Mucosal immunity in the respiratory and female genital tracts. Implications for vaccine development

Abstract

Aims: With the overall objective to guide future vaccination efforts against sexually transmitted and respiratory infections the aims of this thesis were to study the mucosal immune system in the female genital tract and to investigate how to stimulate a local antibody response in the upper respiratory and female reproductive tracts.Methods: Cholera toxin B subunit (CTB) was used as a model immunogen in the immunization studies. Mice were immunized nasally, orally, vaginally or systemically with CTB or CTB conjugates. The antibody response was measured in serum and tissue extracts by ELISA and the presence of antibody secreting cells was determined by ELISPOT. Human volunteers were vaccinated nasally or orally with CTB and the antibody responses in serum and nasal and vaginal secretions were measured by ELISA. Cryostat sections from human cervical and vaginal tissue were analysed for the presence of leukocytes and adhesion molecules by immunohistochemistry. Results and comments: Antibody responses in the female genital tract of mice against CTB and a conjugated antigen were best stimulated by vaginal or nasal immunization. In humans both nasal and oral vaccination induced significant antibody responses in vaginal secretions. In contrast, only nasal and not oral vaccination induced specific IgA in nasal secretions. The kinetics of the antibody response differed after oral and nasal vaccination and the maximal antibody levels in nasal secretions appeared as late as 6 weeks after nasal vaccination. The efficiency of CTB to induce a genital antibody response against conjugated antigens makes it a promising candidate for future conjugate vaccines against genital infections. Since nasal vaccination stimulated a specific antibody response in both nasal and vaginal secretions it might be an efficient and convenient vaccination route for protection against genital as well as respiratory infections. In human ectocervix and vagina the presence and organization of leukocytes and the expression of endothelial adhesion molecules were similar. All cells necessary for induction of an immune response were present. The expression of known specific adhesion molecules, with a notable lack of expression of MAdCAM-1, indicates a different recruitment of lymphocytes in the genital tract from that seen in the intestine.