Immunoglobulin heavy chain transgenic mice expressing Galalpha(1,3)Gal-reactive antibodies.
BACKGROUND
Natural antibodies that bind the carbohydrate antigen Galalpha1-3Galbeta1-4GlcNAc-R (alphaGal) mediate rigorous rejection of porcine xenografts and represent a major immunological hurdle to successful discordant xenotransplantation. However, little is known about how production of antibodies specific for alphaGal is regulated.


METHODS
Transgenic mice expressing an IgM heavy chain isolated from a B-cell hybridoma that produces antibodies specific for alphaGal were constructed. These mice were bred to mutant mice that lack the alphaGal epitope (GT0 mice) or wild-type (GT+) mice to generate animals in which the transgene is expressed in the presence or absence of alphaGal as a "self"-antigen. Development of transgene-expressing B cells and production of alphaGal-specific serum antibodies were then analyzed in transgenic mice on GT0 and GT+ backgrounds.


RESULTS
B cells expressing the transgenic heavy chain and transgene-encoded serum antibodies specific for alphaGal were readily detected in mice on the GT0 background. Most alphaGal-reactive antibodies in GT0 mice used the transgene rather than endogenous Ig heavy chains. In contrast, transgene-encoded serum antibodies specific for alphaGal were not detected in GT+ mice. In transgenic mice on the GT+ background, B cells expressing the transgene underwent deletion as a result of encountering alphaGal during their development, indicating that expression of alphaGal as part of self-mediated efficient negative selection of B cells expressing transgene-encoded alphaGal-specific antibodies.


CONCLUSIONS
The development of transgenic mice expressing a B cell receptor specific for alphaGal provides a novel system to study developmental regulation of B cells making carbohydrate-specific antibodies. In addition, these mice may be useful for examining methods to prevent production of alphaGal-reactive antibodies.
Cretin
Nathalie
N
Transplantation Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA.
Iacomini
John
J
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003433:Crosses, Genetic; D004187:Disaccharides / Q000235:genetics* / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007518:Isoantibodies / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D015183:Restriction Mapping; D013601:T-Lymphocytes / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology
D004187:Disaccharides; D007143:Immunoglobulin Heavy Chains; D007518:Isoantibodies; C055075:galactosyl-(1-3)galactose