Abstract
Xenoantibodies show a particular reactivity to endothelial cells of multiple species. This cross-reactivity is considered negligible in most of the cases, and xenoantibodies are disregarded in assays determining anti-endothelial cell antibodies. However, there is also evidence that xenoantibodies may cause apoptosis to endothelial cells of several species. In this study we examined in non-human primates the characteristics of anti-porcine xenoantibodies targeting non-galactose α1,3-galactose (Gal) antigens, boosted by exposure to porcine red blood cells (PRBC) and the depletion of anti-Gal antibodies with GAS914. Production of anti-non-Gal antibodies correlated on day 10 with an augmented IgM and IgG antibody reactivity to L35 (porcine lymphoblastic cells). On days 20 and 30 there was an increased binding of IgG to AOC-40 (porcine endothelial cells), which paralleled an IgG antibody binding to HMEC-1 (human microvascular endothelial cells). These antibodies caused the apoptosis of AOC-40 and HMEC-1 cells through two different pathways, with and without DNA fragmentation, respectively. Western blotting of anti-non-Gal antibodies showed the increased intensity of several protein bands in AOC-40 and HMEC-1 lysates, and the transient detection of a few new bands, compared to samples before PRBC injection. Treatment with cyclophosphamide in one animal led to the virtual disappearance of anti-non-Gal antibody binding to AOC-40 and HMEC-1 proteins without modifying the cell surface antibody reactivity or apoptosis of these cells. Therefore, exposure of baboons to PRBC increases xenoantibody binding to porcine lymphoblastic cells and to porcine and human endothelial cells. The xenoantibodies caused apoptosis of porcine and human endothelial cells by apparently targeting non-protein antigens. This study substantiates a cross-reactivity of xenoantibodies to endothelial cells from different species, which may be particularly relevant if there is a xenogeneic exposure. In this setting, disregarding these antibodies may impair the proper assessment of the prevalence and role of anti-endothelial cell antibodies in human and animal disorders.
Highlights
Xenotransplantation of pig organs is not a current clinical practice because the tools available to date fail to control the humoral immune response triggered by the xenograft in humans and non-human primates
Xenoantibodies show a particular reactivity to endothelial cells of multiple species.This cross-reactivity is considered negligible in most of the cases, and xenoantibodies are disregarded in assays determining anti-endothelial cell antibodies
In this study we examined in non-human primates the characteristics of anti-porcine xenoantibodies targeting non-galactose α1,3-galactose (Gal) antigens, boosted by exposure to porcine red blood cells (PRBC) and the depletion of anti-Gal antibodies with GAS914
Summary
Xenotransplantation of pig organs is not a current clinical practice because the tools available to date fail to control the humoral immune response triggered by the xenograft in humans and non-human primates. The continuous depletion of these antibodies by polymers containing multiple Gal epitopes and the use of grafts from pigs lacking this epitope (α1,3 galactosyltransferase knockout; Gal-KO) evidenced that antibodies to non-Gal antigens play a major role in AHXR of pig organs in non-human primates [4,5,6]. This rejection is characterized by a thrombotic microangiopathy that results from the activation, proliferation and apoptosis of endothelial cells [7], suggesting a particular reactivity of non-Gal antibodies to these cells [8]. Xenoantibody responses are speciesrestricted not cell-specific and exposure to xenoantigens on other cells aside endothelial produce cross-reactive antibodies to endothelial cells of different species [11]
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