Study elucidates mechanism that is crucial for effective hemophilia therapy

Study elucidates mechanism that is crucial for effective hemophilia therapy

Hemophilia A is the most common severe form of hemophilia. Almost exclusively men are affected. The disease can usually be treated well, but not for all those affected. A study by the University of Bonn has now elucidated an important mechanism that is crucial for the effectiveness of the therapy. 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 a protein that is important for blood clotting: factor VIII. Most patients therefore receive an intravenous injection of functional clotting factor every few days as treatment. But often, especially at the start of treatment, the immune system recognizes the injected active ingredient as foreign and attacks it. This is the most serious complication of hemophilia treatment because factor VIII can no longer work.

In these cases, immune tolerance therapy, which was also developed over 40 years ago at the University Hospital of Bonn (UKB), often helps. The hemophiliacs are regularly injected with a high dose of factor VIII over several months. This causes the immune system to get used to the injected protein and tolerate it. The underlying immune mechanisms are unknown.

However, this doesn't always work. In about 30 percent of patients, tolerance induction is not successful. So the body's defenses continue to attack and destroy the factor VIII protein, meaning that factor VIII cannot be used for treatment. We wanted to know why.”

Prof. Dr. Johannes Oldenburg, Director of the Institute for Experimental Hematology and Transfusion Medicine, UKB

To do this, the team examined two cell types in the immune system, B cells and regulatory T cells. B cells recognize foreign molecules and produce antibodies against them that switch off the function of the molecule. For factor VIII, this means that it is no longer effective in treating hemophilia.

Brake in the immune system

Regulatory T cells prevent an immune response from being too strong or lasting too long. Among them, the researchers have now found a new type that can act specifically against certain B cells and not just non-specifically against all immune responses. “We were able to show that immune tolerance therapy leads to the formation of regulatory T cells that only stimulate B cells to commit suicide against factor VIII,” says Dr.
Janine Becker-Gotot from the Institute for Molecular Medicine and Experimental Immunology (IMMEI) at the UKB. "These T cells have a sensor that allows them to recognize and bind to the corresponding B cells. They also have the ability to press the self-destruct button on the surface of B cells."

This button is a molecule called PD-1. By activating it, it starts a program in the B cell that leads to its death. Every active B cell has this button. “With our experiments, we were able to detect for the first time regulatory T cells that can only activate this self-destruct button in very specific B cells in order to specifically prevent unwanted immune responses,” explains IMMEI director Prof. Dr. Christian Kurts.

The more PD-1 buttons the B cells have on their surface against factor VIII, the easier it is for them to commit suicide through immune tolerance therapy. “The amount of PD-1 varies from person to person,”
Becker-Gotot explains. “If it is very low initially, there is a good chance that many inhibitor-producing B cells will survive and further neutralize the injected factor VIII.”

Test to show for whom immune tolerance therapy makes sense

Interestingly, B cells also produce more PD-1 once they come into contact with regulatory T cells. “We can now test how strong this reaction is,” says the researcher. “If PD-1 levels rise shortly after starting immune tolerance therapy and then persist, that is a clear sign that the treatment will be successful.” The team is currently developing a blood test that can determine whether immune tolerance therapy works or not in patients during long-term treatment.

“Our findings have a high fundamental scientific value,” explains Prof. Kurts, who is a member of the transdisciplinary research area “Life & Health” at the University of Bonn and, like Dr. Becker-Gotot and Prof. Oldenburg are members of the transdisciplinary research area “Life & Health”. the ImmunoSensation Cluster of Excellence. "And not just in hemophilia, but also in other congenital diseases in which missing proteins are replaced therapeutically. In the long term, they could also be used to develop new therapies."

Institutions involved and funding:

In addition to the IMMEI and the Institute for Experimental Hematology and Transfusion Medicine at the University Hospital of Bonn, the IMC University of Applied Sciences 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 of Bonn (Bonfor), a joint graduate school of the Universities of Bonn and Melbourne, the German National Academic Foundation and the European “Innovative Medicines Initiative” (IMI).

Source:

University of Bonn

Reference:

Becker-Gotot, J., et al. (2022) Immune tolerance to infused FVIII in hemophilia A is mediated by PD-L1+ regulatory T cells. The Journal of Clinical Investigation. doi.org/10.1172/JCI159925.

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