Differing mechanisms of early and late B cell hyporesponsiveness induced by mixed chimerism.
Mixed hematopoietic chimerism induced via nonmyeloablative bone marrow transplantation (BMT) leads to unresponsiveness of anti-Gal alpha1,3Gal beta1,4G1cNAc (Gal) natural antibody (NAb)-producing cells in alpha1,3-galactosyltransferase deficient (GalT(-/-)) mice. We analyzed the mechanisms of anti-Gal-producing B cell unresponsiveness induced by Gal(+/+) BMT. C57BL/6 (B6) GalT(-/-) mice received 3Gy whole-body irradiation and BMT from B6-CD45 congenic mice. BMT led to marked reductions in serum anti-Gal IgM levels and in the numbers of splenic anti-Gal-producing cells by 2 weeks post-BMT. B cells with anti-Gal Ig receptors were present in the spleens of 2-week but not 12-week chimeras. In vitro studies and adoptive transfer studies using B6 GalT(-/-)B cell-deficient recipients showed that B cell hyporesponsiveness to Gal at 2 weeks, but not 12 weeks, depended on persistent Gal antigen. Thus, pre-existing B-1 cells are anergic when there is continuous exposure to Gal, whereas long-term unresponsiveness does not require persistent antigen, implicating clonal deletion and/or receptor editing. These results have implications for the potential use of mixed hematopioetic chimerism as an approach to performing organ transplantation in recipients with pre-existing anti-donor IgM antibodies.
Kawahara
T
T
Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Shimizu
I
I
Ohdan
H
H
Zhao
G
G
Sykes
M
M
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D005700:Galactosyltransferases / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011828:Radiation Chimera; D011956:Receptors, Cell Surface / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D018183:Transplantation Chimera; D048069:Tumor Necrosis Factors / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D000906:Antibodies; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D048069:Tumor Necrosis Factors; D019014:fas Receptor; C039707:galactose receptor; D005700:Galactosyltransferases; C487611:alpha 1,3 galactosyltransferase, mouse; D017493:Leukocyte Common Antigens