Identification of the V genes encoding xenoantibodies in non-immunosuppressed rhesus monkeys.
The major immunological barrier that prevents the use of wild-type pig xenografts as an alternative source of organs for human xenotransplantation is antibody-mediated rejection. In this study, we identify the immunoglobulin variable region heavy (IgV(H)) chain genes encoding xenoantibodies to porcine heart and fetal porcine islet xenografts in non-immunosuppressed rhesus monkeys. We sought to compare the IgV(H) genes encoding xenoantibodies to porcine islets and solid organ xenografts. The immunoglobulin M (IgM) and IgG xenoantibody response was analysed by enzyme-linked immunosorbent assay and cDNA libraries from peripheral blood lymphocytes were prepared and sequenced. The relative frequency of IgV(H) gene usage was established by colony filter hybridization. Induced xenoantibodies were encoded by the IGHV3-11 germline progenitor, the same germline gene that encodes xenoantibodies in humans mounting active xenoantibody responses. The immune response to pig xenografts presented as solid organs or isolated cells is mediated by identical IgV(H) genes in rhesus monkeys. These animals represent a clinically relevant model to identify the immunological basis of pig-to-human xenograft rejection.
Kleihauer
Annette
A
Cardiothoracic Surgery Research, The Saban Research Institute, Children's Hospital of Los Angeles, The Keck School of Medicine, University of Southern California, CA, USA.
Gregory
Clare R
CR
Borie
Dominic C
DC
Kyles
Andrew E
AE
Shulkin
Irina
I
Patanwala
Insiyyah
I
Zahorsky-Reeves
Joanne
J
Starnes
Vaughn A
VA
Mullen
Yoko
Y
Todorov
Ivan T
IT
Kearns-Jonker
Mary
M
D000595:Amino Acid Sequence; D000818:Animals; D000910:Antibodies, Heterophile / Q000096:biosynthesis / Q000235:genetics*; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015723:Gene Library; D005803:Genes, Immunoglobulin; D016027:Heart Transplantation / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007515:Islets of Langerhans / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D000910:Antibodies, Heterophile; D018076:DNA, Complementary; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region