Manipulation of B-cell responses with histone deacetylase inhibitors

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 and Edwin D. Hawkins ()
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Michaela Waibel: Cancer Therapeutics Program, Peter MacCallum Cancer Centre
Ailsa J. Christiansen: Cancer Therapeutics Program, Peter MacCallum Cancer Centre
Margaret L. Hibbs: Leukocyte Signaling Laboratory, Monash University, Level 6 Burnet Institute
Jake Shortt: Cancer Therapeutics Program, Peter MacCallum Cancer Centre
Sarah A. Jones: Monash University School of Clinical Sciences, Monash Medical Centre
Ian Simpson: Monash Medical Centre
Amanda Light: The Walter and Eliza Hall Institute of Medical Research
Kristy O’Donnell: The Walter and Eliza Hall Institute of Medical Research
Eric F. Morand: Monash University School of Clinical Sciences, Monash Medical Centre
David M. Tarlinton: The Walter and Eliza Hall Institute of Medical Research
Ricky W. Johnstone: Cancer Therapeutics Program, Peter MacCallum Cancer Centre
Edwin D. Hawkins: Cancer Therapeutics Program, Peter MacCallum Cancer Centre

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7838

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