Anti-Pig IGE and IGA Antibodies in Naive Primates and Nonhuman Primates With Pig Xenografts.

BACKGROUND Natural preformed anti-pig IgM/IgG antibodies in primates play an important role in xenograft rejection. As it is not clear how IgE and IgA engage in the immune system in xenotransplantation, we investigated natural preformed and elicited anti-pig IgE/IgA in naive primates and after xenotransplantation in nonhuman primates. METHODS The binding of IgM/IgG/IgE/IgA antibodies to red blood cells (RBCs) from wild-type (WT), α1,3-galactosyltransferase gene-knockout (GTKO), and GTKO/cytidine monophospho-N-acetylneuraminic acid hydroxylase gene-knockout (CMAHKO)/β-1,4N-acetylgalactosaminyltransferase 2 gene-knockout (β4GalNT2KO) (i.e., triple-knockout pigs) pigs (p) were measured by flow cytometry in naive human (n=50) and baboon (n=14) sera. Antibody binding to WT and GTKO pRBCs was also measured in the sera of baboons (non-sensitized n=7, sensitized n=2) and rhesus monkeys (non-sensitized n=2, sensitized n=11) following WT or GTKO pig organ/tissue xenotransplantation. Deposition of IgM/IgG/IgE/IgA in the grafts was detected by immunohistochemistry. RESULTS The majority humans had natural preformed IgM/IgG/IgE/IgA to WT and GTKO pRBCs. In contrast, IgM/IgG/IgE/IgA to TKO pRBCs were present at lower levels and frequency (p<0.01). Baboons also had IgM/IgG/IgE/IgA antibodies against WT pRBCs, but less to GTKO and TKO (p<0.01). After xenotransplantation into nonhuman primates, when IgM/IgG increased, IgE/IgA also increased, but to a lesser extent. In addition to IgM/IgG, IgE and/or IgA deposition was observed in rejected pig xenografts. CONCLUSIONS Primates develop serum anti-pig IgE/IgA antibodies both naturally and during xenograft rejection. The pathophysiological role, if any, of anti-pig IgE/IgA antibodies remains unknown.