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

Oleg V. Kolupaev, Trisha A. Dant, Hemamalini Bommiasamy, Danny W. Bruce, Kenneth A. Fowler, Stephen L. Tilley, Karen P. McKinnon, Stefanie Sarantopoulos, Bruce R. Blazar, James M. Coghill, Jonathan S. Serody

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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. Wefound an increase in the number of donor CD41 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.

Original languageEnglish (US)
Pages (from-to)2307-2319
Number of pages13
JournalBlood Advances
Volume2
Issue number18
DOIs
StatePublished - Sep 25 2018

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© 2018 by The American Society of Hematology.

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