RRC ID 75014
Author Sumii Y, Kondo T, Ikegawa S, Fukumi T, Iwamoto M, Nishimura MF, Sugiura H, Sando Y, Nakamura M, Meguri Y, Matsushita T, Tanimine N, Kimura M, Asada N, Ennishi D, Maeda Y, Matsuoka KI.
Title Hematopoietic stem cell-derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide.
Journal JCI Insight
Abstract Posttransplant cyclophosphamide (PTCy) is associated with a low incidence of chronic graft-versus-host disease (cGVHD) following hematopoietic stem cell (HSC) transplantation. Previous studies have shown the important roles of B cell immunity in cGVHD development. Here, we investigated the long-term reconstitution of B lymphopoiesis after PTCy using murine models. We first demonstrated that the immune homeostatic abnormality leading to cGVHD is characterized by an initial increase in effector T cells in the bone marrow and subsequent B and Treg cytopenia. PTCy, but not cyclosporine A or rapamycin, inhibits the initial alloreactive T cell response, which restores intra-bone marrow B lymphogenesis with a concomitant vigorous increase in Tregs. This leads to profound changes in posttransplant B cell homeostasis, including decreased B cell activating factors, increased transitional and regulatory B cells, and decreased germinal center B cells. To identify the cells responsible for PTCy-induced B cell tolerance, we selectively depleted Treg populations that were graft or HSC derived using DEREG mice. Deletion of either Treg population without PTCy resulted in critical B cytopenia. PTCy rescued B lymphopoiesis from graft-derived Treg deletion. In contrast, the negative effect of HSC-derived Treg deletion could not be overcome by PTCy, indicating that HSC-derived Tregs are essential for maintaining favorable B lymphopoiesis following PTCy. These findings define the mechanisms by which PTCy restores homeostasis of the B cell lineage and reestablishes immune tolerance.
Volume 8(8)
Published 2023-4-24
DOI 10.1172/jci.insight.162180
PII 162180
PMID 37092551
MeSH Animals Cyclophosphamide / pharmacology Graft vs Host Disease* Hematopoietic Stem Cell Transplantation* Hematopoietic Stem Cells Lymphopoiesis Mice
IF 6.205
Mice RBRC00144