Prognostic importance of antigen-presenting dendritic cells during vaccine therapy in a murine hepatitis B virus carrier

As, the outcome of vaccine therapy was extremely heterogeneous in both human and murine hepatitis B virus (HBV)-carriers, the experiments presented here were performed to find out a prognostic marker of vaccine therapy using an animal model of HBV-carrier state, HBV-transgenic mice (Tg). Neither the prevaccinated titres of viral markers, such as hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) or HBV DNA, nor the function of lymphocytes prior to vaccination, had significant influence on the outcome of vaccine therapy. Two independent, placebo-controlled, trials of vaccine therapy for 12 months, one in 17 HBV-Tg and the other in 26 HBV-Tg (total, n = 43) showed that the eight of 17 and 15 of 26 HBV-Tg that had potent dendritic cell (DC) function at the start of vaccine therapy became completely negative for HBsAg, HBeAg and reduced HBV DNA, whereas all 19 HBV-Tg that had poor DC function at the start of vaccine therapy became complete non-responders, although, the prevaccinated titres of HBsAg, and HBeAg were similar in all 43 HBV-Tg. Further study to find the mechanism underlying this revealed that there was up-regulation of major histocompatibility complex (MHC) class II, CD86 antigens on DC and increased production of interleukin-12 (IL-12) by DC and of IL-2, and tumour necrosis factor-α (TNF-α) in DC/T-cell cultures when vaccine containing HBsAg was injected in HBV-Tg with potent DC function but not in HBV-Tg with poor DC function. This is the first report on the prognostic importance of DC during an immune therapy. Degree of activation of DC following vaccination would possibly help to predict the outcome of vaccine therapy in human HBV-carriers. These data also provide the scientific and logical basis to up-regulate the function of the DC before an immune therapy

Effects of Herpes Simplex Virus Amplicon Transduction on Murine Dendritic Cells

The herpes simplex virus (HSV)-based amplicon is a versatile vaccine platform that has been preclinically vetted as a gene-based immunotherapeutic for cancer, HIV, and neurodegenerative disorders. Although it is well known that injection of dendritic cells (DCs) transduced ex vivo with helper virus-free HSV amplicon vectors expressing disease-relevant antigens induces antigen-specific immune responses, the cellular receptor(s) by which the amplicon virion gains entry into DCs, as well as the effects that viral vector transduction impinges on the physiological status of these cells, is less understood. Herein, we examine the effects of amplicon transduction on mouse bone marrow-derived DCs. We demonstrate that HSV-1 cellular receptors HveC and HveA are expressed on the cell surface of murine DCs, and that HSV amplicons transduce DCs at high efficiency (>90%) with minimal effects on cell viability. Transduction of dendritic cells with amplicons induces a transient DC maturation phenotype as represented by self-limited upregulation of MHCII and CD11c markers. Mature DCs are less sensitive to HSV amplicon transduction than immature DCs regarding DC-related surface marker maintenance. From this and our previous work, we conclude that HSV amplicons transduce DCs efficiently, but impart differential and transient physiological effects on mature and immature DC pools, which will facilitate fine-tuning of this vaccination platform and further exploit its potential in immunotherapy