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Research Summary

My research interests focus on the regulation of immunity and inflammation in mucosal surfaces. The mucosal tissues can be divided into sites where interactions with exogenous antigens and pathogens initiate immune responses (inductives sites) and sites where immune effector cells migrate to exert their functions (effector sites). Mucosal homeostasis generally prevents the development of unwanted immune responses to exogenous antigens. Pathogens and appropriate vaccines can break the homeostasis in mucosal tissues and induce immune responses which will affect both the systemic compartment and multiple mucosal sites. Alteration of mucosal homeostasis could also lead to a variety of pathologic conditions including asthma, food allergies and inflammatory bowel diseases. We study the interactions between mucosal immune cells to better understand molecular events that control the initiation and the Th1 or Th2 nature of immune responses in mucosal sites. We also investigate means to utilize mucosal surfaces for provision of immunity against infectious diseases and strategies to control mucosal pathologies such as allergic reactions. For this purpose, we study adjuvants that could be used in mucosal vaccines to induce both mucosal and systemic immunity. Regulation of mucosal immunity by cytokines/chemokines and other innate factors represent the other major area of our research.

  • Regulation of Mucosal Immunity by Cytokines / Innate Molecule. Our past studies have demonstrated an important role for IL-4- and Th2-type cytokines in the mucosal adjuvant activity of cholera toxin (Journal of Immunology 162: 114-121, 1995; American Journal of Physiology 273: R1509-R1518, 1997). We have also shown that IL-12 can be delivered by mucosal routes to regulate the immune responses induced by cholera toxin as adjuvant (Journal of Experimental Medicine 185: 415-427, 1997). We have now mucosally administered a number of cytokines (i.e., IL-6 and IL-12) and innate molecules (i.e., defensins, chemokines and lactoferrin) and investigated their effects on adaptive immunity to co-administered protein antigens (Journal of Immunology 162:114-121, 1999; Journal of Immunology 162:122-128, 1999; Journal of Immunology 162: 1959-1965, 1999; Proceedings of the National Acadamy of Sciences USA 96: 651-656, 1999; Journal of Immunology 166: 162-169, 2001; Blood 101: 807-814, 2003; Journal of Leukocyte Biology 76: 1240-1247, 2004; and Journal of Nutrition 134: 403-409, 2004).
  • Mucosal Immunity to Category A Bioterrorism Agents. As most agents of infectious diseases, the potential Category A agents of bioterrorim listed by the CDC and the NIAID [i.e., Bacillus anthracis (Anthrax), Clostridium botulinum toxin (Botulinum), Yersinia pestis (Plague), Variola major (Smallpox) and Francisella tularensis (Tularemia)] can be easily disseminated via the GI tract, by eating or drinking contaminated food or water, or via the respiratory tract by inhalation. We have shown that anthrax protective antigen-based can be effectively delivered by mucosal (i.e., nasal route) for induction of protective immunity in both the blood and external secretions including saliva (Journal of Immunology 170: 5636-43, 2003). Our more recent studies have shown that nasal co-administration of protective antigen and the adenylate cyclase edema factor enhanced immunity to protective antigen. In addition, the edema toxin (i.e., protective antigen and edema factor) acted as an adjuvant for co-administered protein antigens. We also found that anthrax toxin receptor targeting by nasal edema toxin does not lead to its accumulation in olfactory and CNS tissues (Journal of Immunology 176:1776-1783, 2006). Based upon these findings we are now considering the development of edema toxin-based vaccines for protection against multiple bioterrorism agents.
  • Mucosal Allergic Responses. While peanut allergic patients can develop cross-reactive allergic reactions to other legumes, the molecular basis of these cross-reactive immunologic reactions are still unknown. We developed an experimental model of peanut allergy where sensitization is achieved by oral or nasal immunization with peanut protein extract and cholera toxin as adjuvant and the effector phase initiated by nasal challenge with peanut protein only, related legume proteins or unrelated proteins. This model has now help determine that sensitization via the oral route more effectively primes for allergic inflammation, while nasal sensitization bias the host toward non-allergic inflammation and a higher potential for non-specific/cross-reactive responses to nasal exposure to unrelated antigens (American Journal of Pathology 167(6): 1621-30, 2005). These models and those used for our vaccination studies above will be used to continue addressing innate mechanisms that control immune responses in mucosal sites.