Treatment of rat hemiparkinson model with xenogeneic neural transplantation: Tolerance induction by anti-T-cell antibodies

Abstract

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.

Survival and functional recovery of transplanted human dopaminergic neurons into hemiparkinsonian rats depend on the cannula size of the implantation instrument

“…The present study employed cyclosporin A in all three groups and did not investigate graft versus host reactions on graft survival. Future studies, aiming to elucidate the contribution of different immunological pathways, would need to include animal groups with differential immunosuppression, such as cyclosporin A which primarily acts on microglial cells or T cell antibodies which preferably influences lymphocytic responses (Okura et al, 1997). It is likely that a considerable percentage of the transplanted human cells may not have survived because of immunological rejection in the present experimental setting using xenografts despite identical immunosuppression in all experimental groups (Barker and Widner, 2004;Brandis et al, 1998;Brundin et al, 1989;Nikkhah et al, 1994a,b;Widner, 1999).…”

Neural stem/progenitor cells as a promising candidate for regenerative therapy of the central nervous system

“…However, this immunosuppressor at doses required to inhibit the rejection process has strong sides effects (Rezzani, 2006) and is only transiently efficient. Graft rejection has also been delayed when the T cell receptor (TCR) and the IL-2 receptor a chain (CD25) were inactivated, and in the case of CD4-positive T cell depletion (Honey et al, 1990; Okura et al, 1997). The administration of two successive high doses of anti-CD4 monoclonal antibodies resulted in a longer survival of discordant xenografts (between species differing from the expression of the gal epitope, like pig and human), although not prolonged, suggesting that other immune components than T cells are implicated (Wood et al, 1996).…”

Immune problems in central nervous system cell therapy

“…Antibodies against T-cell receptor anti-TCR␣␤ and T cells have been used to enhance the survival of intracerebral neural xenografts in rats. 38,39 Larsson and colleagues 40,41 have also explored the use of blockers to T-cell costimulatory molecules as an alternative route to tolerance, therefore highlighting the value of targeting this arm of the immune response for xenograft survival.…”