The spleen’s marginal zone (MZ) B-cells respond to blood coagulation factor VIII (FVIII) and show potential to become the target of future therapies to reduce FVIII inhibitors in hemophilia A, according to new research in mice.
The study, “Marginal zone B cells are critical to factor VIII inhibitor formation in mice with hemophilia A,” appeared in the journal Blood.
Hemophilia A is a genetic condition characterized by a deficiency or lack of FVIII protein, which helps blood to clot. Although factor VIII replacement therapy can be life-saving for patients, FVIII alloantibodies (which react with an antigen from a different individual of the same species), known as inhibitors, often develop.
These inhibitors block factor VIII from working and complicate the control and prevention of bleeding, leading to increased morbidity and mortality, higher costs of care, and a reduced quality of life.
Most physicians currently eliminate FVIII inhibitors through immune tolerance induction (ITI), which involves repeated and lasting exposure to factor VIII to extinguish an immune reaction against the factor.
Although successful 60 to 70 percent of the time, ITI represents a significant burden in time and cost, making strategies to prevent the formation of inhibitors crucial for patient care.
Inhibitor formation is regulated by different factors, including immune T-cells and B-cells. In addition, MZ B-cells, located in the marginal sinus of the spleen (a primary organ in the development of immunity), are involved in the surveillance of blood to discriminate external antigens from the body’s own material.
As a result, marginal zone B-cells may be able to specifically identify and respond to factor VIII, triggering an immune response while also participating in the development of inhibitors.
So, detecting and targeting initiators of FVIII inhibitor development may be a promising strategy to prevent their formation before they activate an immune response.
Scientists studied whether MZ B-cells are early regulators of FVIII inhibitor formation and the potential therapeutic success of a marginal zone B-cell-targeted strategy.
The study’s senior author was Sean R. Stowell, from the Center for Transfusion Medicine and Cellular Therapies, Department of Pathology and Laboratory Medicine at Emory University School of Medicine in Atlanta, Georgia.
The researchers detected factor VIII in the marginal sinus of the spleen of mice with a genetic deficiency in FVIII shortly after its injection, with localization in MZ B-cells. Removing the MZ B-cells completely prevented the development of inhibitors after FVIII was injected.
The scientists also observed that, after re-introducing marginal zone B-cells, an injection of factor VIII caused an antibody response, which demonstrated that the prior removal of those types of B-cells did not result in their failure to respond to factor VIII.
Overall, the results “strongly suggest that MZ B-cells play a critical role in initiating FVIII inhibitor formation and suggest a potential strategy to prevent anti-FVIII alloantibody formation in patients with hemophilia A,” the researchers wrote.
However, given that marginal zone B-cells in humans are located in the spleen, other lymph organs, and in blood circulation, their complete depletion and subsequent regrowth may present a serious risk of infection, the authors cautioned.