The focus of our laboratory is understanding the molecular mechanisms controlling the induction and regulation of mucosal immune responses. The mucosal immune system is anatomically and functionally separate from the immune system responsible for protection against systemic antigenic challenge. Mucosal immune responses may play a significant role in host resistance to infectious agents of disease that initiate infection at mucosal surfaces (HIV, HSV, RSV, influenza, etc.). The mucosal immune system is also involved in the regulation of immunity to environmentally encountered antigens. With human mucosal surfaces measuring in excess of 400 m2, it becomes apparent that protection of the host against pathogenic microorganisms and regulation of immunity at these sites is crucial to the homeostasis of the host.
A current interest in the laboratory is understanding the role cytokines play in the induction of mucosal immune responses. Dependent upon the presence or absence of adjuvant, mucosal immunization may result in drastically different effector responses. For example, mucosal immunization with soluble protein antigens in the absence of mucosal adjuvants may induce antigen-specific tolerance, whereas mucosal immunization in the presence of a mucosal adjuvant may induce antigen-specific secretory IgA (S-IgA) and cytotoxic T lymphocyte responses (CTL). A mucosal adjuvant commonly used is cholera toxin (CT). Although CT has been used as a mucosal adjuvant for years, its mechanism of adjuvanticity is not clear. Literature reports suggest that CT-induced cytokine secretion (IL 1, IL 6, IL 8) may be partially responsible for CT's adjuvant action. We are currently evaluating the effect CT has on cytokine production by mucosal epithelial cells and inductive sites (i.e., Peyer's patch) of the mucosal immune system. We are also evaluating the induction of antigen-specific S-IgA and CTL in mice lacking the STAT 4 or STAT 6 molecule. STAT 4 -/- mice have impaired Th-1 responses while STAT 6 -/- have impaired Th-2 responses. The use of STAT 4 -/- and STAT 6 -/- mice will allow us to determine the role Th1 and Th2 responses play in the regulation of mucosal immune responses.
Another area of interest in this laboratory is the M cell of the Peyer's patch. The M cell is a specialized epithelial cell that overlays the Peyer's patch in the small intestine. The M cell is responsible for transporting antigen from the gut lumen to the Peyer's patch where mucosal immune responses may be induced. Studies are being performed to characterize the M cell based on the cell surface molecule expression. Functional studies are planned if the cell can be cultured in vitro.
Porgador A, Staats, HF, Failoa B, Gilboa E, Palker TJ. Intranasal immunization with CTL epitope peptides from HIV-1 or ovalbumin and the mucosal adjuvant cholera toxin induces peptide-specific CTLs and protection against tumor development in vivo. J Immunol 1997;158:834-41.
Staats, HF. Intranasal immunization with carrier-free synthetic peptides. Mucosal Immunol Update 1997;5:16-20.
Palker TJ, Muir AJ, Spragion DE, Staats HF, Langlois A, Montefiori DC. The V3 domain of SIVMAC251 gp120 contains a linear neutralizing epitope. Virology 1996;224:415-26.
Staats HF, Nichols WG, Palker TJ. Mucosal immunity to HIV-1: systemic and vaginal antibody responses after intranasal immunization with the C4/V3 peptide T1SP10MN(A). J Immunol 1996;157:462-72.
Takahashi I, Kiyono H, Jackson RJ, Fujihashi K, Staats HF, Hamada S, Clements JD, Bost KL, McGhee JR. Epitope maps of Eschericia coli labile toxin B subunit for development of a synthetic oral vaccine. Infect Immun 1996;64:1290-8.
VanCott JL, Staats HF, Carter P, Roberts M, Chatfield S, Kiyono H, McGhee JR. Regulation of mucosal and systemic antibody responses by T helper subsets, macrophages, and derived cytokines following oral immunization with recombinant Salmonella typhimurium. J Immunol 1996;156:1504-14.
Horowitz NS, Staats HF, Palker TJ. Effect of bismuth salts on systemic and mucosal immune responses to orally administered cholera toxin. Immunopharmacology 1995;31:31-41.
Marinaro M, Staats HF, Kiyono H, Jackson RJ, Coste M, Hiroi T, McGhee JR. The adjuvant effect of cholera toxin in mice results from induction of T helper 2 (Th2) cells and cytokines which support IgE responses. J Immunol 1995;155:4621-9.
Xu-Amano J, Jackson RJ, Fujihashi K, Kiyono H, Staats H, McGhee JR. Helper Th1- and Th2-cell responses following mucosal or systemic immunization with cholera toxin. Vaccine 1994;12:903-11.
Xu-Amano J, Jackson RJ, Staats HF, Fujihashi K, Kiyono H, Burrows PD, Elson CO, Pillai S, McGhee JR. Helper T-cell subsets for IgA responses. Oral immunization with tetanus toxoid and cholera toxin as adjuvant selectively induces Th2 cells in mucosa-associated tissues. J Exp Med 1993;178:1309-20.