Elucidation of the mechanism on carbohydrate antigen recognition by B cells through CD1d mediated signaling and establishment of a method to regulate B cells responding to the carbohydrate antigens in ABO-incompatible transplantation and xe

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In ABO-blood group incompatible transplantation and xenotransplantation, grafted organs will be rejected because antibody (Ab)-mediated rejection is induced in responses to blood group A/B antigens, Gal α 1-3Galb1-4GlcNAc (Gal) or N-glycolylneuraminic acid (NeuGc) carbohydrates, which are widely expressed on the organ vessel epithelia. We have attempted to establish a specific immunosuppressive method targeting B cells responding to A/B, Gal and NeuGc carbohydrate antigens.In this study, we have analyzed the role of natural killer T (NKT) cells in the differentiation of B cells responding to the transplant-related carbohydrates. In the wild-type (WT) control mice, anti-A IgM/IgG Ab production occurred and was accelerated after the immunization with human red blood cells (RBCs) and α Galactosylceramide ( α GalCer) (an unique carbohydrate antigen that is presented on CD1d molecules and activates NKT cells). On the other hand, in the CD1d (ligand to the V α 14 T cell receptors used predominantly in NKT cells) knockout (KO) mice, anti-A IgM production was significantly reduced and anti-A IgG-class switching could not be observed. There was no difference in anti-allogeneic MHC Ab production between WT and CD1dKO mice, and IgG-class switching could be normally observed in both background mice. Based on these findings, it is likely that the suppressive modulation of CD1d molecule-mediated signaling between NKT cells and B cells might lead to the avoidance of Ab-mediated rejection in ABO-incompatible transplantation, whereas this strategy could not prevent Ab production from B cells responding to allogeneic MHC antigens. In order to investigate further such roles of NKT cells in the differentiation of B cells responding to the xenogeneic carbohydrate antigens, we have now established Gal/CD1d double KO mice and NeuGc/CD1d double KO mice by mating either Gal KO or NeuGc KO mice with CD1dKO mice.