Rationale for HDAC inhibitor therapy in autoimmunity and transplantation

Area of Science:

• Pharmacology and Immunology
• Molecular Biology and Therapeutics

Background:

• Histone deacetylase inhibitors (HDACi) are being investigated in over 70 clinical trials for cancer treatment.
• HDACi possess antiproliferative and angiostatic properties, suggesting potential as anti-inflammatory and immunosuppressive drugs.

Purpose of the Study:

• To evaluate the therapeutic potential of HDAC inhibitors as anti-inflammatory agents.
• To explore the development of isoform-selective HDAC inhibitors for treating inflammatory and autoimmune diseases, including transplantation.

Main Methods:

• Review of current research on classical HDAC inhibitors (HDACi) and their mechanisms of action.
• Discussion of experimental models assessing the safety and efficacy of HDACi in inflammation.
• Exploration of HDAC subclass and isoform-selective HDACi for targeted therapeutic strategies.

Main Results:

• Current pan-HDACi compounds exhibit broad target distribution and complex mechanisms, limiting their suitability for anti-inflammatory therapy.
• Isoform-selective HDACi present a promising avenue for developing targeted anti-inflammatory and immunosuppressive treatments.
• Targeting specific HDACs may enhance the function of Foxp3+ T regulatory cells, crucial for immune homeostasis.

Conclusions:

• While potent anticancer agents, broad-acting HDAC inhibitors face challenges in anti-inflammatory applications due to off-target effects.
• The development of isoform-selective HDAC inhibitors is critical for advancing HDAC-targeted therapies in autoimmunity and transplantation.
• Targeting specific HDAC isoforms offers a more precise approach to modulating inflammatory responses and promoting immune tolerance.