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Altered B cell Toll-like Receptor 9 responses after the onset of paediatric chronic graft-versus host disease She, Kevin


Chronic Graft-versus-Host disease (cGVHD) is a major complication after blood and marrow transplantation (BMT). B cells appear to play a role in cGVHD as evidenced in murine models and supported clinically by the success of B cell depletion treatment. Immunostimulatory microbial CpG-DNA responses are enhanced in splenocytes from mice with simulated Graft-versus Host Disease and we hypothesized that a similar response to CpG by B cells may be present in human cGVHD. Peripheral B cells from newly diagnosed cGVHD patients enrolled on the COG protocol ASCT0031 were divided into early (3-8 months post-BMT) and late (9 months post-BMT) onset groups and compared to time-matched control patients. A significantly greater percentage of B cells from cGVHD patients rapidly responded to phosphorothioate modified CpG compared to controls. There was a significant correlation between TLR9 expression and CpG response, also confirmed using entirely TLR9 dependent native phosphodiester CpG. There were no differences in response to peptidoglycan (TLRZ, 6) or LPS (TLR4). Patients with hepatic involvement had stronger phosphodiester CpG response. These findings suggest that a larger pool of B cells from patients with cGVHD are specifically primed for TLR9 response, compared to patients who have not developed extensive cGVHD after allogeneic BMT, and may play a role in the pathophysiology or maintenance of cGVHD.

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