We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Complement insufficiency limits efficacy in a xenograft model of hyperacute rejection for cancer therapy.
- Authors
Larkin, James M. G.; Porter, Colin D.
- Abstract
Hyperacute rejection (HAR) is a rapid immunological response to an organ xenotransplant caused by recognition of endothelial galactose(α1,3)galactose (αGal) epitopes and complement-mediated cell lysis by host anti-αGal antibody (‘natural antibody’). The αGal epitope is synthesised by a galactosyl transferase ((α1,3)GT) which humans lack. Because human cells transduced with (α1,3)GT are sensitised to natural antibody/complement-mediated lysis in human serum, delivery of (α1,3)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/(α1,3)GT knock-out mice allowed the growth of human tumour xenografts and the use of ecotropic retrovirus producer cells to generate expression of αGal on tumour vasculature. Lysis of αGal-positive murine endothelial cells with rabbit complement in conjunction with murine anti-αGal antibody in vitro was used to define the conditions necessary for HAR. However, tumour growth retardation and destruction of αGal-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.
- Subjects
XENOGRAFTS; CANCER treatment; GALACTOSE; EPITOPES; GALACTOSYLTRANSFERASES; ENDOTHELIUM
- Publication
Cancer Immunology, Immunotherapy, 2007, Vol 56, Issue 1, p60
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-006-0174-2