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Trained Immunity: RoadMap for drug discovery and development
https://doi.org/10.7554/eLife.108465
General background on Trained Immunity
Trained Immunity as a therapeutic target
Molecular targets and their challenges
RoadMap to DDD in Trained Immunity
Trained Immunity is the nonspecific (pathogen agnostic) memory of innate immune cells, characterized by altered responses upon secondary stimulation. This review provides a RoadMap for the discovery and development of therapeutics targeting Trained Immunity, aimed at researchers with strong scientific backgrounds but limited drug development experience. The article outlines five drug development domains – epigenetic, metabolic, differentiation, inflammatory, and memory changes – that guide the identification of molecular targets, model selection, and biomarker development for the discovery and development of Trained Immunity-based therapeutics. It emphasizes the application of preclinical models and artificial intelligence in target discovery and compound screening. Additionally, the review addresses challenges in translating preclinical Trained Immunity findings to clinical trials and highlights relevant disease indications and ongoing clinical trials. This review integrates scientific findings with development strategy and thereby aims to bridge the gap between discovery and clinical application, advancing the field of Trained Immunity-based therapeutics.
This article serves as a focused RoadMap for discovering and developing new medicines within the field of Trained Immunity. It is of particular interest to those who are looking to translate their novel scientific discoveries into new treatments targeting Trained Immunity, rather than a systematic review. The content is specifically designed for individuals who may be unfamiliar with the translational aspects of drug discovery and development (DDD), but are experts in Trained Immunity.
The objective is to support and guide non-pharma experts in converting their scientific breakthroughs into impactful medicines that address unmet needs in diseases influenced by Trained Immunity.
Trained Immunity is the long-lasting altered functional state of innate immune cells and is the immunologic memory of the innate immune system (
). Via Trained Immunity, innate immune cells show an altered immunologic response after a second, unrelated challenge (
). Trained Immunity is independent of cells of the adaptive immune system and does not need priming or activation via antigens which are required by T cells and B cells (
). Trained Immunity is characterized by altered responsiveness via increased production of cytokines upon secondary stimulation and the upregulation of cell surface receptors. Metabolic and epigenetic changes have an important underlying role that leads to this state of altered responsiveness. Examples of metabolic changes include an increase in glycolysis, changes in oxidative phosphorylation (OxPHOS) and glutaminolysis, altered fatty acid, cholesterol, sphingolipid, and oxylipin synthesis, and increased mitochondrial metabolism (
). Examples of epigenetic changes that underlie the induction of Trained Immunity are histone methylation and histone modifications which remodel the chromatin structure, leading to the change of transcriptionally repressive heterochromatin into transcriptionally permissive euchromatin (
Illustration of Trained Immunity with a focus on the induction of Trained Immunity via Toll-like receptors, Dectin-1, and Nod-like receptor activation.
These receptors are triggered by pathogen-associated molecular patterns (PAMP), and innate immune cells such as monocytes and macrophages are activated to produce inflammatory cytokines. Dectin-1 is the receptor that recognizes β-glucan and thereby initiates β-glucan-induced Trained Immunity. NOD-like receptors recognize Bacillus Calmette-Guérin (BCG) and thereby mediate BCG-induced Trained Immunity. Toll-like receptors recognize various types of PAMPs and can also mediate Trained Immunity (
). The primary immune response to infection is characterized by cytokine production and antigen presentation (
). The primary innate immune response dissipates, and the innate immune cell returns to baseline activation state; however, epigenetic changes, driven by metabolic reprogramming, persist at the chromatin level. This epigenetic reprogramming underlies the induction of Trained Immunity (
). Subsequent restimulation with an unrelated pathogen or immunological trigger initiates a Trained Immunity response that is characterized by adaptive and enhanced effector functions such as increased cytokine production, enhanced antigen presentation, and increased phagocytosis (
). As a secondary effect of Trained Immunity, this may lead to enhanced adaptive immune responses.
Trained Immunity confers nonspecific protection of the host against reinfection. This has been most extensively studied in Bacillus Calmette-Guérin (BCG) vaccination studies. The BCG vaccine was developed to protect against
. It has now been established that the nonspecific protective effects of the BCG vaccine against other infectious diseases are mediated (at least partly) through Trained Immunity. Other studied inducers of Trained Immunity include the cell wall component β-glucan of
and oxidized low-density lipoprotein (oxLDL).
Trained Immunity is divided into central and peripheral Trained Immunity. Central Trained Immunity is the induction of Trained Immunity at the level of the bone marrow, and specifically at the level of hematopoietic stem and progenitor cells (HSPCs). These HSPCs produce innate immune cells such as monocytes. The induction of central Trained Immunity via the reprogramming of HSPCs results in long-term and systemic changes of circulating innate immune cells, with altered responsiveness (
). The BCG vaccine and β-glucan induce central Trained Immunity by introducing epigenetic and metabolic changes in HSPCs (
). Furthermore, the pro-inflammatory cytokine IL-1β also induces central Trained Immunity. In fact, IL-1β plays a central role in the induction of Trained Immunity, both by BCG and β-glucan (
). Thus, the IL-1β pathway presents one of the important targets to mediate Trained Immunity responses, as will be discussed later. Peripheral Trained Immunity occurs outside of the bone marrow and the lymphoid organs. It is a tissue-specific form of Trained Immunity where innate immune cells are ‘trained’ locally and acquire altered responsiveness after a primary stimulus (
). Training of cells residing in these peripheral tissues can also occur in non-immune cells, such as epithelial cells and fibroblasts (
The immunological, metabolic, and epigenetic pathways that underlie the induction of Trained Immunity present potential therapeutic targets for drug discovery. Developing drugs that target the receptors or metabolic and epigenetic processes that mediate Trained Immunity could potentially be used in disease settings that require altered effector functions of innate immune cells, such as during immune paralysis, in cancer, or as a vaccine adjuvant. The BCG vaccine, an inducer of Trained Immunity, is already approved for the treatment of bladder cancer. Downregulating Trained Immunity responses in clinical indications with hyperinflammation, such as rheumatic diseases, may also provide novel therapeutic approaches.
For the purposes of developing a RoadMap to discovery and development of drugs targeting Trained Immunity, we use five drug development domains to facilitate discussing the different aspects of Trained Immunity (
). The drug development domains that we describe and discuss in this review are epigenetic, metabolic, differentiation, inflammatory, and memory changes that together help to describe the effects and aspects of Trained Immunity that are