Abstract
Abstract Purpose B cell tolerance is critical for donor cell engraftment across immune barriers after in utero hematopoietic cell transplantation (IUHCT). Using our fetal transplant model we studied how B cells achieve tolerance to allogeneic MHC antigens. Methods 10×106 C57Bl/6-GFP (H2Kb) bone marrow (BM) cells were injected intravenously into gestational day 14 Balb/c (H2Kd) fetuses. Mice were sacrificed at 3 days (P3), 1 and 4 months of age and donor-specific B cell tolerance including deletion, receptor editing and functional inactivation were assessed. Age matched naïve C57Bl/6 and Balb/c mice served as controls. Results The % of alloantigen specific splenic B cells was significantly decreased in allogenic chimeras as compared to controls (p=0.016) consistent with clonal deletion. Alloreactive B cells that escape deletion can undergo receptor editing. There was a significant increase in the % of B cells undergoing editing (lambda light chain expression) at P3 in recipients of IUHCT compared to controls (10.8% vs. 8.4%; p=0.02). Alloreactive B cells can be functionally inactivated such that they no longer make antibodies or express IgM. In contrast to naïve Balb/c mice immunized with C57Bl/6 splenocytes, immunization of recipients of IUHCT failed to elicit an anti-donor antibody response (MFI fold change: IUHCT-0.89 naïve-2.77; p<0.05). Furthermore, IgM expression on alloantigen specific splenocytes in chimeric animals was lower than controls (MFI: chimeric-1206, control-1472 ; p=0.03). Conclusion B cell tolerance after IUHCT is achieved by partial deletion in alloreactive splenic B cells, receptor editing in early mature splenocytes, and the remainder of alloreactive B cells demonstrate a functionally inactive phenotype.
Published Version
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