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The Human Antibody Response to Porcine Xenoantigens Is Encoded by IGHV3-11 and IGHV3-74 IgV_H Germline Progenitors¹

Transplantation Biology Research Laboratory, Department of Cardiothoracic Surgery, University of Southern California School of Medicine, Los Angeles, CA 90033

Preformed and induced Ab responses present a major immunological barrier to the use of pig organs for human xenotransplantation. We generated IgM and IgG gene libraries established from lymphocytes of patients treated with a bioartificial liver (BAL) containing pig hepatocytes and used these libraries to identify IgV_H genes that encode human Ab responses to pig xenoantigens. Genes encoded by the V_H3 family are increased in expression in patients following BAL treatment. cDNA libraries representing the V_H3 gene family were generated, and the relative frequency of expression of genes used to encode the Ab response was determined at days 0, 10, and 21. Ig genes derived from the IGHV3-11 and IGHV3-74 germline progenitors increase in frequency post-BAL. The IGHV3-11 gene encodes 12% of V_H3 cDNA clones expressed as IgM Abs at day 0 and 32.4–39.0% of cDNA clones encoding IgM Abs in two patients at day 10. IGHV3-11 and IGHV3-74 genes encoding IgM Abs in these patients are expressed without evidence of somatic mutation. By day 21, an isotype switch occurs and IGHV3-11 IgV_H progenitors encode IgG Abs that demonstrate somatic mutation. We cloned these genes into a phagemid vector, expressed these clones as single-chain Abs, and demonstrated that the IGHV3-11 gene encodes Abs with the ability to bind to the gal (1,3) gal epitope. Our results demonstrate that the xenoantibody response in humans is encoded by IgV_H genes restricted to IGHV3-11 and IGHV3-74 germline progenitors. IgM Abs are expressed in germline configuration and IgG Abs demonstrate somatic mutations by day 21.

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