Since the mucosal tissues and surfaces are: 1) often the first site of contact with infectious agents, 2) the most common location of life-threatening cancers and 3) in constant contact with environmental antigens, a better understanding of factors that control the induction and regulation of mucosal immune responses may aid the development of vaccines and treatments for infectious agents such as HIV and agents of bioterrorism, cancers and environmental allergies. Research interests in the Staats’ lab currently focus on:
1. IDENTIFYING AND CHARACTERIZING NOVEL MUCOSAL ADJUVANTS AND THEIR MECHANISM OF ACTION
2. OPTIMIZING NASAL IMMUNIZATION FOR USE IN HUMANS IDENTIFYING AND CHARACTERIZING NOVEL MUCOSAL ADJUVANTS AND THEIR MECHANISM OF ACTION
We have been successful at identifying novel mucosal adjuvants. However, their cellular and molecular mechanism of mucosal adjuvanticity remains to be determined. We have determined that the combination of IL-1α, IL-12 and GM-CSF used as a mucosal adjuvant enhanced the expression of the costimulatory molecule B7.1 and the antigen-presenting molecule MHC Class II on antigen-presenting cells within the nasal-associated lymphoid tissue (NALT). Increased expression of B7.1 and MHC Class II correlated with the induction of antigen-specific immunity after nasal immunization. Our previous work suggests that dendritic cells (DC) are the predominant antigen-presenting cell (APC) responsible for the induction of vaccine-induced immune responses after nasal immunization. However, it is not clear if the mucosal adjuvants directly or indirectly activate the NALT DC. We are currently investigating if nasal vaccine adjuvants mediate their adjuvant activity by activating mucosal epithelial cells that then activate APC or if nasal vaccine adjuvants directly activate APC. A better understanding of the cellular and molecular mechanisms associated with the activity of nasally administered adjuvants will guide the development of more effective nasal adjuvants and vaccines. More recent studies in our laboratory have focused on the use of cationic mast cell activators as vaccine adjuvants. OPTIMIZE NASAL IMMUNIZATION IN NON-HUMAN PRIMATES
Nasal immunization in laboratory mice induces serum and mucosal antibody responses comparable to those induced by needle vaccination (i.e., intramuscular, subcutaneous). In rabbits and non-human primates, larger animal models that have a nasal cavity architecture similar to humans, nasal immunization is not as effective as parenteral immunization. Recent studies in our lab have determined that nasal immunization in rabbits or non-human primates often lacks efficacy due to inconsistencies in vaccine delivery to the nasal cavity of the host. For example, in one model using rabbits, a liquid vaccine formulation delivered intranasally inconsistently induced antigen-specific immune responses. Gamma scintigraphy imaging studies determined that the lack of vaccine efficacy was associated with rapid clearance of the vaccine formulation from the rabbit nasal cavity. Similar studies in non-human primates determined that a liquid vaccine formulation delivered intranasally was rapidly swallowed into the stomach. We are currently evaluating modified vaccine formulations and delivery techniques to determine if the immunogenicity of nasal vaccines can be increased if we enhance vaccine retention in the nasal cavity of rabbits or non-human primates.