The future clinical implications of trained immunity

ABSTRACT

Introduction

Trained Immunity (TI) refers to the long-term modulation of the innate immune response, based on previous interactions with microbes, microbial ligands, or endogenous substances. Through metabolic and epigenetic reprogramming, monocytes, macrophages, and neutrophils develop an enhanced capacity to mount innate immune responses to subsequent stimuli and this is persistent due to alterations at the myeloid progenitor compartment.

Areas covered

The purpose of this article is to review the current understanding of the TI process and to discuss its potential clinical implications in the near future. We address the evidence of TI involvement in various diseases, the currently developed new therapy, and discuss how TI may lead to new clinical tools to improve existing standards of care.

Expert opinion

The state of the art in this domain has made considerable progress, linking TI-related mechanisms in multiple immune-mediated pathologies, starting with infections to autoimmune disorders and cancers. As a relatively new area of immunology, it has seen fast progress with many of its applications ready to be investigated in clinical settings.

KEYWORDS:

• Atherosclerosis
• cancer
• inflammation
• trained immunity
• transplantation
• vaccination

Article highlights

• Trained innate immunity refers to long-term modifications of the immune cell reactivity through epigenetic and metabolic changes. It is induced by pattern recognition through mTOR signaling and leads to enhanced subsequent innate immune responses.

• Therapeutic strategies targeting TI can lead to the development of new classes of immunostimulant and immunosuppressive drugs, useful in various clinical settings. The use of TI-based drugs has already been studied in the context of cancer, rheumatoid arthritis, and transplantology.

• Existing vaccines and non-specific immune boosters can lead to heterologous protection, which is explained within the TI framework. It may also contribute to tumor cell removal by increasing the activity of T cells, which is reflected in the effectiveness of BCG in different types of cancer.

• Maladaptive activation of the pathways involved in TI is proposed to be another part of the pathophysiology of autoimmune and inflammatory disorders. The effectiveness of mTOR inhibitors in these pathologies can be partially explained by the inhibition of TI. More efficient strategies that target TI may prove useful as chronic anti-inflammatory medication.

• The use of HDL nanoparticles allows for precise targeting of hematopoietic stem cells. Drugs that both activate and suppress TI, such as MTP10-HDL and mTORi-HDL, show great promise in animal studies.

Declaration of interest

L Joosten declares that he is the scientific founder of Trained Therapeutix Discovery (TTxD) and owns two patents related to trained immunity. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work is supported by a Competitiveness Operational Program Grant of the Romanian Ministry of European Funds (HINT, ID P_37_762; MySMIS 103587). T.O.C. is supported by a grant from the Ministry of Research, Innovation and Digitization, CNCS/CCCDI – UEFISCDI, project number PD-2019-0802, within PNCDI III (Romania).