BAFF promotes heightened BCR responsiveness and manifestations of chronic GVHD after allogeneic stem cell transplantation.

Autor:	Jia W; Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.; Department of Immunology, Duke University School of Medicine and Duke Cancer Institute, Durham, NC., Poe JC; Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.; Department of Immunology, Duke University School of Medicine and Duke Cancer Institute, Durham, NC., Su H; Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.; Department of Immunology, Duke University School of Medicine and Duke Cancer Institute, Durham, NC., Anand S; Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.; Department of Immunology, Duke University School of Medicine and Duke Cancer Institute, Durham, NC., Matsushima GK; Neuroscience Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC., Rathmell JC; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN.; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN., Maillard I; Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA., Radojcic V; Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; and., Imai K; Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.; Department of Immunology, Duke University School of Medicine and Duke Cancer Institute, Durham, NC., Reyes NJ; Department of Ophthalmology., Cardona DM; Department of Pathology, and., Li Z; Biostatistics and Bioinformatics, Basic Science Department, Duke University Medical Center, Durham, NC., Suthers AN; Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.; Department of Immunology, Duke University School of Medicine and Duke Cancer Institute, Durham, NC., Curry-Chisolm IM; Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.; Department of Immunology, Duke University School of Medicine and Duke Cancer Institute, Durham, NC., DiCioccio RA; Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.; Department of Immunology, Duke University School of Medicine and Duke Cancer Institute, Durham, NC., Saban DR; Department of Ophthalmology., Chen BJ; Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.; Department of Immunology, Duke University School of Medicine and Duke Cancer Institute, Durham, NC., Chao NJ; Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.; Department of Immunology, Duke University School of Medicine and Duke Cancer Institute, Durham, NC., Sarantopoulos S; Division of Hematological Malignancies and Cellular Therapy, Department of Medicine and.; Department of Immunology, Duke University School of Medicine and Duke Cancer Institute, Durham, NC.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2021 May 06; Vol. 137 (18), pp. 2544-2557.
DOI:	10.1182/blood.2020008040
Abstrakt:	Patients with chronic graft-versus-host disease (cGVHD) have increased B cell-activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major histocompatibility complex-mismatched model with cGVHD-like manifestations, we first examined B-lymphopenic μMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B-cell number. Mice that later developed cGVHD had significantly increased numbers of recipient fibroblastic reticular cells with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD, because BAFF transcript in CD4+ T cells from diseased mice and patients was increased. cGVHD manifestations in mice were associated with high BAFF/B-cell ratios and persistence of B-cell receptor (BCR)-activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR responsiveness to surrogate antigen and NOTCH ligand. BAFF Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR activation or when alloantigen was present in vivo. Using T cell-depleted (BM only) BAFF Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells, and alloantibody production. We demonstrate that pathologic production of BAFF promotes an altered B-cell compartment and augments BCR responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in patients with cGVHD. (© 2021 by The American Society of Hematology.)
Databáze:	MEDLINE
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