Helminth products as macrophage “trainers”: a novel therapeutic tool for the treatment of immune mediated diseases

The innate immune system can display characteristics of immunological memory. This phenomenon, termed “trained immunity”, refers to the long-term functional reprogramming of innate immune cells after the encounter with infectious or non-infectious agents that influences their capacity to respond to a secondary stimulus. Many infectious stimuli, including bacterial or fungal cells and their components (LPS, β-glucan, chitin) are considered potent inducers of innate immune memory, enhancing the pro- inflammatory effects of the innate immune system. However, innate immune cells also arbitrate anti- inflammatory responses, therefore following exposure to appropriate cues they can be trained to be anti-inflammatory.

Research in the past decade has highlighted the broad benefits of pro-inflammatory trained immunity for host defence in the context of infectious disease; however, anti-inflammatory trained immunity could on the other hand have a protective influence against the development of immune-mediated diseases, of important therapeutic implications. Diseases mediated by a dysregulated immunity, such as inflammatory bowel disease, rheumatoid arthritis or asthma, are often treated with immunosuppressive drugs, which, although effective, are not voided of serious side effects. We have previously shown that immunomodulatory strategies that, instead of suppressing, promote the body’s natural protective innate immune responses can effectively ameliorate disease progression in models of inflammatory bowel disease.

Innate immune memory may also play a role in the connection between early life exposure to microbes and patterns of disease susceptibility. Of note, epidemiological studies reveal a significantly lower incidence of immune mediated diseases in developing countries with a high prevalence of parasite infections. Thus, it is possible that parasites could induce an anti-inflammatory training program in our immune system that may be key in preventing the development of those conditions.

This project aims to examine the hypothesis that helminth-derived products can effectively induce a training program in macrophages, reprogramming them to be more anti-inflammatory in response to a secondary inflammatory stimulus. A secondary aim in the wider project will be to establish if anti- inflammatory trained immunity induced by helminth products confines a reduced susceptibility to inflammatory bowel disease.