Haemophilia A, the most common severe form of haemophilia, affects almost exclusively males and can usually be with factor VII injections, but not for all sufferers, as the immune system may treat the factor as an intruder. New research has uncovered an important immune mechanism that targets B cells, which is crucial in making the the therapy effective. The study is published online in the Journal of Clinical Investigation.
Haemophilia A patients have a defect in factor VIII, a protein key for 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 recognises the injected agent as foreign to the body and attacks it. This is the most serious complication of haemophilia treatment because factor VIII can then no longer work.
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 haemophilia sufferers with a high dose of factor VIII over several months, letting the immune system learn to tolerate it. The underlying immune mechanisms are unknown. “However, this doesn’t always work,” explains Prof Dr Johannes Oldenburg at the UKB. “In about 30 percent 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.”
To this end, the team looked at two cell types in the immune system, B cells and regulatory T cells. B cells recognise foreign molecules in the body and produce antibodies against them, which switch off the function of the molecule. For factor VIII, this means that it is no longer effective in haemophilia treatment.
Brake in the immune system
Regulatory T cells moderate the strength and duration of the immune response. The researchers have now found a new type of Treg cell that can act specifically against certain B cells rather than the overall immune response. “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 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, on activation, leads to apoptosis. 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,” explains IMMEI Director Prof Dr Christian Kurts.
The more PD-1 buttons the B cells against factor VIII carry on their surface, the easier it is for them to be driven to suicide 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 neutralise the injected factor VIII.”
Test to show in whom immunotolerance therapy is useful
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,” 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. “And not just for haemophilia, 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.”
Source: University of Bonn
