This Program Project will study entry paths used by STD pathogens, develop and test human monoclonal antibodies as microbicides for blocking pathogen entry, and characterize how antibodies are deployed and function in preventing infectious entry of pathogens in the female reproductive tract. Project 1. Mucosal entry paths used by STD pathogens will investigate entry paths that topical microbicides must blocks: (a) Cell vectors, such as HIV-infected leukocytes, may penetrate genital epithelial and carry HIV directly to target cells in the lymph nodes. (b) Microtrauma that occurs during consensual intercourse, increasing the risk that pathogens will contact target cells. (c) Upper tract exposure. Uterine peristalis causes uptake of vaginal fluids that may expose the upper reproductive tract to STD pathogens. Project 2. Blocking STD pathogen entry with mucosal antibodies will develop monoclonal human antibodies as highly potent and specific microbicides. Pharmacokinetics of a """"""""plantibody"""""""" against HSV-2 (a human monoclonal produced in corn for large scale, inexpensive production) will be determined in mouse and rabbit vaginas. New human monoclonals will be developed against HPV, and against leukocyte cell vectors for HIV. Protective efficacy will be tested in vitro and in SCID mouse models. Using mouse monoclonals to identify adhesins and host receptors, human monoclonals against chlamydia and gonorrhea will be generated and tested in mice. Monoclonals will also be tested for their ability to markedly reduce a commensal bacterium in the mouse vagina. Project 3. Uptake of Ig by vaginal epithelial cells will investigate how cervico-vaginal epithelial cells (in tissue culture and in vivo_ deploy Ig in the vaginal epithelium, and the effects of physiological modulators (hormones, cytokines) on Ig uptake, storage and release. Human monoclonals identified in Project 2 will be applied to explants of human genital tissues and immortalized epithelial cell lines, to determine whether monoclonals that have been taken up by epithelial cells are effective for blocking HIV, HSV-2, and chlamydia infections, and for blocking adhesions and transepithelial migration of leukocytes.
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