Manipulation of B-cell responses with histone deacetylase inhibitors.

Abstract

Histone deacetylase inhibitors (HDACi) are approved for treating certain haematological malignancies, however, recent evidence also illustrates they are modulators of the immune system. In experimental models, HDACi are particularly potent against malignancies originating from the B-lymphocyte lineage. Here we examine the ability of this class of compounds to modify both protective and autoimmune antibody responses. In vitro, HDACi affect B-cell proliferation, survival and differentiation in an HDAC-class-dependent manner. Strikingly, treatment of lupus-prone Mrl/lpr mice with the HDACi panobinostat significantly reduces autoreactive plasma-cell numbers, autoantibodies and nephritis, while other immune parameters remain largely unaffected. Immunized control mice treated with panobinostat or the clinically approved HDACi vorinostat have significantly impaired primary antibody responses, but these treatments surprisingly spare circulating memory B cells. These studies indicate that panobinostat is a potential therapy for B-cell-driven autoimmune conditions and HDACi do not induce major long-term detrimental effects on B-cell memory.

• Authors: Michaela Waibel, Ailsa J Christiansen, Margaret L Hibbs, Jake Shortt, Sarah A Jones, Ian Simpson, Amanda Light, Kristy O'Donnell, Eric F Morand, David M Tarlinton, Ricky W Johnstone, Edwin D Hawkins
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 6838 (Apr 27 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 25913720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Indoles
• Panobinostat

Topics

• Animals
• B-Lymphocytes (drug effects)
• Cell Differentiation (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Drug Evaluation, Preclinical
• Female
• Germinal Center (drug effects)
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Hydroxamic Acids (pharmacology, therapeutic use)
• Immunologic Memory (drug effects)
• Indoles (pharmacology, therapeutic use)
• Lupus Erythematosus, Systemic (drug therapy)
• Male
• Mice, Inbred C57BL
• Panobinostat