The hypothesis was tested that mucosal stimulation with unmatched mononuclear cells would induce systemic alloimmune responses. Rectal or vaginal mucosal administration of 10(4)-10(7) unmatched mononuclear cells induced significant dose-dependent T-cell proliferation stimulated by the allogeneic cells in rhesus macaques. This was associated with a significant upregulation of CD8(+) T-cell-derived suppressor factor, as well as the CC chemokines CCL3, CCL4 and CCL5. In addition, there was a dose-dependent increase in antibodies to CCR5. These responses were associated with decreased in vitro simian immunodeficiency virus (SIV) infectivity of CD4(+) T cells. A further investigation of SIV infectivity of CD4(+) T cells separated from multiparous macaques also showed significant inhibition compared with male macaques. It is suggested that vaginal or rectal exposure to allogeneic stimulation by a partner's HLA antigens in seminal fluid, as occurs during sexual intercourse, or immunization by semi-allogeneic fetuses in multiparous females may elicit protection against SIV or human immunodeficiency virus infection.