The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/4/1335/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 8, April 20, 1998 1335-1342

Articles

Tolerization of Anti–Gal{alpha}1-3Gal Natural Antibody–forming B Cells by Induction of Mixed Chimerism

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

From the * Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02129; and {ddagger} 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–Gal{alpha}1-3Gal (Gal) natural antibodies (NAbs) in their sera. We evaluated the ability to tolerize anti-Gal NAb–producing B cells in {alpha}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.

Address correspondence to Megan Sykes, Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, MGH East, Bldg. 149-5102, 13th St., Boston, MA 02129. Phone: 617-726-4070; Fax: 617-724-9892; E-mail: sykes{at}helix.mgh.harvard.edu

1 Abbreviations used in this paper: BMC, bone marrow cells; BMT, bone marrow transplantation; ELISPOT, enzyme-linked immunospot; FCM, flow cytometric; Gal, Gal{alpha}1-3Gal; GalT, {alpha}1,3-galactosyltransferase; KO, knockout; NAb, natural antibody; RAG, recombination activating gene; TCD, T cell depleted; WT, wild-type.


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