The building block of "happiness hormone" activates immune cells

For decades, researchers have been trying to discover the various mechanisms of our immune system. In recent decades, we have paved the way for a new era of cancer treatment: if your own immune system can be specifically activated, the body can defend itself against cancer cells and other invaders. For this approach, which revolutionized cancer therapy, there was the Nobel Prize for Medicine this year. Now, an international research team led by Josef Penninger of IMBA Vienna and Clifford Woolf of the Boston Children's Hospital at Harvard brings new insights into the biology of immune cells, which promise medical applications extremely versatile.

Keyplayer for the immune response

The amazing thing about this: The immune cells of our body, called T cells, are activated by a molecule that plays an important role in the metabolism of our nervous system. Until now, it was known that tetrahydrobiopterin, or BH4, was necessary for the production of messengers such as the "happiness hormone", serotonin and dopamine. "What is fascinating in our discovery, is that a system known in neurobiology can play such an important role in the immune defense of T cells," said Josef Penninger, founding director of the company. IMBA and last author of the current publication in the journal Nature. "This new approach links two completely different systems in our body and differs from all previously known immune control points, and the treatment options are varied: from autoimmune diseases to asthma and allergies. to cancer! "

BH4 is involved in many metabolic processes of our body. Since the 1980s, it was also known that people with iron deficiency or anemia often had immune problems, but this relationship could not be explained. We now know why: BH4 controls the growth of T cells, the "soldiers of our immune system," through the regulation of iron metabolism and mitochondrial function – the power plants of cells.

T cells patrol our body and expose pathogens or degenerate cells that could become tumors. During such encounters, the T cells are activated, they multiply and move to a kind of attack mode to target intruders or targeted cancer cells. Often a problem: incorrectly activated T cells are directed against the body's own cells – this occurs for example in 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 in the world and urgently needed treatments.Here our discovery can be extremely helpful.The inhibition of BH4 inhibits the mode of And the constant attack of these self-aggressive T cells, preventing them from destroying healthy tissue or causing chronic inflammation, "said Shane Cronin, a postdoctoral fellow at IMBA and first author of the current publication in Nature. In collaboration with Clifford Woolf of the Boston Children's Harvard Hospital and Kai Johnsson, of the Max Planck Institute for Medical Research in Heidelberg, researchers have developed a new drug called QM385, which inhibits BH4, and "tames" immune cells during violent, excessive reactions. The first clinical trials are in sight.

BH4 is also an important candidate for future cancer immunotherapies because activated T cells detect and fight cancer cells. Researchers have now found in mice that BH4 helps T cells target the targeted tumor. In addition, kynurenine, a molecule capable of disabling the immune system in tumors, has shown that BH4 is blocked. The administration of BH4 causes new growth of T cells.

"Knowledge of new relationships in biology and emerging diseases is particularly valuable because applications can be very versatile, who would have thought that our immune system could be controlled by a molecule known in neurobiology and could eventually lead to new applications against autoimmune diseases, asthma, cancer and immune deficiency? ", explains Shane Cronin. "If you can find cross connections between different biological systems of the body, such as the nervous system and the immune system in this case, you can sometimes make amazing discoveries." In the past, the team around Josef Penninger, for example, using the RANKL signaling pathway, has successfully linked bone metabolism to the hormonal system. Denosumab, a resulting drug, is used in therapy, from bone loss to the bad cancer pill, which is being tested in Austria.

Original publication:
"The BH4 metabolite 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, USA, Ludwig Boltzmann Institute of Experimental and Clinical Traumatology, Institute of Molecular Medicine, University Medical Center of Johannes Gutenberg University Mainz, Germany, Department of Internal Medicine II (Infectious Diseases) Immunology, Rheumatology and Pneumology), University of Medicine Innsbruck, Austria, Institute of Chemical Sciences and Engineering, Institute of Bioengineering, National Research Center (NRP) in Chemical Biology, School Federal Polytechnic of Lausanne (EPFL), Lausanne, Switzerland Division of Cardiovascular Medicine, British Center for Research Excellence of the British Heart Foundation, John Radcliffe Hospital, Oxford University, United Kingdom, Center for Wellcome Trust Human Genetics, Roosevelt Drive, University of Oxford, UK, Division of Gastroenterology and Liver, Dep Medical Medicine Center Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS), Harvard University, Boston, MA, USA, LABOX, Department of Bioquimica, Federal University of Santa Catarina, Florianopolis, SC, Brazil. Institute for Research in Molecular Pathology IMP, Vienna, Austria, Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany, Department of Neuroscience, CHU de Québec Research Center – Laval University, Quebec QC Canada, Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec QC Canada, Karolinska Institute, Department of Solna Medicine, Center for Molecular Medicine, Karolinska Solna University Hospital, Stockholm, Sweden, Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, United States Apeiron Biologics AG, Vienna, Austria, Quartet Medicine, 400 Technology Square, Cambridge, United States, Department of Anesthesia, Harvard Medical School, Boston, United States; Boston Children & # 39; s Hospital, Boston, USA, Department of Pharmacology & Physiology, University of Montreal, Montreal, QC, Canada, Max Planck Institute for Medical Research, Department of Chemical Biology, Heidelberg, Germany

scientific contact:
Ms. Ines Mehu-Blantar
Senior Communications Officer
IMBA – Institute of Molecular Biotechnology GmbH
Dr. Bohr-Gbade 3, 1030 Vienna
M: +43 664 808473828
E .: [email protected]
www.imba.oeaw.ac.at

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

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