Manipulation of B-cell responses with histone deacetylase inhibitors.
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.
1] Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
Michaela
M
Waibel
1] Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
Ailsa J
AJ
Christiansen
Leukocyte Signaling Laboratory, Department of Immunology, Monash University, Level 6 Burnet Institute, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
Margaret L
ML
Hibbs
1] Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria 3010, Australia [3] Department of Medicine, Monash University School of Clinical Sciences, Monash Medical Centre, Clayton, Victoria 3800, Australia [4] Department of Clinical Haematology, Monash Medical Centre, Clayton, Victoria 3800, Australia.
Jake
J
Shortt
Department of Medicine, Monash University School of Clinical Sciences, Monash Medical Centre, Clayton, Victoria 3800, Australia.
Sarah A
SA
Jones
Department of Pathology, Monash Medical Centre, Clayton, Victoria 3800, Australia.
Ian
I
Simpson
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, Victoria 3052, Australia.
Amanda
A
Light
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, Victoria 3052, Australia.
Kristy
K
O'Donnell
Department of Medicine, Monash University School of Clinical Sciences, Monash Medical Centre, Clayton, Victoria 3800, Australia.
Eric F
EF
Morand
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, Victoria 3052, Australia.
David M
DM
Tarlinton
1] Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
Ricky W
RW
Johnstone
1] Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria 3010, Australia.
Edwin D
ED
Hawkins
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005260:Female; D018858:Germinal Center / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D007156:Immunologic Memory / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy; D008297:Male; D008810:Mice, Inbred C57BL; D000077767:Panobinostat
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat