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Epigenetic drug discovery: breaking through the immune barrier

Key Points

  • Epigenetic dysfunction has been extensively studied in the context of oncology but is increasingly emerging as a key driver of pathology in immune-mediated inflammatory diseases.

  • The diversity of cell types in the immune system and the ability of these cells to 'remember' both this identity and prior encounters with pathogens or antigens has long suggested a crucial role for epigenetics.

  • Dramatic progress in the identification, optimization and development of new inhibitors for multiple epigenetic targets has enabled unprecedented advancement of these inhibitors towards clinical studies in a few short years.

  • The increased understanding of the importance of epigenetic memory in immune system diseases together with the availability of novel epigenetic drugs will lead to the imminent and inevitable transition of these molecules into autoimmune and inflammatory disease clinical trials.


Immune-mediated diseases are clinically heterogeneous but they share genetic and pathogenic mechanisms. These diseases may develop from the interplay of genetic factors and environmental or lifestyle factors. Exposure to such factors, including infectious agents, is associated with coordinated changes in gene transcription owing to epigenetic alterations. A growing understanding of how epigenetic mechanisms control gene expression patterns and cell function has been aided by the development of small-molecule inhibitors that target these processes. These chemical tools have helped to reveal the importance of epigenetics in guiding cell fate decisions during immune responses and have also highlighted the potential for targeting epigenetic mechanisms for the treatment of inflammation and immune-mediated diseases. In this Review, we discuss the most advanced areas of epigenetic drug development for autoimmune and inflammatory diseases and summarize the promising preclinical data in this exciting and evolving field. These agents will inevitably begin to move into clinical trials for use in patients with immune-mediated diseases.

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Figure 1: Regulation of gene transcription by DNA methylation.
Figure 2: Epigenetic modifications linked to activation-induced alterations in gene expression in immune cells.
Figure 3: BET bromodomain inhibitors target multiple mechanisms associated with rheumatoid arthritis.


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The authors thank members of the Epinova Discovery Performance Unit and Tarakhovsky laboratory for helpful discussions and sharing of informative unpublished data.

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Corresponding author

Correspondence to Rab K. Prinjha.

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Competing interests

D.F.T., P.P.T. and R.K.P. are employees and shareholders of GlaxoSmithKline, which is involved in Research and Development of epigenetic inhibitors for the treatment of disease. A.T. has received research support and consultancy payments from GlaxoSmithKline.

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CpG dinucleotides

Sequences of DNA in which a cytosine nucleotide is followed by a guanine nucleotide in the 5′ → 3′ direction. CpG islands are regions with a high frequency of CpG sites, and are most frequently found near gene promoters.

Innate immune cells

White blood cells that mediate innate immunity and include basophils, dendritic cells, eosinophils, Langerhans cells, mast cells, monocytes, macrophages, neutrophils, innate lymphoid cells and natural killer cells. Innate immune cells use germ line-encoded receptors to recognize evolutionarily conserved features of pathogens.

Adaptive immune cells

White blood cells, including T cells and B cells, that express highly diverse antigen receptors that confer exquisitely specific recognition of proteins. Based on the clonal distribution of these receptors, which are generated through somatic recombination of variable gene segments, T cell and B cell populations are able to adapt to changing protein sequences associated with pathogen evolution.

Major histocompatibility complex

(MHC). A cluster of genes encoding proteins that are important for lymphocyte activation. MHC molecules bind to small fragments of proteins from inside a cell and present these at the cell surface. By scanning MHC molecules, lymphocytes can assess cells for signs of infection or damage.

Effector T cell subsets

Activated T cells that express specialized functions linked to defence against different types of pathogen, and which are commonly defined by their production of particular cytokines. The best characterized effector T cell subsets include T-helper 1 (TH1) (interferon-γ (IFNγ)), TH2 (interleukin-4 (IL-4), IL-5 and IL-13) and TH17 (IL-17A and IL-17F).


A small protein released by cells that typically affects the behaviour of other cells through binding to specific receptors. Cytokines can stimulate diverse functional responses and have a key role in controlling the function of the immune system. Certain pro-inflammatory cytokines (for example, tumour necrosis factor and interleukin-6) have been shown to have a causative role in human inflammatory disease, whereas others (for example, IL-10) have an anti-inflammatory function.

Regulatory T cells

(Treg cells). A special subset of T cells that prevent other immune cells from attacking the body's own tissues and other harmless environmental materials, such as food and commensal organisms. Defects in Treg cells cause severe inflammatory and autoimmune disease.

Peripheral blood mononuclear cells

(PBMCs). Cells found in the circulating blood that have round nuclei, including lymphocytes (T cells and B cells), monocytes, macrophages and dendritic cells.

SLE disease activity index

(Systemic lupus erythematosus disease activity index). Composite scoring system derived from a list of clinical symptoms and laboratory tests that is used to evaluate the activity of lupus in clinical studies, primarily for the purpose of determining whether a new drug evaluated for the disease is effective.


A class of cytokine proteins that regulate immune and inflammatory responses primarily by modulating cell migration properties and localization of target cells such as leukocytes. The biological functions of chemokines are typically mediated by signalling through G protein-coupled chemokine receptors.

Allogeneic haematopoietic cell transplantation

The transplantation of multipotent haematopoietic stem cells, usually derived from bone marrow, peripheral blood or umbilical cord blood, in which the major histocompatibility complex (MHC) of the recipient differs from that of the donor. The MHC mismatch causes donor and recipient immune cells to respond to one another, potentially resulting in graft rejection (recipient responding to donor) or graft-versus-host disease (donor responding to recipient).

Hyper-IgD and periodic fever syndrome

(HIDS). A periodic fever syndrome, characterized by attacks of fever, joint pain and skin lesions, which is associated with elevated blood levels of the immunoglobulin D (IgD) subclass of immunoglobulin.

Schnitzler syndrome

An autoimmune and inflammatory disorder characterized by chronic hives and periodic fever, bone and joint pain, weight loss, fatigue, swollen lymph glands and an enlarged spleen and liver.


A large multiprotein complex, comprising > 30 subunits, that binds to and relays information from transcription factors and is required for gene transcription by RNA polymerase II.


A protein complex containing the cyclin-dependent kinase CDK9 and one of several cyclin subunits (cyclin T1, T2 or K) that has an essential role in the regulation of gene transcription by RNA polymerase II (Pol II). CDK9-mediated phosphorylation of both negative regulators of Pol II and subunits of Pol II itself allow for the productive transcriptional elongation of mRNAs by Pol II.

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Tough, D., Tak, P., Tarakhovsky, A. et al. Epigenetic drug discovery: breaking through the immune barrier. Nat Rev Drug Discov 15, 835–853 (2016).

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