Clinical bottom line
Emerging therapies targeting trained immunity represent a novel approach to modulating innate immune memory mechanisms implicated in autoimmune diseases. Early preclinical and translational studies suggest these interventions may recalibrate dysregulated innate immune responses, potentially reducing chronic inflammation and autoimmunity. However, clinical evidence remains limited, and safety profiles are not fully established. These therapies warrant cautious optimism as putative adjuncts or alternatives to conventional immunosuppressants, pending validation in rigorously designed clinical trials.
What the evidence shows
Trained immunity refers to the epigenetic and metabolic reprogramming of innate immune cells, such as monocytes and macrophages, resulting in a heightened or altered inflammatory response upon re-exposure to stimuli. This concept challenges the classical view that immunological memory is exclusive to adaptive immunity and implicates trained immunity in the pathogenesis of several autoimmune diseases (Municio et al., 2021).
Therapeutic strategies under investigation aim to modulate trained immunity by targeting metabolic pathways (e.g., glycolysis, cholesterol synthesis), epigenetic regulators (e.g., histone modification enzymes), or pattern recognition receptor signaling. Municio et al. (2021) provide a comprehensive review of agents such as inhibitors of the NOD2 receptor, modulators of the mTOR pathway, and epigenetic drugs that have shown promise in preclinical autoimmune models. These approaches may reduce the proinflammatory phenotype of trained innate cells, thereby dampening chronic tissue inflammation characteristic of diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS).
While direct clinical trial data on trained immunity-targeting therapies in autoimmune patients are sparse, the mechanistic rationale is supported by translational studies demonstrating aberrant trained immunity signatures in patient-derived monocytes and macrophages. Chatenoud et al. (2020) highlight the potential of combining these novel agents with existing biologics to enhance efficacy and reduce adverse effects by more precisely modulating innate immune activation.
Safety considerations remain paramount. Given the role of trained immunity in host defense against infections, therapies dampening this response could increase susceptibility to opportunistic infections. Municio et al. (2021) emphasize the need for careful dose optimization and monitoring in early-phase trials.
Caveats and uncertainty
The field of trained immunity in autoimmunity is nascent, and many proposed therapies remain at the preclinical or early translational stage. There is a paucity of randomized controlled trials directly assessing clinical efficacy and safety in autoimmune populations. Most data derive from in vitro studies or animal models, which may not fully recapitulate human disease complexity.
Heterogeneity among autoimmune diseases and patient subsets complicates extrapolation. The extent to which trained immunity contributes to disease activity versus adaptive immune dysregulation varies, potentially limiting the generalizability of these therapies. Long-term effects on immune competence and infection risk are unknown.
Furthermore, the interplay between trained immunity and existing immunomodulatory treatments is not well characterized. Potential drug-drug interactions and additive immunosuppression require systematic evaluation.
How this may change practice
If ongoing and future clinical trials confirm safety and efficacy, therapies targeting trained immunity could expand the therapeutic armamentarium for autoimmune diseases by addressing innate immune dysregulation. This may be particularly relevant for patients refractory to conventional biologics or those with contraindications to broad immunosuppression.
Integration of trained immunity modulators could facilitate more personalized treatment strategies, especially if biomarkers identifying patients with prominent innate immune activation are developed. Combination regimens incorporating these agents might improve disease control while minimizing adverse effects.
Clinicians should remain informed about emerging data but exercise caution until robust clinical evidence is available. Participation in clinical trials evaluating these therapies should be encouraged to accelerate knowledge generation.