Intrastriatal ventral mesencephalic xenografts of porcine tissue in rats: Immune responses and functional effects

Transplantation of neural tissue from other species has the potential to im prove function in patients with neurodegenerative disorders. We investigate d the functional effects of embryonic porcine dopaminergic neurons transpla nted in a rat model of Parkinson's disease and the immune responses to the grafts in immunosuppressed and nonimmunosuppressed hosts. Twenty-three rats with unilateral 6-hydroxydopamine lesions received dissociated, 27-day-old embryonic porcine ventral mesencephalic tissue in the right striatum. Eigh teen rats received cyclosporine (10 mg/kg, IF, daily) during the whole peri od of 14 weeks, in combination with prednisolone (20 mg/kg, IF, daily) the first 4 days. Five rats served as nonimmunosuppressed controls. All rats we re tested For amphetamine-induced rotational behavior at 3-week intervals. Two immunosuppressed rats were excluded due to severe side effects of the t reatment. Functional recovery was seen in 9 of 16 immunosuppressed rats at 12 weeks. Six animals remained functionally recovered at 14 weeks and conta ined an average of 5750 +/- 1450 (SEM) dopaminergic neurons. Between 9 and 14 weeks, three immunosuppressed rats rejected their grafts, based on rotat ion scores and immunohistochemical demonstration of cell infiltrates. One a dditional immunosuppressed rat showed evidence of ongoing rejection at 14 w eeks. The striata in animals with ongoing or recent rejection contained lar ge numbers of CD4- and CD8-positive lymphocytes, NK cells, macrophages, and microglia cells, whereas scar tissue was found in rats with grafts rejecte d at earlier time points (ra = 11). Embryonic porcine ventral mesencephalic tissue matures in the adult rat striatum, reinnervates the host brain, and restores behavioral defects. Immunosuppressive treatment was necessary for long-term graft survival and functional recovery, but did not sufficiently protect from rejection mechanisms. Porcine neural tissue is an interesting alternative to embryonic human tissue for intracerebral transplantation in neurodegenerative diseases. However, to achieve stable graft survival in d iscordant xenogeneic combinations, an appropriate immunosuppressive treatme nt or donor tissue modifications are needed.