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.

Selective HDAC6 inhibition decreases early stage of lupus nephritis by down-regulating both innate and adaptive immune responses

“…This was evident in the studies comparing the pan-HDAC inhibitor panobinostat and vorinostat, which altered B cell function in multiple myeloma and T cell function in cutaneous T cell lymphoma, respectively [33,34]. Also of interest, the action of panobinostat on B cells occurred at low concentrations (in the nanomolar range), whereas at elevated concentrations effects on T cell function were observed [35]. In our prior studies we showed the pan-HDAC inhibitor vorinostat (also known as suberanilohydroxamic acid) could decrease disease in lupus mice through targeting T cells, although it had some toxicity at elevated concentrations when administered longterm to lupus mice [36,37].…”

“…However, clinical trials were somewhat disappointing, possibly because rituximab was not very effective at targeting plasma cells that are CD20-negative. The studies using panobinostat showed efficacy in targeting all B cells, including plasma cells [35], which may be a better therapeutic target. Although these results are promising, the rationale for more selective HDAC inhibition remains paramount as we seek to understand their precise mechanism.…”

HDAC expression and activity is upregulated in diseased lupus-prone mice

“…Studies have suggested that treatment of SLE with HDAC inhibitors may be able to correct aberrant B and T cell development[60]. SLE is a chronic autoimmune disease requiring long-term treatment[61].…”

NET silencing by let-7i in postural tachycardia syndrome

“…MeCP2 resides in a co-repressor complex with HDAC activity (14), and vorinostat (suberoylanilide hydroxamic acid or SAHA) has been approved by the FDA for the treatment of hematological malignancies and is currently being evaluated for other diseases (15). Using human leukocytes isolated from healthy and POTS participants, we developed an experimental assay to test NET reactivation because there are no comparative ex vivo models or human studies to assess the efficacy of therapies directly in POTS.…”