EXPERIMENTAL AUTOIMMUNE ORCHITIS INDUCED BY TESTIS AND SPERM ANTIGEN-SPECIFIC T-CELL CLONES - AN IMPORTANT PATHOGENIC CYTOKINE IS TUMOR-NECROSIS-FACTOR

Testicular autoimmune disease (autoimmune orchitis) develops in mice i mmunized with testis antigen in adjuvant, occurs spontaneously in dogs , mink, and horses, and is a potential cause of human infertility. Thi s is the first study to investigate autoimmune orchitis using monoclon al T cells. Despite the use of crude tissue antigens, 100% of the T ce ll lines/clones transferred autoimmune disease of the male gonad to no rmal syngeneic mice, with pathology that affected the testis, the epid idymis and/or the vas deferens. Thus orchitogenic peptides are likely of restricted number and/or of dominant immunogenicity. Upon transfer to normal mice, the mildest and earliest pathology elicited by the clo ned T cells invariably occurred in a specific region, the testicular s traight tubules. Although testis antigen-derived T cell clones respond ed preferentially to testis antigen, and sperm antigen-derived clones responded more to sperm antigens, each of the 16 clones respond to bot h antigens. Thus common orchitogenic antigens exist in these germ cell populations though their quantity may differ in distribution. All orc hitogenic T cell lines and clones expressed CD4 and the alphabeta T ce ll receptor; and when activated, they produced interleukin 2, interfer on gamma, and tumor necrosis factor (TNF), but not interleukin 4. This cytokine profile characterizes the Thl CD4+ T cell subset, known to b e responsible for the delayed type immunological reaction. Importantly , since disease transfer was significantly and reproducibly attenuated when recipients were injected with neutralizing antibody to TNF, but not neutralizing antibody to interferon gamma TNF has been defined as a cytokine important in the pathogenesis of this autoimmune disease.