Hemophilia: Train the immune system to be tolerant

Hemophilia A is the most common severe type of hemophilia
.
It affects almost exclusively men
.
The disease is usually well treated, but not all patients are treated
.
A study from the University of Bonn now sheds light on an important mechanism
that makes treatment effective.
The findings can help better tailor treatment plans
to patients.
They have been published online for the first time; The final version will soon be published in the Journal of
Clinical Investigation.

People with hemophilia A have a deficiency in coagulation factor VIII, a
protein that is important for blood clotting.
Therefore, most patients receive intravenous injections of functional clotting factors every few days as therapy
.
But usually, especially at the beginning of treatment, the immune system recognizes the injected drug as a foreign substance and attacks
it.
This is the most serious complication of hemophilia treatment because factor VIII no longer works
.

In this case, immune-resistant therapies developed at the University Hospital Bonn (UKB) more than 40 years ago often help
.
This includes regular injections of factor VIII into hemophilia patients over several months
.
The immune system thus gets used to and tolerates
the injected proteins.
The underlying immune mechanism is unknown
.
"However, this does not always work," explains
Professor Johannes Oldenberg, director of the Institute of Experimental Hematology and Transfusion Medicine at Royal Roads University.
"In about 30 percent of patients, tolerance induction was not successful
.
So your body's own defense system continues to attack and destroy factor VIII proteins, which means factor VIII cannot be used for treatment
.
We wonder why
this is.
”

To do this, the team studied two cell types in the immune system, B cells and regulatory T cells
.
B cells recognize foreign molecules in the body and produce antibodies, which turn off the function of
the molecules.
For factor VIII, this means that it is no longer effective
in the treatment of hemophilia.

The brakes of the immune system

Regulatory T cells can prevent the immune response from being too strong or lasting too long
.
The researchers have now discovered a new type in it that specifically fights certain B cells, rather than non-specifically against all immune responses
.
Dr Janine Becker-Gotot, from the UKB Institute of Molecular Medicine and Experimental Immunology (IMMEI), said: "We were able to demonstrate that immunotolerant therapy leads to the production of regulatory T cells that specifically induce B cells to commit suicide
against factor VIII.
" "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 press the self-destruct button
on the surface of B cells.
”

This button is a molecule
called PD-1.
By activating it, it initiates a program in B cells that causes B cells to die
.
Every active B cell has this button
.
Professor Christian Kurts, Director of IMMEI, explains: "Our experiment allowed us to detect for the first time regulatory T cells, which can only activate this self-destruct button in very specific B cells to specifically prevent unwanted immune responses
.
"

The more PD-1 buttons against factor VIII that B cells carry on their surface, the more likely they are 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 low in the first place, a lot of the inhibitor-producing B cells have a good chance of surviving and continuing to neutralize injected factor
VIII.
"

Tests to show who is useful for immune tolerance therapy

Interestingly, B cells also produce more PD-1
when they come into contact with regulatory T cells.
"We can now test how strong this response is," the researchers said
.
"If PD-1 levels rise shortly after starting immunotolerant therapy and then remain at that level, that's a clear sign that treatment will be successful
.
" The team is currently developing a blood test that can be used to detect whether immunotolerant therapies are effective
during a patient's long-term treatment.

"Our findings have great fundamental scientific value," explains Prof.
Kurts, a member of the interdisciplinary research field Life and Health at the University of Bonn and, like Dr.
Becker-Gotot and Prof.
Oldenburg, a member of
the Cluster of Excellence in Immune Sensation.
"This applies not only to hemophilia, but also to other congenital diseases
that replace missing proteins by treatment.
In the long term, they can also be used to develop new treatments
.
”

Participating Organisations and Funding:

In addition to the Institute of Experimental Hematology and Transfusion Medicine at IMMEI and the University Hospital Bonn, IMC is also involved in the study at the
University of Applied Sciences in Krems (Austria) and the University of Melbourne (Australia).
The work was funded
by the German Research Foundation (DFG), the University Hospital of Bonn (Bonfor), a joint graduate school of the University of Bonn and the University of Melbourne, the German National Academic Foundation (studenstiftung des Deutschen Volkes) and the European Innovative Medicines Initiative (IMI).

Journal Reference:

1. 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, Christian Kurts.
   Immune tolerance against infused FVIII in hemophilia A is mediated by PD-L1+ regulatory T cells.
   Journal of Clinical Investigation, 2022; DOI: 10.
   1172/JCI159925