Complement insufficiency limits efficacy in a xenograft model of hyperacute rejection for cancer therapy.
Hyperacute rejection (HAR) is a rapid immunological response to an organ xenotransplant caused by recognition of endothelial galactose(alpha1,3)galactose (alphaGal) epitopes and complement-mediated cell lysis by host anti-alphaGal antibody ('natural antibody'). The alphaGal epitope is synthesised by a galactosyl transferase ((alpha1,3)GT) which humans lack. Because human cells transduced with (alpha1,3)GT are sensitised to natural antibody/complement-mediated lysis in human serum, delivery of (alpha1,3)GT to tumour vasculature in patients is a potential therapeutic strategy, by mimicking the pathophysiology of organ rejection. We therefore sought to develop an animal model of HAR for cancer therapy. Nude/(alpha1,3)GT knock-out mice allowed the growth of human tumour xenografts and the use of ecotropic retrovirus producer cells to generate expression of alphaGal on tumour vasculature. Lysis of alphaGal-positive murine endothelial cells with rabbit complement in conjunction with murine anti-alphaGal antibody in vitro was used to define the conditions necessary for HAR. However, tumour growth retardation and destruction of alphaGal-positive tumour endothelium were minimal after their administration, despite sera retaining post hoc cytolytic activity with fresh complement. The major limitation of this experimental system, of relevance to other therapeutic approaches, results from the use of a xenograft, in which additional xenoreactivities lead to complement insufficiency. Development of a tractable preclinical model in which to evaluate HAR for cancer therapy requires a syngeneic experimental system.
Larkin
James M G
JM
The Institute of Cancer Research, London, UK.
Porter
Colin D
CD
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D003165:Complement System Proteins / Q000172:deficiency*; D003602:Cytotoxicity, Immunologic; D004187:Disaccharides / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005700:Galactosyltransferases / Q000235:genetics / Q000502:physiology; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007075:Immunoglobulin M / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D011817:Rabbits; D012190:Retroviridae / Q000502:physiology; D012514:Sarcoma, Kaposi / Q000097:blood / Q000276:immunology* / Q000473:pathology; D014183:Transplantation, Heterologous
D004187:Disaccharides; D007075:Immunoglobulin M; C055075:galactosyl-(1-3)galactose; D003165:Complement System Proteins; D005700:Galactosyltransferases; C037959:beta-D-galactosyl-N-acetylglucosaminylglycopeptide alpha-1,3-galactosyltransferase