Retraining the immune system to treat haemophilia A

Retraining the immune system to treat haemophilia A

A study from the University of Bonn (UKB) has discovered an important mechanism that is crucial for improving therapy for Haemophilia A patients.

The most common and severe form of haemophilia is haemophilia A  and the disease almost exclusively affects males. In many cases, haemophilia A is easily treated, but this is not the case for all patients.

Preliminary findings have been published online and the final version will be published in the Journal of Clinical Investigation.

Why is Haemophilia A difficult to treat?

People with Haemophilia A have a defect in the protein factor VIII, which is needed blood clotting. Most patients receive an intravenous injection containing factor VIII every few days as part of their treatment. However, the patient’s immune system often mistakes the protein for a harmful foreign agent and attacks it. Once this happens factor VIII can no longer work in that patient’s body, making this the most serious complication of haemophilia A.

These cases can be helped by immune tolerance therapy, which was developed at the University Hospital Bonn over 40 years ago. Immune tolerance therapy involves regular injections of a high dose of factor VIII for several months, causing the immune system to get used to the protein and eventually tolerate it.

The underlying immune mechanisms behind this process are unknown. “However, this does not always work,” explained Professor Dr Johannes Oldenburg, Director of the Institute for Experimental Haematology and Transfusion Medicine at the UKB.

“In about 30% of patients, tolerance induction does not lead to success. So, your body’s own defences 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.”

Reprogramming cells in the immune system

The research team decided to examine two cell types in the immune system, B cells and regulatory T cells. B cells can recognise foreign molecules in the body and produce antibodies against the molecules causing them to lose their functions. This is what causes factor VIII to become ineffective in haemophilia A treatment.

Regulatory T cells prevent the immune response from being too potent or lasting too long. The researchers have identified a new type of cell that can act specifically against specifically against B cells, rather than 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,” explained 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 recognise 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.”

This “button” is a molecule called PD-1, which when activated causes the B cell to malfunction and die. Every active B cell has this button. “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,” explained IMMEI Director, Dr Christian Kurts.

The more PD-1 molecules the B cells carry on their surface, the easier it is for them to be driven to malfunction by immune tolerance therapy.

“The amount of PD-1 varies from person to person. If it’s very low to begin with, there’s a good chance that many inhibitor-producing B cells will survive and continue to neutralise the injected factor VIII,” said Becker-Gotot.

“Our findings have great basic scientific value, and not just for haemophilia A, 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,” concluded Dr Kurts.

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