Nourishirazi, Erika

Background: Vaccines aid in saving lives from infections and biological warfare attacks. They should be effective in all target populations otherwise the likelihood that an unprotected person will transmit disease to a vulnerable individual is greatly increased. There is compelling evidence that smokers are less responsive to vaccination. We have reported that both therapeutic and prophylactic vaccines fail to protect and cure animals from disease due to negative effects of nicotine in biological activities of DCs. Using in vitro mouse culture system we have identified an appropriate TLR agonist capable of correcting the defects in DCs exposed to nicotine. Hypothesis: In order to translate these studies to human, we tested the hypothesis that appropriate TLR agonists will also correct the degrading effects of nicotine on human DCs and consequently DC-NK cross talk and T cell polarization. Methods: Monocyte-derived DCs were generated in culture media containing growth factors GM-CSF and IL-4 with or without nicotine treatment. DCs were activated with indicated TLR agonists and their phenotypes and cytokine profiles were analyzed by flow cytometry and ELISA, respectively. Results: Among the TLR agonists tested, we found that nicotine has less effect on human DC maturation in response to TLR4 plus TLR7/8 agonists as evidenced by expression levels of their costimulatory CD80/83/86/40 and antigen-presenting HLA-DR molecules as well as inflammatory cytokines IL-12, IL-10,TNF-α and IL-1β production. Conclusion: We are currently investigating whether these TLR agonists also augment human DC-NK bidirectional signals essential for T cell differentiation in a nicotinic environment.