Effects of immunosuppressive treatment on host responses against intracerebral porcine neural tissue xenografts in rats.
BACKGROUND
Embryonic xenogeneic neural tissue is an alternative for transplantation in Parkinson's disease, but immune responses limit the application. The aims of this study were to enhance the in vitro viability rates by donor tissue pretreatment; to compare the efficacy of cyclosporine A (CsA) and tacrolimus (FK) in inhibiting xenograft rejection in rats; to evaluate additional inductive therapy with prednisolone (PRE) or mycophenolate mofetil (MMF).


METHODS
Tirilazad (a lipid peroxidase inhibitor) or FK and acYVAD-cmk (a caspase inhibitor), were added to embryonic porcine ventral mesencephalic tissue and viability was assessed in vitro. Tirilazad-treated tissue was grafted to the striatum of rats that were either left untreated or immunosuppressed with FK (1 mg/kg) or CsA (15 mg/kg) alone or in combination with a 2-week PRE (20 mg/kg) or MMF (40 mg/kg) induction course. Xenograft survival and host responses were determined using immunohistochemistry.


RESULTS
Pretreatment with tirilazad enhanced tissue survival in vitro. After transplantation into untreated controls, there was no graft survival at twelve weeks. Neural cell counts were significantly improved in immunosuppressed recipients, but there were no differences between the treatment groups. Additional inductive treatment reduced the infiltration with CD4+ and CD8+ cells, and macrophage infiltration was reduced compared with animals given CsA or FK alone.


CONCLUSIONS
Pretreatment of the donor tissue with free-radical scavengers reduces cell loss caused by tissue trauma. Porcine neural tissue xenografts survive significantly better in animals immunosuppressed with either FK or CsA. Additional inductive treatment with PRE or MMF reduced the infiltration of host cells into the xenografts.
Wennberg
L
L
Department of Transplantation Surgery, Karolinska Institute, B56, Huddinge University Hospital, 141 86 Stockholm, Sweden. lars.wennberg@transpl.hs.sll.se
Czech
K A
KA
Larsson
L C
LC
Mirza
B
B
Bennet
W
W
Song
Z
Z
Widner
H
H
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D001835:Body Weight; D001921:Brain / Q000473:pathology / Q000601:surgery*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D002452:Cell Count; D004359:Drug Therapy, Combination; D016332:Fetal Tissue Transplantation / Q000276:immunology*; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009417:Nerve Tissue / Q000196:embryology / Q000473:pathology / Q000637:transplantation*; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D011281:Pregnatrienes / Q000494:pharmacology; D011309:Preservation, Biological; D051381:Rats; D011917:Rats, Inbred Lew; D016019:Survival Analysis; D013552:Swine / Q000196:embryology; D014183:Transplantation, Heterologous / Q000276:immunology*
D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D011281:Pregnatrienes; C053355:tirilazad