Donor B-cell alloantibody deposition and germinal center formation are required for the development of murine chronic GVHD and bronchiolitis obliterans

Chronic GVHD (cGVHD) poses a significant risk for HSCT patients. Preclinical development of new therapeutic modalities has been hindered by models with pathologic findings that may not simulate the development of human cGVHD. Previously, we have demonstrated that cGVHD induced by allogeneic HSCT aft...

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Bibliographic Details
Published in:Blood 2012-02, Vol.119 (6), p.1570-1580
Main Authors: Srinivasan, Mathangi, Flynn, Ryan, Price, Andrew, Ranger, Ann, Browning, Jeffrey L., Taylor, Patricia A., Ritz, Jerome, Antin, Joseph H., Murphy, William J., Luznik, Leo, Shlomchik, Mark J., Panoskaltsis-Mortari, Angela, Blazar, Bruce R.
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
Biological and medical sciences
Blood Donors
Bronchiolitis Obliterans - immunology
Bronchiolitis Obliterans - prevention & control
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - metabolism
Chronic Disease
Chronic obstructive pulmonary disease, asthma
Female
Fluorescent Antibody Technique
Germinal Center - drug effects
Germinal Center - immunology
Graft vs Host Disease - immunology
Graft vs Host Disease - pathology
Graft vs Host Disease - prevention & control
Hematologic and hematopoietic diseases
Humans
Immunoglobulin G - genetics
Immunoglobulin G - immunology
Isoantibodies - immunology
Leukocyte Common Antigens - immunology
Leukocyte Common Antigens - metabolism
Liver Cirrhosis - immunology
Liver Cirrhosis - metabolism
Lymphotoxin beta Receptor - genetics
Lymphotoxin beta Receptor - immunology
Male
Medical sciences
Mice
Mice, 129 Strain
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Pneumology
Pulmonary Fibrosis - immunology
Pulmonary Fibrosis - metabolism
Recombinant Fusion Proteins - immunology
Recombinant Fusion Proteins - pharmacology
Transplantation
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Summary:Chronic GVHD (cGVHD) poses a significant risk for HSCT patients. Preclinical development of new therapeutic modalities has been hindered by models with pathologic findings that may not simulate the development of human cGVHD. Previously, we have demonstrated that cGVHD induced by allogeneic HSCT after a conditioning regimen of cyclophosphamide and total-body radiation results in pulmonary dysfunction and airway obliteration, which leads to bronchiolitis obliterans (BO), which is pathognomonic for cGVHD of the lung. We now report cGVHD manifestations in a wide spectrum of target organs, including those with mucosal surfaces. Fibrosis was demonstrated in the lung and liver and was associated with CD4+ T cells and B220+ B-cell infiltration and alloantibody deposition. Donor bone marrow obtained from mice incapable of secreting IgG alloantibody resulted in less BO and cGVHD. Robust germinal center reactions were present at the time of cGVHD disease initiation. Blockade of germinal center formation with a lymphotoxin-receptor–immunoglobulin fusion protein suppressed cGVHD and BO. We conclude that cGVHD is caused in part by alloantibody secretion, which is associated with fibrosis and cGVHD manifestations including BO, and that treatment with a lymphotoxin-β receptor–immunoglobulin fusion protein could be beneficial for cGVHD prevention and therapy.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2011-07-364414