BAFF receptor mAb treatment ameliorates development and progression of atherosclerosis in hyperlipidemic ApoE(-/-) mice.

Abstract

AIMS:

Option to attenuate atherosclerosis by depleting B2 cells is currently limited to anti-CD20 antibodies which deplete all B-cell subtypes. In the present study we evaluated the capacity of a monoclonal antibody to B cell activating factor-receptor (BAFFR) to selectively deplete atherogenic B2 cells to prevent both development and progression of atherosclerosis in the ApoE(-/-) mouse.

METHODS AND RESULTS:

To determine whether the BAFFR antibody prevents atherosclerosis development, we treated ApoE(-/-) mice with the antibody while feeding them a high fat diet (HFD) for 8 weeks. Mature CD93(-) CD19(+) B2 cells were reduced by treatment, spleen B-cell zones disrupted and spleen CD20 mRNA expression decreased while B1a cells and non-B cells were spared. Atherosclerosis was ameliorated in the hyperlipidemic mice and CD19(+) B cells, CD4(+) and CD8(+) T cells were reduced in atherosclerotic lesions. Expressions of proinflammatory cytokines, IL1β, TNFα, and IFNγ in the lesions were also reduced, while MCP1, MIF and VCAM-1 expressions were unaffected. Plasma immunoglobulins were reduced, but MDA-oxLDL specific antibodies were unaffected. To determine whether anti-BAFFR antibody ameliorates progression of atherosclerosis, we first fed ApoE(-/-) mice a HFD for 6 weeks, and then instigated anti-BAFFR antibody treatment for a further 6 week-HFD. CD93(-) CD19(+) B2 cells were selectively decreased and atherosclerotic lesions were reduced by this treatment.

CONCLUSION:

Anti-BAFFR monoclonal antibody selectively depletes mature B2 cells while sparing B1a cells, disrupts spleen B-cell zones and ameliorates atherosclerosis development and progression in hyperlipidemic ApoE(-/-) mice. Our findings have potential for clinical translation to manage atherosclerosis-based cardiovascular diseases.

• Authors: Tin Kyaw, Peng Cui, Christopher Tay, Peter Kanellakis, Hamid Hosseini, Edgar Liu, Antonius G Rolink, Peter Tipping, Alex Bobik, Ban-Hock Toh
• Journal: PloS one (PLoS One) Vol. 8 Issue 4 Pg. e60430 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23560095 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigens, CD
• Apolipoproteins E
• B-Cell Activation Factor Receptor
• Cytokines
• Tnfrsf13c protein, mouse

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Antigens, CD (genetics, immunology)
• Apolipoproteins E (deficiency, genetics, immunology)
• Atherosclerosis (complications, drug therapy, immunology, pathology)
• B-Cell Activation Factor Receptor (antagonists & inhibitors, genetics, immunology)
• B-Lymphocyte Subsets (drug effects, immunology, pathology)
• Cytokines (biosynthesis, immunology)
• Diet, High-Fat
• Disease Progression
• Hyperlipidemias (complications, drug therapy, immunology, pathology)
• Lymphocyte Depletion
• Male
• Mice
• Mice, Knockout
• Spleen (drug effects, immunology, pathology)