Autoimmune diseases are usually treated with drugs that block the entire immune system, rendering the body very susceptible to all kinds of infections. A team of Constance researchers under the leadership of Prof. Marcus Groettrup has developed a treatment method that only targets part of the immune system and is therefore far better tolerated by patients.
If the immune system is working properly, the body automatically switches on effective immune defence reactions to fend off viruses or other pathogens. However, in people with an autoimmune disease, the patients' immune system attacks itself because it can't tell the difference between healthy tissue and antigens. The most common autoimmune diseases are rheumatoid arthritis, type-1 diabetes, multiple sclerosis and Crohn's disease (an inflammatory bowel disease), which are the result of an overactive immune response by the body against its own cells. This causes severe inflammations, forcing people who suffer from such diseases to take so-called immunosuppressive drugs for the rest of their lives in order to keep the immune system working properly. "Whilst immunosuppressives are effective in the treatment of autoimmune diseases, they often create problems for sufferers. When our immune system is suppressed to alleviate autoimmune diseases, its response against other intruders becomes ineffective," said the immunologist Prof. Marcus Groettrup.
At the University of Constance, Groettrup and his team of five researchers have achieved groundbreaking results, which have provided the key to the selective blocking of parts of the immune system. “It’s no longer a case of ‘all-or-nothing’. The new findings will improve patients’ tolerance to the drug, as it blocks disease progression in a dose-dependent way,” said Prof. Groettrup. How does Prof. Groettrup’s new principle work? The key to this new method is the immunoproteasome (a specific form of the proteasome found in many cells of the immune system) along with a drug that was originally developed for the treatment of leukaemia, PR-957. The immunoproteasome, an enzyme complex with three subunits, is central to the immune defence. When an infection occurs, the immunoproteasome cleaves the bacterial and viral proteins that have attacked a cell, and transports the protein debris to the cell surface where the cell is seen to be infected and is killed by the T-lymphocytes, a highly specialised subgroup of white blood cells. Groettrup and his team found that PR-957 selectively targets a subunit of the immunoprotease in a knock-out mouse experiment. The results were surprising. “These mice had a reduced immune response, but the effects were far less drastic than we had originally assumed,” explains Groettrup. The scientists were particularly surprised to see what happened with the T-lymphocytes, which usually go out of control in people suffering from autoimmune diseases and lead to inflammatory reactions: The T-lymphocytes completely disappeared when the immunoproteasome subunits were removed. This shows that the inhibition of the immunoproteasome can attenuate inflammatory reactions.
After coming across the research results in a scientific publication, a San Francisco-based company called Proteolix approached the Constance researchers and this lead to a very fertile cooperation between the two partners. Proteolix has further developed the inhibitor PR-957, originally used for the treatment of leukaemia. The cooperation partners carried out an experiment in which they used the inhibitor PR-957 to treat mice suffering from rheumatoid arthritis. The experiment led to a promising result. The researchers found that the disease did not progress further, and that the immune system effectively fought off the viruses to which the animals were exposed. And what was even more promising - the animals did not show any obvious side effects. The scientists took their research a step further. They tested the substances against type-1 diabetes and found that the mice did not develop the disease. What happened in the animals’ bodies? “The T-lymphocytes, which, in the case of diabetes, damage the pancreatic cells that are needed to produce insulin, are kept in check,” explains Groettrup, whose team is already planning further tests to find out whether PR-957 is also effective against autoimmune diseases such as multiple sclerosis and Crohn’s disease. “We can make great progress and help patients if we succeed in attenuating these chronic diseases very early in their development and preventing new disease episodes.”
Groettrup is convinced that his team is on the right track. Five years of research have been worth the effort. The researchers’ work paves the way to a well-tolerated and effective autoimmune therapy, which reduces specific inflammatory mechanisms without tying up the whole system. The preclinical model is ready and details will now be published in the renowned journal Nature Medicine, the most frequently quoted biomedical journal and a door opener to pharmaceutical companies and investors. The preparations for clinical trials have begun: “If the effect of PR-957 is as good in humans as we have seen in our animal models and if there are as few side effects in humans as in mice, this type of treatment would mean a revolution in treatment outcome,” said Prof. Groettrup.
Further information:Prof. Dr. Marcus GroettrupUniversity of ConstanceDepartment of ImmunologyUniversitätsstrasse 1078457 KonstanzTel.: 0049 7531 882130E-mail: Marcus.Groettrup(at)uni-konstanz.de