Study by the University of Bonn elucidates an important immune mechanism
Hemophilia A is the most common severe form of hemophilia. It affects almost exclusively males. The disease can usually be treated well, but not for all sufferers. Researchers at the cluster of Excellence ImmunoSensation2 now elucidated an important mechanism that is crucial for making the therapy effective. The results could help better tailor treatment to patients. They have already been published online in a preliminary version; the final version will soon be published in the "Journal of Clinical Investigation."
Hemophilia A patients have a defect in factor VIII, a protein important for blood clotting. Most patients therefore receive an intravenous injection of the functional clotting factor every few days as treatment. But frequently, and especially at the start of treatment, the immune system recognizes the injected agent as foreign to the body and attacks it. This is the most serious complication of hemophilia treatment.
In these cases, immune tolerance therapy, which was also developed at the University Hospital Bonn (UKB) more than 40 years ago, often helps. This involves regularly injecting the hemophiliacs with a high dose of factor VIII over several months. The immune system thereby gets used to the injected protein and tolerates it. The underlying immune mechanisms are unknown. "However, this doesn't always work," explains Prof. Dr Johannes Oldenburg, Director of the Institute for Experimental Haematology and Transfusion Medicine at the UKB. "In about 30 percent of patients, tolerance induction does not lead to success. So your body's own defenses continue to attack and destroy the factor VIII protein, which means that factor VIII cannot be used for treatment. We wanted to know the reason for this." To this end, the team investigated B cells and regulatory T cells with regard to elimination of administered factor VIII.
Brake in the immune system
Regulatory T cells prevent an immune response from being too strong or lasting too long. The researchers have now found a new type among them that can act specifically against certain B cells rather than just non-specifically against all immune responses. "We were able to show that immunotolerance therapy results in the generation of regulatory T cells that exclusively induce B cells against factor VIII to commit suicide," says Dr. Janine Becker-Gotot of the Institute of Molecular Medicine and Experimental Immunology (IMMEI) at UKB. "These T cells have a sensor that allows them to recognize and attach to the corresponding B cells. In addition, they have the ability to push the self-destruct button on the surface of B cells."
Responsible is the Programmed Cell Death Protein 1 (PD-1), a receptor on the B-cell surface. Upon activation of this “button”, the respective B-cell undergoes apoptosis. "Our experiments enabled us for the first time to detect regulatory T cells that can activate this self-destruct button only in very specific B cells, in order to specifically prevent unwanted immune responses," explains IMMEI Director Prof. Dr. Christian Kurts.
The more PD-1 the B cells directed against factor VIII carry on their surface, the easier it is for them to be driven to undergo apoptosis by immune tolerance therapy. "The amount of PD-1 varies from person to person," Becker-Gotot explains. "If it's very low to begin with, there's a good chance that many inhibitor-producing B cells will survive and continue to neutralize the injected factor VIII."
Test to predict individual success rate of immunotolerance therapy
Interestingly, B cells also express more PD-1 once they come into contact with regulatory T cells. "We can now test how strong this reaction is," the researcher says. "If PD-1 levels go up shortly after starting immune tolerance therapy and then stay up, that's a clear sign that the treatment is going to be successful." The team is currently developing a blood test that can be used to detect whether or not immune tolerance therapy is working in patients during the prolonged treatment.
"Our findings have great basic scientific value," explains Prof. Kurts, who is a member of the Transdisciplinary Research Area "Life & Health" at the University of Bonn. "And not just for hemophilia, but also for other congenital disorders where missing proteins are replaced therapeutically. In the long term, they could also be used to develop new treatments."
Funding
In addition to the IMMEI and the Institute of Experimental Haematology and Transfusion Medicine at the University Hospital Bonn, the IMC University of Applied Sciences in Krems (Austria) and the University of Melbourne (Australia) were involved in the study. The work was funded by the German Research Foundation (DFG), the University Hospital Bonn (Bonfor), a joint graduate college of the Universities of Bonn and Melbourne, the German National Academic Foundation (Studienstiftung des Deutschen Volkes) and the European "Innovative Medicines Initiative" (IMI).
Publication
Janine Becker-Gotot, Mirjam Meissner, Vadim Kotov, Blanca Jurado-Mestre, Andrea Maione, Andreas Pannek, Thilo Albert, Chrystel Flores, Frank A. Schildberg, Paul A. Gleeson, Birgit M. Reipert, Johannes Oldenburg, and Christian Kurts: Immune tolerance against infused FVIII in hemophilia A is mediated by PD-L1+ regulatory T cells; The Journal of Clinical Investigation; DOI: 10.1172/JCI159925
Contact
Institute of Molecular Medicine and Experimental Immunology (IMMEI)
University Hospital Bonn
Phone: +49 228-287 11066
E-mail: jgotot@uni-bonn.de
