J. Exp. Med., Volume 187, Number 8, April 20, 1998 1335-1342

Tolerization of Anti-Gal1-3Gal Natural Antibody-forming B Cells by Induction of Mixed Chimerism

By Yong-Guang Yang,^* Emil deGoma,^* Hideki Ohdan,^* Jennifer L. Bracy,^* Yuanxin Xu, John Iacomini,^* Aron D. Thall, and Megan Sykes^*

From the ^* Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02129; and  BioTransplant, Inc., Charlestown, Massachusetts 02129

Xenotransplantation could overcome the severe shortage of allogeneic organs, a major factor limiting organ transplantation. Unfortunately, transplantation of organs from pigs, the most suitable potential donor species, results in hyperacute rejection in primate recipients, due to the presence of anti-Gal1-3Gal (Gal) natural antibodies (NAbs) in their sera. We evaluated the ability to tolerize anti-Gal NAb-producing B cells in 1,3-galactosyltransferase knockout (GalT KO) mice using bone marrow transplantation (BMT) from GalT^+/+ wild-type (WT) mice. Lasting mixed chimerism was achieved in KO mice by cotransplantation of GalT KO and WT marrow after lethal irradiation. The levels of anti-Gal NAb in sera of mixed chimeras were reduced markedly 2 wk after BMT, and became undetectable at later time points. Immunization with Gal^+/+ xenogeneic cells failed to stimulate anti-Gal antibody production in mixed chimeras, whereas the production of non-Gal-specific antixenoantigen antibodies was stimulated. An absence of anti-Gal-producing B cells was demonstrated by enzyme-linked immunospot assays in mixed KO+WT KO chimeras. Thus, mixed chimerism efficiently induces anti-Gal-specific B cell tolerance in addition to T cell tolerance, providing a single approach to overcoming both the humoral and the cellular immune barriers to discordant xenotransplantation.

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