Liposomal tacrolimus administered systemically and within the donor cell suspension improves xenograft survival in hemiparkinsonian rats.
The most widely used immunosuppressant in neural transplantation is cyclosporine- A (CsA). However, CsA has significant toxic effects when administered systemically. Tacrolimus (FK506), is a more potent immunosuppressant than CsA and can be prepared in lipid micelles (LTAC). This liposomal preparation allows for the administration of tacrolimus to the site of transplantation, possibly reducing the systemic side effects of immunosuppression. In this study we investigated the ability of LTAC to promote graft survival in hemiparkinsonian rats implanted with fetal mouse xenografts when LTAC is administered systemically to the host, when added to the donor cell suspension, or in combination. Rats with unilateral 6-hydroxydopamine lesions were transplanted with 800,000 fetal mouse ventral mesencephalic (VM) cells and were randomly divided into four groups. Group 1 was not immunosuppressed; Group 2 received daily systemic injections of LTAC; Group 3 received LTAC within the cell suspensions of mouse VM cells; and Group 4 received LTAC in the cell suspensions along with daily systemic administration of LTAC. Transplanted rats were assessed for rotational behavior 3 and 6 weeks posttransplantation. Cell survival was assessed using tyrosine hydroxylase (TH) immunohistochemistry. A significant reduction in rotational scores was observed only in the group of animals receiving the combination of LTAC-treated donor cells and systemic LTAC administration. This functional improvement correlated with a significantly greater survival of TH-immunoreactive cells in this group of animals. The other groups had poor cell survival and no significant functional improvement. We conclude that a combination of systemic immunosuppression and treatment of the cell suspension with LTAC may be a superior strategy to optimize xenograft survival. This strategy may have important implications for clinical neural transplantation.
Alemdar
A Y
AY
Neural Transplantation Laboratory, Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada.
Baker
K A
KA
Sadi
D
D
McAlister
V C
VC
Mendez
I
I
D000818:Animals; D005260:Female; D016332:Fetal Tissue Transplantation; D006085:Graft Survival / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D008081:Liposomes; D008636:Mesencephalon / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020734:Parkinsonian Disorders / Q000503:physiopathology / Q000601:surgery*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D016559:Tacrolimus / Q000008:administration & dosage* / Q000494:pharmacology; D014019:Tissue Donors; D014183:Transplantation, Heterologous
D007166:Immunosuppressive Agents; D008081:Liposomes; D016559:Tacrolimus