To obtain basic knowledge for the application of xenogeneic neural transplantation to patients with Parkinson's disease, the rejection process of xenogeneic neural grafts in rats was examined and a therapy to control it was developed. Tissues including the ventral mesencephalon were taken from mouse embryos and transplanted into the right lateral ventricle of mature male rats. Transplanted xenografts were usually rejected by day 15. To prevent the graft rejection, host rats were treated with anti-T-cell receptor alphabeta (anti-TCR alphabeta) or anti-CD2 monoclonal antibody (mAb) or by a combination of the two. Anti-TCR alphabeta (1 mg/kg) and anti-CD2 (7 mg/kg) mAb were administered for 3 consecutive days (day -2, -1, and 0 of transplantation). Although the administration of mAb against either CD2 or TCR alphabeta did not induce tolerance, the combination therapy with anti-CD2 and anti-TCR alphabeta mAb produced graft survival for more than 100 days. The tolerance induced by this combined antibody therapy is antigen specific because rats with long-term surviving neural xenograft accepted a second neural graft from the same donor strain C3H/He mouse, but not from a third-party strain BALB/c mouse, without additional treatment. In addition, T cells isolated from these rats did not respond to cultured C3H/He brain cells, but did respond vigorously to BALB/c brain cells in mixed lymphocyte reaction. More importantly, the finding that xenograft transplantation with the proper treatment reduced the rotation rate of 6-OHDA-lesioned rats confirmed that surviving grafts functioned properly. The results of the present study suggest that xenogeneic neural transplantation in combination with T-cell-targeted immunotherapy is an effective approach for treatment of Parkinson's disease.