[Aim]We have previously demonstrated that B cells recognizing blood group A antigens belong to CD11b+CD5+B-1a cells, and treatment with calcineurin inhibitors(CNIs), which blocks B-1a cell differentiation, resulted in the persistent reduction of A antigen-responsive B cells in mice. In this study, we have found that B cells that recognize blood group B antigens are phenotypically distinct CD11b+CD5dim/-B-1b cells, and are not influenced by CNIs in Α-galactosyltransferase-deficient(GalT-/-)mice.

[Methods]GalT-/-and GalT+/+mice were immunized with either blood group A or -B RBCs. B cells with anti-blood group B receptors determinants were phenotypically analyzed. In in vitro B-cell differentiation assays, resting B cells isolated from Balb/c mice spleen were treated with anti-IgM F(ab′)2, an analog of TI-2 antigens, in the presence or absence of LPS, or CD40L and IL-4, which provide T-dependent inductive signals, with various immunosuppressants.

[Results]In GalT+/+mice, immunization with A-RBCs led to a significant elevation of anti-A Abs; however, immunization with B-RBCs barely increased anti-B Abs. This finding may be explained by the presence of blood group B-like structures, ΑGal epitopes, present on cells in those mice. In GalT-/-mice, similarly elevated anti-A and anti-B Abs were detected in the sera after immunizations. In those mice, B cells bearing receptors that recognize B epitopes, which were identified in the peritoneal cavity, exhibited a CD5 dim/-CD11b+B-1b cell phenotype, whereas B cells with receptors for A epitopes showed a CD5+CD11b+B-1a cell phenotype. Cyclosporin A(CsA)treatment completely prevented the elevation of anti-A Abs in response to immunization with A-RBCs; however, CsA did not have any effect on anti-B Abs in response to immunization with B-RBCs. In a B-cell differentiation assay, B cells stimulated with anti-IgM F(ab′)2 developed into CD5+B-1a cells, whereas B cells stimulated with anti-IgM F(ab′)2 and LPS developed into CD5dimB-1b cells. In contrast, B cells stimulated with CD40L/IL-4 developed into CD5-B-2 cells. CsA only inhibited the differentiation into B-1a cells, whereas mycophenolic acid efficiently inhibited differentiation into all subtypes of B cells.

[Conclusions]These findings indicate a difference in sensitivity in blood group A and blood group B antigen-responsive B cells CNIs, which likely explains the lower survival rate of B-antigen disparate allografts compared to that of A-antigen disparate allografts in ABO-incompatible kidney transplantation documented in a national database.

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