A role for complement in the rejection of porcine ventral mesencephalic xenografts in a rat model of Parkinson's disease.
Vascularized whole organ discordant xenografts placed in the periphery are rejected by a rapid "hyperacute" process that involves preformed antibody binding to the xeno-antigens on the donor endothelial cells with complement activation. In the CNS, xenografts are classically thought to be rejected more slowly by a T-cell-dependent process. We now report that xenografts of embryonic porcine ventral mesencephalic tissue in the 6-hydroxydopamine-lesioned, nonimmunosuppressed rat induce both a humoral and a cell-mediated response. Over the first 10 d after implantation, the xenografts matured with identifiable TH neurons and pig-specific neurofilament fibers extending along host white matter tracts. During this period of time, IgM and complement binding were observed within the graft, as well as a CD8 cellular infiltrate, leading to rejection of the transplant over the next 25 d. These intracerebral xenografts were not associated with an early systemic antibody response. A role for complement in this rejection process was further investigated using cobra venom factor (CVF), which systemically depleted the rats of complement for 7 d. CVF treatment, when given in the period immediately before and after grafting, delayed but did not prevent the cellular immune response induced by the graft, demonstrating that xenografted neural tissue can activate the humoral arm of the rejection process, in particular the complement cascade. This suggests that interventions targeting this aspect of the immune rejection process may be of great importance for the future development of xenotransplantation for neurodegenerative conditions.
Barker
R A
RA
Cambridge Centre for Brain Repair, Forvie Site, Cambridge CB2 2PY, United Kingdom. rab46@cus.cam.ac.uk
Ratcliffe
E
E
McLaughlin
M
M
Richards
A
A
Dunnett
S B
SB
D018663:Adrenergic Agents; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D004546:Elapid Venoms / Q000494:pharmacology; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D007075:Immunoglobulin M / Q000187:drug effects / Q000276:immunology; D008636:Mesencephalon / Q000637:transplantation; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000628:therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*; D014185:Transplantation, Isogeneic / Q000502:physiology
D018663:Adrenergic Agents; D004546:Elapid Venoms; D007075:Immunoglobulin M; D016627:Oxidopamine