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

Abstract

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.

• Authors: Mathangi Srinivasan, Ryan Flynn, Andrew Price, Ann Ranger, Jeffrey L Browning, Patricia A Taylor, Jerome Ritz, Joseph H Antin, William J Murphy, Leo Luznik, Mark J Shlomchik, Angela Panoskaltsis-Mortari, Bruce R Blazar
• Journal: Blood (Blood) Vol. 119 Issue 6 Pg. 1570-80 (Feb 09 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22072556 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Immunoglobulin G
• Isoantibodies
• Lymphotoxin beta Receptor
• Recombinant Fusion Proteins
• Leukocyte Common Antigens

Topics

• Animals
• B-Lymphocytes (immunology, metabolism)
• Blood Donors
• Bronchiolitis Obliterans (immunology, prevention & control)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• Chronic Disease
• Female
• Fluorescent Antibody Technique
• Germinal Center (drug effects, immunology)
• Graft vs Host Disease (immunology, pathology, prevention & control)
• Humans
• Immunoglobulin G (genetics, immunology)
• Isoantibodies (immunology)
• Leukocyte Common Antigens (immunology, metabolism)
• Liver Cirrhosis (immunology, metabolism)
• Lymphotoxin beta Receptor (genetics, immunology)
• Male
• Mice
• Mice, 129 Strain
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Pulmonary Fibrosis (immunology, metabolism)
• Recombinant Fusion Proteins (immunology, pharmacology)