Similarities in the immunoglobulin response and VH gene usage in rhesus monkeys and humans exposed to porcine hepatocytes

Xenoantibodies produced following exposure to isolated hepatocytes and solid organ liver grafts were predominantly encoded by genes in the VH3 family, with a minor contribution from the VH4 family. Immunoglobulin heavy-chain gene (VH) cDNA library screening and gene sequencing of IgM libraries identified the genes as most closely-related to the IGHV3-11 and IGHV4-59 germline progenitors. One of the genes most similar to IGHV3-11, VH3-11cyno, has not been previously identified, and encodes xenoantibodies at later time points post-transplant. Sequencing of IgG clones revealed increased usage of the monkey germline progenitor most similar to human IGHV3-11 and the onset of mutations.The small number of IGVH genes encoding xenoantibodies to porcine hepatocytes in non-human primates and humans is highly conserved. Rhesus monkeys are an appropriate preclinical model for testing novel reagents such as those developed using structure-based drug design to target and deplete antibodies to porcine xenografts.The use of porcine cells, tissues, and organs for transplantation or extracorporeal perfusion would greatly benefit the 86,000 patients on the United Network for Organ Sharing transplant waiting list, as well as those considered medically unsuitable for transplantation of scarce human organs or tissues [1]. Unfortunately, humans and Old World primates vigorously reject pig tissues due to xenoantibodies that react with the polysaccharide galactose α (1,3) galactose (αGal) present on the surface of many porcine cells. This rejection is the result of two processes, involving both preformed, circulating xenoantibodies, and those antibodies whose production is stimulated by the presence of the xenograft [2-4]. Despite this immunological barrier, porcine cells and tissues have been used clinically: pig heart valves have been utilized since 1967 [5], and islets have been transplanted into at least ten diabetic patients [6]. Numerous patients have also undergone extracorporeal per