Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD.

Abstract

Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients after allogeneic bone marrow (BM) or stem cell transplantation (allo-SCT). Recent work has indicated that both T and B lymphocytes play an important role in the pathophysiology of cGVHD. Previously, our group showed a critical role for the germinal center response in the function of B cells using a bronchiolitis obliterans (BO) model of cGVHD. Here, we demonstrated for the first time that cGVHD is associated with severe defects in the generation of BM B lymphoid and uncommitted common lymphoid progenitor cells. We found an increase in the number of donor CD4+ T cells in the BM of mice with cGVHD that was negatively correlated with B-cell development and the frequency of osteoblasts and Prrx-1-expressing perivascular stromal cells, which are present in the B-cell niche. Use of anti-DR3 monoclonal antibodies to enhance the number of donor regulatory T cells (Tregs) in the donor T-cell inoculum ameliorated the pathology associated with BO in this model. This correlated with an increased number of endosteal osteoblastic cells and significantly improved the generation of B-cell precursors in the BM after allo-SCT. Our work indicates that donor Tregs play a critical role in preserving the generation of B-cell precursors in the BM after allo-SCT. Approaches to enhance the number and/or function of donor Tregs that do not enhance conventional T-cell activity may be important to decrease the incidence and severity of cGVHD in part through normal B-cell lymphopoiesis.

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Published Version (Please cite this version)

10.1182/bloodadvances.2017014977

Publication Info

Kolupaev, Oleg V, Trisha A Dant, Hemamalini Bommiasamy, Danny W Bruce, Kenneth A Fowler, Stephen L Tilley, Karen P McKinnon, Stefanie Sarantopoulos, et al. (2018). Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD. Blood advances, 2(18). pp. 2307–2319. 10.1182/bloodadvances.2017014977 Retrieved from https://hdl.handle.net/10161/17668.

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