Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice

Blood Advances
Steven SchuttXue-Zhong Yu

Abstract

Hematopoietic stem cell transplantation (HCT) is a curative procedure for hematological malignancies, but chronic graft-versus-host disease (cGVHD) remains a major complication after allogeneic HCT. Because donor B cells are essential for cGVHD development and B cells are sensitive to endoplasmic reticulum (ER) stress, we hypothesized that the IRE-1α/XBP-1 pathway is required for B-cell activation and function and for the development of cGVHD. To test this hypothesis, we used conditional knock-out mice deficient of XBP-1 specifically in B cells. Recipients transplanted with donor grafts containing XBP-1-deficient B cells displayed reduced cGVHD compared with controls. Reduction of cGVHD correlated with impaired B-cell functions, including reduced production of anti-double-stranded DNA immunoglobulin G antibodies, CD86, Fas, and GL7 surface expression, and impaired T-cell responses, including reduced interferon-γ production and follicular helper T cells. In a bronchiolitis obliterans cGVHD model, recipients of transplants containing XBP-1-deficient B cells demonstrated improved pulmonary function correlated with reduced donor splenic follicular helper T cells and increased B cells compared with those of wild-type control donor g...Continue Reading

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Citations

May 3, 2019·The Journal of Clinical Investigation·M Hanief SofiXue-Zhong Yu
Jun 9, 2020·Frontiers in Immunology·Alycia GardnerBrian Ruffell
Oct 18, 2020·Nature Chemical Biology·Juan R Del ValleChih-Chi Andrew Hu
May 16, 2019·Journal of Medicinal Chemistry·Andong ShaoChih-Chi Andrew Hu

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