Anti‐Galα1‐3Gal IgM and IgG antibody levels in sera of humans and old world non‐human primates

Abstract

Organs transplanted from pig to primate are rejected within minutes or hours by an antibody-dependent, complement-mediated mechanism [hyperacute rejection (HAR)]. Even after depletion of anti-Gal alpha 1-3Gal (Gal) antibody (Ab), for example by extracorporeal immunoadsorption, return of natural Ab is believed to be a major factor in the initiation of acute humoral xenograft rejection. Various non-human primates are used as recipients of pig organs in experimental discordant xenotransplantation (XTx) models. However, anti-Gal IgM and IgG levels in non-human primates may differ from those in humans. Serum levels of anti-Gal IgM and IgG were measured by enzyme-linked immunosorbent assay (ELISA) in humans (n=14), chimpanzees (n=8), baboons (n=214), cynomolgus monkeys (n=29), rhesus monkeys (n=23) and Japanese monkeys (n=6). The mean level of anti-Gal IgM was significantly higher in chimpanzees than in other groups, while in rhesus monkeys it was significantly lower than in other groups, except baboons and Japanese monkeys. The mean human anti-Gal IgG level was higher than in other groups and this difference reached statistical significance except with regard to chimpanzees. The mean anti-Gal IgG level in baboons was significantly lower than that in humans, chimpanzees and cynomolgus monkeys. The measured differences in anti-Gal IgM and IgG levels may affect the kinetics of Ab removal and rate of return in different species, and thus may have relevance for translating work in non-human primate models to the clinical setting.

Characterization of Anti-Gal Antibody-Producing Cells of Baboons and Humans

“…These results are similar to those obtained in the Gal knockout mouse model (14). In contrast, the frequency of anti-Gal IgG-secreting cells in naïve baboons was low, consistent with the low concentration of anti-Gal IgG Abs in serum (6). Anti-Gal IgG-secreting cells were mainly found in LN.…”

“…These NAbs bind to Gal epitopes present on endothelial and other pig cells (4), leading to hyperacute and delayed xenograft rejection (5). Compared to humans, baboons are reported to have comparable levels of anti-Gal IgM and lower levels of anti-Gal IgG Abs (6,7). Methods to remove circulating anti-Gal Abs (8 -11), have prevented hyperacute rejection in primates, but delayed xenograft rejection still ocurred (8 -11).…”

The Molecular Basis for Galα(1,3)Gal Expression in Animals with a Deletion of the α1,3Galactosyltransferase Gene

“…On face value, this suggests that the Gal␣(1,3)Gal synthesized by iGb3S does not play a major role in this initial mode of rejection; this may need to be re-examined. First, humans have higher levels of anti-Gal␣(1,3)Gal Ab than most primates (32). Second, transplanted primates are often subjected to potent immunosuppression that would best be avoided in humans.…”

Anti‐Gal IgG potentiates natural killer cell migration across porcine endothelium via endothelial cell activation and increased natural killer cell motility triggered by CD16 cross‐linking

“…The concentration of anti-Gal IgG Ab in the sera of 14 healthy human individuals has been measured and shown to be between 43.1 and 256.5 ? g/ml [32]. Thus, 160 ?…”