Xenotransplantation for brain repair: reduction of porcine donor tissue immunogenicity by treatment with anti-Gal antibodies and complement.
BACKGROUND
Transplantation of embryonic neural tissue is a potential treatment for Parkinson's disease. Because human donor material is in short supply, porcine xenografts are considered a useful alternative. Current immunosuppressive therapies fail, however, to protect intracerebral neural xenografts from host CD4 T lymphocytes. To reduce the immunogenicity of porcine donor tissue, we attempted to remove microglial cells with antibodies against the alpha-galactosyl epitope (Galalpha1,3Galbeta1,4GlcNAc-R), or anti-Gal, and complement, and studied whether this pretreatment can reduce direct and indirect T-cell responses to the tissue.


METHODS
Brain tissue from 27-day-old pig embryos was dissociated and treated with human anti-Gal and rabbit complement. The microglial content was analyzed by flow cytometry. [3H]thymidine incorporation in cocultures of the brain cells and purified human CD4 T cells was used to determine direct T-cell responses. Indirect T-cell responses were studied by grafting pretreated and control-pretreated (no anti-Gal) nigral tissue into the lesioned striatum of immunocompetent rats with 6-hydroxydopamine-induced hemiparkinsonism. Amphetamine-induced circling behavior was used to measure graft function.


RESULTS
Anti-Gal and complement reduced the microglial content to 11-24% of control and abolished the ability of the brain cells to induce human CD4 T-cell proliferation. Pretreated nigral tissue reduced hemiparkinsonism by more than 50% in five of eight rats at some point during the 10-week follow-up. Rats receiving control-pretreated nigral tissue did not display this degree of improvement.


CONCLUSIONS
Pretreatment with anti-Gal and complement can reduce the immunogenicity of porcine neural tissue, and might, therefore, be a valuable alternative or supplement to immunosuppression in neural xenotransplantation.
Brevig
T
T
Department of Anatomy and Neurobiology, University of Southern Denmark. t.brevig@dadlnet.dk
Meyer
M
M
Kristensen
T
T
Zimmer
J
J
Holgersson
J
J
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D016380:Brain Tissue Transplantation / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002240:Carbohydrate Sequence; D018920:Coculture Techniques; D003165:Complement System Proteins / Q000494:pharmacology*; D004622:Embryo, Mammalian; D000939:Epitopes / Q000276:immunology; D016332:Fetal Tissue Transplantation / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008636:Mesencephalon / Q000196:embryology / Q000276:immunology / Q000637:transplantation; D017628:Microglia / Q000276:immunology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000601:surgery; D020734:Parkinsonian Disorders / Q000601:surgery*; D011817:Rabbits; D051381:Rats; D011917:Rats, Inbred Lew; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology; D014312:Trisaccharides / Q000276:immunology*
D000906:Antibodies; D000939:Epitopes; D014312:Trisaccharides; C076569:alpha-galactosyl epitope; D003165:Complement System Proteins