Details

Autor(en) / Beteiligte

• Friel, Lara Anne

Titel

Effect of host immune response and calcium channel blockers on the survival of ventral mesencephalic cultures and intrastriatal grafts

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

1999

Link zum Volltext

• ProQuest

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Low cell survival confounds efforts to utilize fetal tissue transplantation as a replacement therapy in Parkinson's disease. Neuron death in ventral mesencephalic (VM) grafts was assumed to be necrotic until recent efforts revealed that these cells also undergo apoptosis. Cytotoxic T-lymphocytes, primary effectors in allograft rejection, can kill by inducing their targets to undergo apoptosis. This suggests that apoptosis observed in VM grafts may result from a number of signals; e.g. action of immune cells, loss of matrix attachment, and growth factor withdrawal. To determine the contribution of immune response to apoptotic death of VM, apoptosis was studied in rat allogeneic and syngeneic VM cultures and grafts. A dose-dependent increase in apoptosis and decrease in dopaminergic neuron survival was found in VM cultures incubated with allogeneic, but not syngeneic, lymphocytes. Apoptosis was not found in allogeneic or syngeneic VM grafts 7-weeks post-transplantation. In the African green monkey, one VM graft of 12 in two hosts showed evidence of graft rejection 5 1/2 weeks post-transplantation, including infiltration and perivascular cuffing of lymphocytes, stellate cells resembling microglia, and apoptosis. Calcium channel blockers (CCB) have been found to be of therapeutic benefit in solid organ transplantation paradigms mainly by increasing blood flow through grafted tissues and by decreasing calcium-mediated ischemic damage. CCB also have neurotrophic and/or neuroprotective effects on CNS neurons. Therefore, the effect of nimodipine, an L-type CCB, on VM cultures and grafts was studied. Incubation of E14 VM cultures in the equivalent of therapeutic serum concentrations of nimodipine significantly increased dopaminergic neuron survival compared to cultures treated with media alone. In vivo, nimodipine was administered to rats post-transplantation (20 mg/kg i.p. every other day for 4 weeks) or the donor cell suspension was pre-treated with nimodipine (100 μg/L). Host treatment resulted in decreased dopaminergic neuron survival, while suspension treatment had no effect compared to controls. Alterations in the administration of nimodipine (different concentrations i.p., subcutaneous pellets, etc.) could result in increased survival. A greater understanding of how immune response and calcium modulation effect graft survival may lead to increased potential for transplantation as a therapy for Parkinson's disease.