The building block of "happiness hormone" activates immune cells

For decades, scientists have been trying to uncover the various mechanisms of our immune system. The findings lead to a new era of cancer treatment in recent decades. If the immune system can be specifically activated, the body can defend itself against cancer cells and other invaders. For this approach, which has transformed cancer therapy, this year's Nobel Prize for Medicine. The international research team led by Josef Penninger of Vienna IMBA and Clifford Woolf of Boston Children's Hospital in Harvard brings a whole new insight into the biology of immune cells that promise extremely versatile medical applications.

Keyplayer for an immune response

An amazing thing: our body's immune cells, called T-cells, are activated by a molecule that plays an important role in metabolism in our nervous system. So far it has been known that tetrahydrobiopterin or BH4 is needed to produce messengers such as the "good fortune" serotonin and dopamine. "The fascinating thing about our discovery is that a system that is actually known in neurobiology can play such a key role in the immune defense of T cells," says Josef Penninger, founding director of IMBA and the last author of the current publication in Nature. "This new approach links two completely different systems in our body and differs from all of the previously known immune control points. In addition, treatment options are wide: from autoimmune diseases, asthma and allergies to cancer!"

BH4 is involved in many metabolic processes in our body. Since the 1980s, it has also been known that people with iron deficiency or anemia often suffer from immune problems, but this relationship can not be explained. Now we know why: BH4 controls the growth of T cells, "the soldiers of our immune system", through regulation of iron metabolism and mitochondrial functions – cellular power plants.

T cells guard our body and expose pathogens or degenerate cells that can become tumors. At such meetings, T cells are activated, multiplied, and attacked to feel intruders or targeted cancer cells. Often the problem is that poorly activated T cells are directed against the body's own cells – this is the case for allergic reactions and autoimmune diseases such as colitis, asthma, multiple sclerosis, arthritis or certain skin diseases.

Hattrick: Clinical use against autoimmune diseases, allergies and cancer

"Autoimmune diseases and allergies are among the most common emerging diseases around the world and are urgently needed, and our discovery can be extremely useful." Inhibition of BH4 inhibits a constant way of seizure of these autoaggressive T cells, preventing them from destroying healthy tissues or causing chronic inflammation, said Shane Cronin, a postdoctoral colleague at IMBA and the first author of the current Nature publication. Together with Clifford Woolf of Boston Children's Hospital in Harvard and Kai Johnsson of the Max Planck Institute for Medical Research in Heidelberg, scientists developed a new drug called QM385 that inhibits BH4 and dampens immune cells in violent excessive reactions. First clinical trials are in operation.

BH4 is also an important candidate for future cancer immunotherapy because activated T cells feel and fight against cancer cells. Scientists have found in mice that BH4 helps T cells target the target tumor. In addition, it has been shown that BH4 is blocked by kynurenin, a molecule that can disable the immune system in tumors. Administration of BH4 causes T cells to grow again.

"Knowledge of new biology and disease relationships is particularly valuable because applications can be very versatile. Who would think that our immune system could be controlled by a molecule known from neurobiology and could lead to new applications against autoimmune diseases, asthma , cancer and immunodeficiency? "says Shane Cronin. "If you can find a connection between different biological systems in the body, such as the nervous system and the immune system, you can sometimes make amazing discoveries." In the past, the team around Joseph Penninger, for example, using the RANKL signaling pathway, has succeeded in linking bone metabolism and the hormonal system. Treatment with the resulting Denosumab drug ranges from bone loss to a breast cancer pill that is currently being tested in Austria.

Original publications:
"Metabolite BH4 controls T cell proliferation in autoimmunity and cancer", Cronin et al. Nature, 2018, DOI: 10.1038 / s41586-018-0701-2

This research project is a collaboration of the following institutions: IMBA – Institute of Molecular Sciences of the Austrian Academy of Sciences, Department of Neurobiology, Harvard Medical School, Boston, USA; FM, Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA USA, Institute for Experimental and Clinical Traumatology Ludwig Boltzmann, Institute for Molecular Medicine, University Medical Center Johannes Gutenberg University Mainz in Germany, Institute of Internal Medicine II (Infectious Diseases) Immunology, Rheumatology and pneumology), Innsbruck Medical University, Austria, Institute of Chemical Sciences and Engineering, Institute of Bioengineering, National Center for Competence in Research (NCCR) in Chemical Biology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford University in the UK, Wellcome Trust Center for Human Genetics, Roosevelt Drive, University of Oxford, UK, Department of Gastroenterology and Heart Center, Beth Israel Deaconess Medical Center (BIDMC) and Harvard University doctors (HMS), Harvard University, Boston, MA, USA, LABOX, Department of Bioquimica, Federal University of Santa Catarina, Florianopolis, SC, Brazil. Research Institute of Molecular Pathology IMP, Vienna, Austria, Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolic Research, Cologne, Germany, Department of Neuroscience, Research Center CHU de Quebec – Université Laval, Quebec QC Canada, Department of Molecular Medicine, , University of Laval, Quebec QC Canada, Karolinsky Institute, Solna Medical Clinic, Center of Molecular Medicine, Carolina University Hospital Solna, Stockholm, Sweden, Department of Neurosurgery, Johns Hopkins Medical School, Baltimore, USA Apeiron Biologics AG, 400 Technology Square, Cambridge, USA, Department of Anesthesia, Harvard Medical School, Boston, USA; Boston Children's Hospital, Boston, USA, Department of Pharmacology and Physiology, University of Montreal, Montréal, QC, Canada, Max Planck Institute for Medical Research, Department of Chemical Biology, Heidelberg, Germany

scientific contact:
Ines Méhu-Blantar
Senior Communications Manager
IMBA – Institute of Molecular Biotechnology GmbH
Dr. Bohr-Gasse 3, 1030 Vienna
M: +43 664 808473828
E: [email protected]

Original publications:
"Metabolite BH4 controls T cell proliferation in autoimmunity and cancer", Cronin et al. Nature, 2018, DOI: 10.1038 / s41586-018-0701-2

idw 2018/11

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