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Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans.
- Source :
-
Blood [Blood] 2014 Jun 19; Vol. 123 (25), pp. 3988-98. Date of Electronic Publication: 2014 May 12. - Publication Year :
- 2014
-
Abstract
- Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Having shown that germinal center (GC) formation and immunoglobulin deposition are required for multiorgan system cGVHD and associated bronchiolitis obliterans syndrome (BOS) in a murine model, we hypothesized that T follicular helper (Tfh) cells are necessary for cGVHD by supporting GC formation and maintenance. We show that increased frequency of Tfh cells correlated with increased GC B cells, cGVHD, and BOS. Although administering a highly depletionary anti-CD20 monoclonal antibody (mAb) to mice with established cGVHD resulted in peripheral B-cell depletion, B cells remained in the lung, and BOS was not reversed. BOS could be treated by eliminating production of interleukin-21 (IL-21) by donor T cells or IL-21 receptor (IL-21R) signaling of donor B cells. Development of BOS was dependent upon T cells expressing the chemokine receptor CXCR5 to facilitate T-cell trafficking to secondary lymphoid organ follicles. Blocking mAbs for IL-21/IL-21R, inducible T-cell costimulator (ICOS)/ICOS ligand, and CD40L/CD40 hindered GC formation and cGVHD. These data provide novel insights into cGVHD pathogenesis, indicate a role for Tfh cells in these processes, and suggest a new line of therapy using mAbs targeting Tfh cells to reverse cGVHD.<br /> (© 2014 by The American Society of Hematology.)
- Subjects :
- Animals
Antibodies, Monoclonal immunology
Antibodies, Monoclonal pharmacology
Antigens, CD20 immunology
Antigens, CD20 metabolism
B-Lymphocytes drug effects
B-Lymphocytes metabolism
Bronchiolitis Obliterans genetics
Bronchiolitis Obliterans metabolism
CD4-Positive T-Lymphocytes immunology
CD4-Positive T-Lymphocytes metabolism
CD40 Antigens immunology
CD40 Antigens metabolism
CD40 Ligand immunology
CD40 Ligand metabolism
Chronic Disease
Flow Cytometry
Germinal Center drug effects
Germinal Center metabolism
Graft vs Host Disease genetics
Graft vs Host Disease metabolism
Inducible T-Cell Co-Stimulator Ligand immunology
Inducible T-Cell Co-Stimulator Ligand metabolism
Inducible T-Cell Co-Stimulator Protein genetics
Inducible T-Cell Co-Stimulator Protein immunology
Inducible T-Cell Co-Stimulator Protein metabolism
Interleukins genetics
Interleukins immunology
Interleukins metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Confocal
Receptors, CXCR5 genetics
Receptors, CXCR5 immunology
Receptors, CXCR5 metabolism
Receptors, Interleukin-21 genetics
Receptors, Interleukin-21 immunology
Receptors, Interleukin-21 metabolism
Syndrome
T-Lymphocytes, Helper-Inducer drug effects
T-Lymphocytes, Helper-Inducer metabolism
B-Lymphocytes immunology
Bronchiolitis Obliterans immunology
Germinal Center immunology
Graft vs Host Disease immunology
T-Lymphocytes, Helper-Inducer immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 123
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 24820310
- Full Text :
- https://doi.org/10.1182/blood-2014-03-562231