Autoimmune diseases are caused by our immune system attacking cells or tissues of our own body. This happens when antibodies or T lymphocytes recognize proteins in our organs and disrupt their function. The result can be one of many common ailments such as rheumatism, multiple sclerosis, Crohn’s disease and diabetes. It was recently discovered that a large protein complex – the immunoproteasome – plays a role in the development of these diseases. Inhibitors are now being developed by the pharmaceutical industry to fight immunoproteasomes as a new way of treating autoimmune disease. The Steinbeis Transfer Center for Immunoproteasome Drug Targeting, which was founded at the University of Konstanz in 2011, is providing important support in this area.
The most exciting and often the most rewarding experiments are the ones where something completely unexpected is discovered. Research has already been underway for 20 years into immunoproteasomes – a large, cylindrical protein complex which breaks down proteins in cells. Immunoproteasomes can be found in our white blood cells but they are also significantly up-regulated in other tissues when they become inflamed. The only previously understood function of immunoproteasomes was that they fragmented proteins from viruses and bacteria. These fragments are needed to stimulate killer T cells which kill off infected cells and thus prevent the spreading of viruses or bacteria. A bit of a damper was put on immunologists’ initial enthusiasm, however, when the gene for the immunoproteasomes was switched off in genetically modified mice: The so-called immunoproteasome knock-out mice still had no difficulty fighting infections caused by viruses or bacteria.
As people ran around flapping, Jacqueline Möbius and Dr. Michael Basler at the Chair of Immunology at the University of Konstanz were working on a key experiment with an eye-opening outcome. They removed T lymphocytes from an immunoproteasome knock-out mouse and a control mouse and transferred them to a virus-infected mouse. Whereas the T cells from the control mouse multiplied in the infected recipient mouse, the T cells from the immunoproteasome-deficient mouse could no longer be found in the infected recipient mouse.
At first the researchers thought they had made a mistake, but they kept repeating the result: T cells that are lacking immunoproteasomes cannot survive in a virus-infected mouse, but they can in a recipient mouse that was not infected. Out of this chance discovery, an idea was born: if T cells need immunoproteasomes to survive infections, inhibiting immunoproteasomes could check T cells in an undesired inflammation – such as autoimmune diseases. As they were mulling over the results, a call came in from Dr. Chris Kirk at a small startup company from San Francisco called Proteolix. He had developed the world’s first specific immunoproteasome inhibitor, although his goal had been to use it to treat a type of leukemia (multiple myeloma). He did not achieve what he had set out to do, but his immunoproteasome inhibitor, PR-957, allowed the scientists from Konstanz to test their hypothesis.
Working in collaboration with Proteolix, the research colleagues of Prof. Dr. Marcus Groettrup – all part of the Chair of Immunology at the University of Konstanz – were successful in showing that PR-957 (now known as ONX 0914) prevents the formation or progression of a number of autoimmune diseases in preclinical mouse models, such as diabetes, rheumatism, and multiple sclerosis. The scientists proved that inhibiting immunoproteasomes suppresses the production of inflammatory transmitters through the white blood cells which sustain these diseases. Shortly after the results were published in Nature Medicine in 2009, the team received the first collaboration queries from pharmaceutical companies and these were too much to manage under the auspices of academic research within the department. To do justice to interest in the development of testing methods to seek out further and better immunoproteasome inhibitors, in 2011 Marcus Groettrup set up the Steinbeis Transfer Center for Immunoproteasome Drug Targeting. In addition to providing scientific advice, the center helps with the validation of new immunoproteasome inhibitors and provides support on the testing of substances in cellular test systems in in-vitro and in preclinical models. The center also works on consulting projects and collaborative scientific research. Exchanging experiences with industry is extremely valuable to the university chair. The students come into contact with pharmaceutical companies, opening the door to possible internships in industry, and there have also been job offers. The Steinbeis transfer center also provides ways to generate enthusiasm for the new treatment approach and makes it easier to trial new immunoproteasome inhibitors by providing technical and scientific support. If the efficacy could be proven among patients within the coming years, not only would it be a chance for patients and pharmaceutical companies, scientific research into the impact of immunoproteasomes on autoimmunity would also benefit strongly.
Prof. Dr. Marcus Groettrup is director of the Steinbeis Transfer Center for Immunoproteasome Drug Targeting at the University of Konstanz. The transfer center provides support with the development of tests for high-throughput searches for immunoproteasomes and inhibitor validation. It is also involved in scientific consulting projects and technical support for pharmaceutical companies.
Prof. Dr. Marcus Groettrup
Steinbeis Transfer Center Immunoproteasome drug targeting (Konstanz)
Marcus.Groettrup@stw.de