Towards Small Molecule Drugs that can Induce Trained Immunity
Trained immunity is a phenomenon whereby some forms of vaccination can produce a broad improvement in defenses against pathogens, perhaps via a lasting suppression of the chronic inflammation generated by the innate immune system in old age. The innate immune system reacts in a maladaptive way to some of the forms of damage characteristic of aging, such as mislocalization of fragments of mitochondrial DNA. The mechanisms by which trained immunity produces a reduction in this maladaptive reaction are not well understood, but nonetheless, researchers here report on progress towards identifying small molecule inducers of trained immunity. Given a good side-effect profile and low cost, such small molecule drugs could be broadly beneficial.
Trained immunity is characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenges, providing nonspecific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite its promise for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as β-glucan or the Bacillus Calmette-Guérin (BCG) vaccine. This limited collection of training compounds also limits the study of the genes most involved in training responses as each molecule has both training and nontraining effects.
Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future applications. To identify small molecule inducers of trained immunity, we screened a library of 2,000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over two dozen small molecules in several chemical classes that induce a training phenotype in the absence of initial immune activation - a current limitation of reported inducers of training. A surprising result was the identification of glucocorticoids, traditionally considered immunosuppressive, providing an unprecedented link between glucocorticoids and trained innate immunity. We chose seven of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating alternative avenues for studying and applying innate immune training.