Cambridge Healthtech Institute’s Emily Le, PhD recently spoke with Mihai G. Netea, PhD, Professor, Internal Medicine at Radboud University Medical Center, The Netherlands about his upcoming keynote presentation “Therapeutic Targeting of Trained Immunity”, to be delivered at the Targeting Innate Immunity Congress.

PRESENTATION: WEDNESDAY, SEPTEMBER 25 AT 9:00 AM

KEYNOTE PRESENTATION: Therapeutic Targeting of Trained Immunity

I will share my thoughts and vision of how to target innate immune cells and regulate trained immunity to achieve long-term therapeutic benefits in a range of immune-related diseases. These include conditions characterized by excessive trained immunity, such as inflammatory and autoimmune disorders, allergies and cardiovascular disease and conditions driven by defective trained immunity, such as cancer and certain infections.

Q. Please tell us a bit about your background and your current role

I was born and studied medicine in Cluj-Napoca, Romania. After finishing my medical studies, I worked on a PhD project on the regulation of proinflammatory cytokines in sepsis at the Radboud University Nijmegen, The Netherlands. After finishing my PhD, I worked as a post-doc at the University of Colorado in the laboratory of Prof. Charles Dinarello, on the novel proinflammatory cytokines IL-18 and IL-32. After returning to Nijmegen, I completed my clinical training as an infectious diseases specialist. Currently, I work as an internist and infectious diseases specialist and I head the division of Experimental Medicine, Department of Internal Medicine, Nijmegen University Nijmegen Medical Center.

Q. What is your current research interest?

My main research interests are the understanding the factors influencing variability of human immune responses, the biology of sepsis and immunoparalysis in bacterial and fungal infections, and the study of the memory traits of innate immunity.

Q. Can you tell us the story of when and how you discovered “trained immune system”?

The discovery of trained immunity was made after a chance observation. At the beginning of 2010, we assigned a small project to a young and ambitious undergraduate student: the project was aimed to assess the impact of BCG vaccination on Toll-like receptor expression and its impact on specific anti-mycobacterial immune responses. She performed a series of studies with blood donated by students who were vaccinated with BCG before their departure for internships in developing countries. As expected, the specific interferon-g (IFNg) response toward M. tuberculosis was strongly increased 2 weeks after BCG vaccination. As a non-related stimulus, intended as a negative control not to be affected by BCG, we used C. albicans; the choice was simply due to the availability of the stimulus, which was being used for the other projects ongoing in the lab. Surprisingly, the response to C. albicans was also strongly upregulated; even more, this was the case not only for the production of lymphocyte-derived IFNg, but also for the monocyte-derived interleukin-1b (IL- 1b) and tumor necrosis factor (TNF). Suspicious of either a chance finding or potential mistakes during this first small study, we asked for permission from the ethical committee to extend the experiment and double the number of participants. When we validated the observation in these additional participants we were forced to conclude the obvious: that BCG vaccination has strong non- specific effects that extend to the immune response against pathogens other than mycobacteria. Confronted with this finding, we initiated a comprehensive search of the literature that taught us that many such non-specific effects of BCG had been previously reported in human and murine studies. This literature strongly suggested that these nonspecific effects of BCG are not mediated by specific lymphocyte- mediated mechanisms, but possibly through non-specific adaptation within innate immunity. We started to work on this hypothesis, and 2 years later we were able to validate it and described the mechanisms responsible for these effects.

Q. What is the significance of this discovery?

I hope that this discovery opens new ways in which we study and understand the innate immune response, and host defense in general. This process has also the potential to a new understanding of hyperinflammatory and autoimmune diseases, and it may represent a therapeutic target. Finally, we hope that its beneficial effects can be integrated to improve the efficacy of vaccines.

Q. What are your thoughts on the race between adaptive and innate immune-based therapy?

I do not see this as a race, but rather a complementary quest for innovative therapies. I think that many diseases will be treated by various combinations of immunotherapies targeting both innate and adaptive immune mechanisms.

Q. What advice do you have for young scientists who are entering this field?

Be open to the unexpected, and do not easily dismiss experiments which give you answers that were not initially expected.

Q. As the Targeting Innate Immunity Congress is approaching, what presentations or sessions are you looking forward to the most? (final agenda is here)

I am looking forward to the entire conference, but personally from my research interests I am looking forward to the sessions on targeting myeloid cells for immunotherapy.

SPEAKER BIOGRAPHY:

Mihai G. Netea, PhD, Professor, Internal Medicine, Radboud University Medical Center, The Netherlands

Mihai Netea was born and studied medicine in Cluj-Napoca, Romania. He completed his PhD at the Radboud University Nijmegen, The Netherlands, on studies investigating the cytokine network in sepsis. After working as a post-doc at the University of Colorado, he returned to Nijmegen where he finished his clinical training as an infectious diseases specialist, and where he currently heads the division of Experimental Medicine, Department of Internal Medicine, Nijmegen University Nijmegen Medical Center. He is mainly interested in understanding the factors influencing variability of human immune responses, the biology of sepsis and immunoparalysis in bacterial and fungal infections, and the study of the memory traits of innate immunity. He is the recipient of the Spinoza Prize 2016, and an ERC Advanced grant in 2019.