This proposal is focused on developing a new contraceptive method for men. The project begins with our previous finding that immunization of male rodents with sperm surface proteins leads to either of two effects: anti-sperm antibody becomes bound to sperm in the epididymis or sperm are completely eliminated from the epididymis, leading to infertility. In this project we propose to use rodent studies to define the mechanisms of these two phenomena and to develop optimal protocols for obtaining each effect. These immunization protocols will then be tested in monkeys to determine if they affect primate sperm and induce infertility. Simultaneously, a new approach to male contraception will be tested that is designed to cause the disruption (by immunological or pharmacological means) of cell-cell interactions in the testis, thus blocking sperm development.
Our first aim i s to systematically optimize immunization conditions in mice by altering four variables: choice of antigen, adjuvant, dose and route of administration. The mice will first be evaluated for antibody bound to epididymal sperm or loss of sperm in the epididymis. The immunized male mice will also be scored for presence of orchitis or epididymitis which may be relatively minimal or absent with specific choices among the four variables. The optimal protocol(s) that leads to antibody-bound sperm in the epididymis or ejaculate will be tested for the ability of the sperm to function in vitro fertilization and in vivo fertility of immunized mice. An efficacious protocol will then be tested in male monkeys. The optimal protocol that leads to loss of epididymal sperm in mice will be used to study the mechanism of this loss and tested to determine if epididymal sperm will be eliminated in male monkeys. If contraceptive efficacy is obtained, but inflammation is present, we will test peptide immunogen specifically designed to produce antibodies without an inflammatory response. We will also study early germ cell to identify cell adhesion molecules present outside the blood-testis barrier and therefore subject to inhibition by antibodies or pharmacological agents, that will not have to cross the barrier.
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