“Training” of precursors of white blood cells leads to a sustained positive response of the hematopoietic system. This effect could help accelerate the formation of new white blood cells, which are vitally needed during chemotherapy, a process that can slow down hematopoiesis. In a publication that appeared in the prestigious journal Cell, the scientists Dr. Ioannis Mitroulis and Prof. Triantafyllos Chavakis of the Institute of Clinical Chemistry and Laboratory Medicine of the University Hospital Carl Gustav Carus at the TU Dresden together with international colleagues describe this groundbreaking training effect on the innate immune system, which could be exploited therapeutically to prevent specific side effects of chemotherapy.

Two main systems protect us from infections, the innate and the adaptive immunity. Innate immunity acts rapidly as the first line of defense to buy time until adaptive immunity is activated and takes over. Adaptive immunity targets and clears the pathogen in a very specific fashion and builds up immunological memory. In this way, the adaptive immune response ‘remembers’ the earlier infection and responds faster and stronger when it re-encounters the same pathogen in the future.

Although immunological memory has been considered to be an exclusive property of adaptive immunity, this dogma has been recently challenged by several research groups including Prof. Netea’s laboratory (Nijmegen, The Netherlands). In particular, certain microbial infections or vaccines promote an enhanced response of white blood cells of innate immunity to a secondary infection with the same or even different pathogens. This process of innate immunological memory has been termed trained innate immunity, because white blood cells need to be ‘trained’ with appropriate stimuli (such as pathogen-derived molecules or vaccines) to be able to respond faster and stronger against future infections. Trained innate immunity has impressive long-term effects (up to months), which has been puzzling since white blood cells (such as monocytes) have a relatively short life in the circulation. This paradox has now been resolved by a study spearheaded by the Institute for Clinical Chemistry and Laboratory Medicine of the University Clinic Dresden, Germany. This study has shown for the first time that trained innate immunity acts on the precursors of the circulating white blood cells in the bone marrow, known as hematopoietic stem and progenitor cells (HSPCs). As HSPCs can give rise to many generations of white blood cells, the study may explain the long-term effects of trained innate immunity.

The research team of Prof. Chavakis (director of the Institute for Clinical Chemistry and Laboratory Medicine of the University Clinic Dresden) investigated together with the group of Prof. Hajishengallis (University of Pennsylvania, Philadelphia, PA, USA) and Prof. Netea (Radboud University, Nijmegen, The Netherlands) the actions of beta-glucan, a molecule found in the cell walls of fungi and plants and a prototype stimulus of trained immunity, on precursor cells in the bone marrow. They found that the innate immune training of HSPCs by beta-glucan resulted in a sustained beneficial response by the hematopoietic system. This beneficial response involved actions of the inflammatory cytokine interleukin-1beta and changes in the metabolism (especially lipid metabolism) of HSPCs.

This beta-glucan-mediated beneficial response could be used to protect the bone marrow from the adverse effects of chemotherapy. Chemotherapy-associated myelosuppression (suppression of the generation of white blood cells in the bone marrow) is a common and serious complication in tumor patients being treated with chemotherapy. “We think that the principle of trained immunity could be used to prevent such adverse effects of chemotherapy”, says Dr. Mitroulis, the first author of this article, from the Institute for Clinical Chemistry and Laboratory Medicine of the University Clinic Dresden, who has recently been awarded junior group leader status at the National Center for Tumor Diseases Dresden. Hence, the findings indicate a possible strategy to pre-condition the immune system prior to administration of chemotherapy to prevent myelosuppression and leukopenia. “It is also conceivable that this principle may find therapeutic application in malignant hematologic diseases”, Prof. Chavakis added. The group plans to follow up on their work into this and other directions, including inflammatory disease.  

The work was supported by the European Research Commission (Grant DEMETINL), the Deutsche Forschungsgemeinschaft (grants CH279/5-1, TR-SFB127, SFB854/B26N) and the National Institutes of Health (grants DE024716 and DE026152).

Publication:
Modulation of Myelopoiesis Progenitors Is Integral Component of Trained Immunity
Mitroulis et al., 2018, Cell, January 11, 2018
DOI: http://dx.doi.org/10.1016/j.cell.2017.11.034

Contact:
Prof. Dr. T. Chavakis
Director, Institute of Clinical Chemistry and Laboratory Medicine
University Hospital Dresden at the TU Dresden
Fetscherstrasse 74, 01307 Dresden
https://www.uniklinikum-dresden.de/de/das-klinikum/kliniken-polikliniken-institute/ikl

Dr. I. Mitroulis
Institute of Clinical Chemistry and Laboratory Medicine
University Hospital Dresden at the TU Dresden
Fetscherstrasse 74, 01307 Dresden
and
Junior Research Group Leader at the National Center for Tumor Diseases (NCT) Dresden