Certain immune system proteins found to drive FVIII inhibitors

These complement proteins work 'synergistically' to activate T-cell responses

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Researchers have identified immune system proteins that might drive the development of inhibitors, or neutralizing antibodies, against factor VIII (FVIII) replacement therapies in people with hemophilia A.

These proteins, called complement proteins, appear to work collaboratively with danger signals that alert the body to critical situations in order to activate immune cells that have the ability to recognize FVIII.

“The knowledge gained in this study could help with the development of approaches to reduce the risk of inhibitor formation during treatment of haemophilia A patients,” Zoe Waibler, PhD, the study’s senior author, head of the Product Testing of Immunological Drugs Section, and deputy head of immunology at the Paul-Ehrlich-Institut in Germany, said in a press release.

The findings were reported in a study, “Complement protein C3a enhances adaptive immune responses towards FVIII products,” which was published in the journal Haematologica.

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Third of patients will develop inhibitors against FVIII replacement therapy

Hemophilia A is caused by the lack of FVIII, a blood clotting protein. The mainstay treatment for it is replacement therapy, which consists of providing a version of FVIII — either lab-made (recombinant) or derived from healthy human plasma (a liquid component of blood) — to patients.

About a third of patients will develop inhibitors, a type of neutralizing antibody against FVIII that can limit the therapy’s effectiveness and raise the risk of severe bleeding episodes.

The cellular processes leading to inhibitor development haven’t been fully worked out.

It has been suggested that certain immune system “danger signals” might be involved. The function of these molecular signals is to tell the body when there is a critical situation that needs to tackled, for example, when an infectious agent enters the body or when the body is subjected to stress due to trauma or surgery.

Waibler’s team previously identified that plasma-derived FVIII products, but not recombinant ones, activated a family of immune cells called dendritic cells in the presence of a danger signal called lipopolysaccharide (LPS). Of note, LPS is an inflammatory molecule present on the surface of bacteria.

In turn, this drove the growth, or proliferation, of certain classes of T-cells, a type of immune cell important for inhibitor development.

The knowledge gained in this study could help with the development of approaches to reduce the risk of inhibitor formation during treatment of haemophilia A patients.

Researchers investigate components of plasma that drive immune response

Now, the team set out to investigate which specific components of plasma might drive the observed immune responses. Plasma-derived products contain a number of other human blood proteins in addition to FVIII.

As they previously observed, when recombinant FVIII was added to cell cultures with LPS-stimulated dendritic cells, no T-cell cell growth was observed. But when human plasma was added in, T-cells began to proliferate, supporting the idea that there’s something in plasma driving T-cell response.

Some, but not all, T-cells that were activated appeared to be the ones that specifically recognized and targeted FVIII.

The C3a and C5a proteins were found to be present in plasma-derived FVIII products, but not in recombinant ones. These proteins are part of the complement cascade, a part of the immune system that helps the body get rid of foreign and harmful substances.

Heat is known to inactivate these proteins. When researchers added heat-treated plasma to cell cultures containing LPS-stimulated dendritic cells and recombinant FVIII, T-cells no longer proliferated as strongly.

Moreover, when antibodies or pharmacological agents designed to block the activity of these complement proteins were added to cell cultures, T-cell proliferation was likewise reduced.

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These findings altogether suggest that C3a and C5a along with certain danger signals work “synergistically” to drive T-cell responses, according to the team.

“In case of FVIII-substituted [hemophilia A] patients … these danger signal plus complement-mediated T cell responses are (largely or to a certain amount) directed towards the infused FVIII,” the team wrote.

They noted that these complement proteins and danger signals likely come from the patients’ own body in response to FVIII, which may explain why inhibitors develop with both plasma-derived and recombinant treatments.

In summary, the data present a model of “how event-related substitution of FVIII in [hemophilia A] patients might contribute to inhibitor development,” the researchers wrote.

Avoiding treatment during times when danger signals in the body are elevated, such as during an infection, might reduce the risk of inhibitor development, according to the researchers.