THE COMMON MUCOSAL IMMUNE-SYSTEM FOR THE REPRODUCTIVE-TRACT - BASIC PRINCIPLES APPLIED TOWARD AN AIDS VACCINE

The concept of the Collaborative Mucosal Immunization Research Group f or AIDS (CMIG) was originally conceived by the AIDS Vaccine Branch, Na tional Institute of Allergy and Infectious Diseases (NIAID) in order t o provide support for a cooperative research environment for the devel opment of mucosal immunity to AIDS. We have purposely organized five g roups of investigators at five different locations to determine how ef fective mucosal immunity to AIDS can be optimally approached. CMIG rec ognizes that both rectal (homosexual) as well as vaginal (heterosexual ) infections with HIV are two of the major ways that AIDS currently di sseminates through the human population. Thus, we have chosen the SIV model of infection of rhesus macaques, but more importantly the CMIG h ave joined two of our five components in order to use the significant expertise developed for mucosal transmission of SIV and immunity. Thus , we have brought the extensive expertise with vaginal and rectal immu nization and immunity to spread [Drs. Chris Miller and Marta Marthas, California Regional Primate Research Center (CRPRC), Davis and Drs. Th omas Lehner and Martin Cranage, United Medical and Dental School Guy's Hospital, London and the Centre for Applied Microbiology and Research (Guy's/CAMR)]. Two additional components were added in order to perfo rm mucosal immune response studies required to develop and to optimize a mucosal vaccine. First, extensive CD4(+) T helper (Th) cell (e.g., Th1 and Th2) and CD8(+) T cell subset studies are a major effort of th e coordinating group at the University of Alabama at Birmingham (Drs. Hiroshi Kiyono and Jerry R. McGhee). This component is closely interac ting with both the CRPRC and Guy's/CAMR components in terms of SIV-spe cific CD4(+) and CD8(+) T cell subset responses. For example, SIV-spec ific CTL responses are jointly examined using different techniques by CRPRC, Guy's/CAMR and UAB investigators. Further, it is also important to examine a balance between SIV-specific and Th1 and Th2 cell respon ses following mucosal immunization since the Th cell-derived cytokines are essential for the induction of appropriate antigen-specific mucos al immune responses. This issue is currently being extensively examine d by the CMIG effort and a summary of our findings is discussed in thi s review. A major question in mucosal immunity involves the functions of secretory IgA (S-IgA) antibodies and this area is of particular imp ortance in rectal and reproductive tract immunity. A novel and excitin g in vitro epithelial cell assay system is used to study how effective ly S-IgA neutralizes SIV infection (Drs. John Huang, John Nedrud and M ichael Lamm, Case Western Reserve, Cleveland). A clear advantage of th is CMIG effort is the unique expertise in design of mucosal delivery s ystems for an AIDS vaccine. We are using state-of-the-art recombinant bacteria, i.e., rSalmonella and rVibrios for mucosal immunization [Drs . Yichen Lu and Bryan Roberts, Virus Research Institute (VRI), Boston] . In addition, we are also testing other mucosal delivery systems incl uding DNA vaccine, microspheres, cholera toxin (CT) and CT-B, recombin ant poliovirus, and immune complexes. These studies represent the firs t efforts to induce not only Th cell mediated S-IgA responses, but als o CTL responses to SIV in primates immunized with different mucosal ve ctor delivery systems. In order to focus our effort for the induction of SIV-specific immune responses following mucosal immunization, inves tigators from the CMIG are attempting to understand the induction and regulation of antigen-specific immune responses in rhesus macaques muc osally immunized with different preparations of SIV vaccines.