and Viral Genomix, Philadelphia, USA
Background: Improving the potency of DNA vaccines is an important focus for this technology. Recent attention to the role of costimulatory molecules, cytokines and other signaling molecules as part of a plasmid vaccine has illustrated the important role of second signals for in vivo T-cell activation and support in vivo targeting of dendritic cells (DC) to stimulate cellular immunity. We recently reported that one can use the death pathway to deliver antigen to DCs, which acquire antigen from apoptotic cells.
Results: We have now extended these studies to several different members of the death receptor family and compared their effects on immune induction. We observed that Fas, TNFalpha, and NGF, which are all members of the death receptor family, drive increased inflammation in muscle following plasmid vaccination with vaccines that contain HIV antigens. Interestingly, DCs surround the injection site resulting in improved antigen uptake in vivo. We observed that the increases in T cells at the site of injection were accompanied by rapid migration of dendritic cells away from the site of injection. In vivo the death of antigen-bearing cells resulted in up to 10-fold increased acquisition of antigen by DC in the draining lymph nodes, presumably by cells that had migrated from the injection site. The increases in antigen in APCs correlated with significant enhancement of antigen-specific CTL responses and the elaboration of T helper-1 (Th1) type cytokines and chemokines.
Conclusions: Induction of cellular immune responses through apoptosis has important implications for in vivo vaccine development and represents a simple approach to target the DC compartment in vivo resulting in more effective HIV immunogens.
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