Researchers develop new protein to treat autoimmune diseases

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It is estimated that between 5 and 8% of the world’s population today suffer from autoimmune diseases, conditions in which the immune system attacks healthy tissues in the body. Currently, for most of these diseases, there are only treatments to control the symptoms. Recently, researchers have developed a protein that can activate and increase the number of regulatory immune cells that can prevent the occurrence of autoimmune diseases in mice. Even if clinical application is still far away, this discovery opens up a new avenue in therapeutic research.

Generally speaking, if infectious agents such as bacteria or viruses enter the body, immune cells kill or suppress them, eliminating the infection. This is called an immune response.

An autoimmune disease occurs when, instead of attacking bacteria, viruses, or other sources of infection, the immune system attacks its own healthy organs and tissues in the body. There are over 80 types of autoimmune diseases that affect a wide variety of parts of the body.

Some are well known, such as type 1 diabetes, multiple sclerosis, lupus, and rheumatoid arthritis, while others are rare and difficult to diagnose. In uncommon autoimmune diseases, patients can suffer for years before they are properly diagnosed. Most of these diseases are incurable. Some require lifelong treatment to relieve symptoms.

They affect about 5 million people in France, according to the Pasteur Institute, and make up the third group of diseases in terms of morbidity and mortality in industrialized countries, after cancer and cardiovascular disease.

Doctors don’t know why autoimmune diseases occur at all, or why women suffer from them more than men. However, research suggests that these diseases are likely the result of an interaction between genetic and environmental factors.

On the one hand, gender and ethnic characteristics are associated with a certain probability of developing an autoimmune disease. On the other hand, an environmental factor such as infection, stress, medication, diet, or even ultraviolet radiation can also play a role in these pathologies.

It is in this context that a team of engineers at Johns Hopkins University attempted to develop a regulatory cell-based tool for the prevention and treatment of autoimmune diseases at the cellular level. They have developed a protein that activates and increases the number of special regulatory T cells (called Tregs) that help prevent such disorders. Their results are published in the journal Cell Reports.

Regulatory T cells, the key to autoimmune disease?

Regulatory T cells, or Tregs, are white blood cells that regulate the immune system. They inhibit key components of the adaptive and innate immune response such as T cell proliferation and cytokine production. This feature will modulate interleukin-2 (IL-2). Indeed, natural Tregs are characterized by the expression of both the CD4 T cell co-receptor and CD25, which is a component of the IL-2 receptor.

Jamie Spangler, assistant professor of chemical and biomolecular engineering and biomedical engineering and a member of the research team, said in a statement, “Tregs are essential for maintaining balance in our immune system, and when they fail, people can develop autoimmune diseases.”

Incidentally, IL-2 is the first FDA-approved pro-inflammatory agent administered in high doses to treat metastatic cancer. In contrast, low doses of IL-2 have already been used to treat certain autoimmune diseases such as diabetes and ulcerative colitis, as well as transplant rejection. However, low-dose IL-2 strategies are limited by the harmful effects of off-target immune cell activation and the short serum half-life of IL-2.

Recent work has shown that complexes containing human IL-2 (hIL-2) and anti-hIL-2 antibody F5111 overcome these limitations by stimulating Treg preferentially over other immune cells.

A protein designed to control the immune system

That is why the authors created a single-chain protein called immunocytokine F5111 (IC), which combines the cytokine interleukin-2 and the anti-cytokine antibody F5111. This molecule has been tested in mice predisposed to colitis and diabetes.

Graphical presentation of the principle of the study and its result. © D. VanDyke et al., 2022.

They found that the protein provided animals with significant protection against the development of related autoimmune diseases. In particular, F5111 IC contributed to the activation and expansion of Treg.

Study lead author Derek VanDyke, PhD student in the Department of Chemical and Biomolecular Engineering, explains: “In the case of an autoimmune disease, your own immune system is basically attacking yourself, and these Tregs are used to suppress that attack.” .

The authors argue that since autoimmune diseases are the result of a malfunction in the body’s defense system, suppression of this reaction can help prevent the manifestation of the disease. Therefore, they plan to demonstrate the versatility of F5111 IC by testing in additional settings such as graft rejection models and an experimental multiple sclerosis autoimmune encephalomyelitis model.

Since early detection and prevention are not always possible, these results represent a roadmap for the development of Treg-based immunotherapies that may be clinically applicable to the treatment of autoimmune diseases.

Cell Reports.

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