Restoring Immune Tolerance in Autoimmune Disease

Our immune system exists to help our bodies fight and destroy infectious agents like viruses or bacteria. The challenge is making sure that the immune system only targets these invading pathogens, without attacking our own bodies and tolerating harmless substances like the food and pollen we encounter. 

“By default, the immune system will attack everything, and we have to teach it what not to attack,” says Adrian Liston, Professor of Pathology at the University of Cambridge. 

Understanding how this immune tolerance mechanism works can help scientists develop therapies for autoimmune diseases that help our immune system be tolerant to harmless substances without widespread immune suppression.

What Is Immune Tolerance & How Does It Work?

Immune tolerance is the idea that the immune system does not respond to parts of our own body and therefore, won’t attack our own cells, tissues, and organs (1). Generally, this tolerance is divided into two types: central tolerance and peripheral tolerance.

Central Immune Tolerance and the Role of the Thymus

Central tolerance is primarily built during early development (ex: prenatal and neonatal stages) when T cells develop in the thymus and B cells develop in the bone marrow. These cells generate receptors that will bind molecules called antigens to cause an immune response. Because the receptors are generated at random, a subset of these receptors recognize antigens produced from our own bodies (self-antigens). Central tolerance eliminates the T and B cells that react to these self-antigens.

While the bulk of central tolerance develops in early development, the thymus does produce new T cells throughout life (2). However, Ann Griffith, Associate Professor at University of Texas at San Antonio, says that the number of new T cells produced declines with age as the tissue atrophies. “Each wave of newly developing T cells in the thymus continues to require the selection processes that promote tolerance,” she says. However, she notes that there is evidence that the selection process is impaired with aging, which is partially why there is an increased risk for T cell autoimmunity with age.

Thymic peptides, which are short amino acid fragments naturally derived from the thymus, have roles in central tolerance and have an anti-inflammatory potential (3). Examples of these include thymosin alpha-1, which has been found to promote an anti-inflammatory status in blood samples from multiple sclerosis patients (4). However, there is currently limited evidence on the use of thymic peptides in autoimmune disease contexts and the evidence so far has been preliminary using animal models or small scale trials and have yielded mixed results (5, 6, 7). 

Peripheral Immune Tolerance: Protecting the Body Beyond the Thymus

Because central tolerance isn’t perfect, the body needs a way to promote immune tolerance beyond the thymus and bone marrow once T and B cells enter the lymph nodes and tissues. This peripheral tolerance prevents the self-reactive cells that have escaped central tolerance from attacking our own body. Peripheral tolerance keeps these self-reactive immune cells at bay either by suppressing their activity, deleting these cells, or keeping them in an inactive state (8).

Liston points out another important function for peripheral tolerance: preventing the immune system from reacting to harmless, but foreign, substances like food or pollen. “Central tolerance does not work on that extended self,” he said. “It only works on a very narrow definition of our genome-encoded self.”

When failures in “teaching” immune tolerance happens, this can lead to conditions like allergies, if the immune system recognizes food or pollen as dangerous, or autoimmune diseases,if the immune system attacks our own body.

Therapies That Aim to Restore Immune Tolerance

An ideal in treating autoimmune diseases is to address the root cause of disease, rather than widespread immune suppression.

“Immune suppression is not the answer in the field of immune tolerance because immune suppression is not going into the root of the problem,” says Eva Martínez-Cáceres, Professor of Immunology at Universitat Autònoma de Barcelona.

Re-teaching the immune system to become tolerant to harmless antigens like those from our own bodies is one way to address this.

While immune tolerance begins in the thymus and bone marrow, it’s hard to target the thymus therapeutically. Griffith says that “its location near the heart, and the fact that the blood vessels in some critical anatomical areas of the thymus have relatively low permeability to circulating factors both make it difficult to selectively and efficiently deliver therapeutics.”

This is why many of the therapies to re-educate the immune system focuses on the peripheral immune system.

Low-Dose IL-2 Therapy and Regulatory T Cells

Low dose IL-2 therapy’s goal is to boost the regulatory T cells in the immune system. Liston calls these cells the “brakes on the immune system.” These regulatory T cells are a type of immune cell that helps the body maintain tolerance to self-antigens and suppress the growth of the more pro-inflammatory T cells. “You don’t want to have too few regulatory T cells because you’re going to react against everything,” he adds. “You don’t want to have too many regulatory T cells, otherwise you’ll react against nothing.” One way to control this is with IL-2, which acts as a “food source” for regulatory T cells (9). While Liston says that low dose IL-2 is “pretty safe,” there have been a limited range of conditions where the therapy has been tested on a large scale. One problem is because IL-2 therapy is already on the market. “It’s not commercially viable for any company to run very large trials to show that it definitively works, [for example], in lupus,” says Liston. “If it gets approved for lupus because the company that runs the trial pays for the cost, then any manufacturer is able to support that because the drug is off patent.”

Instead, where the field is headed now is making second generation IL-2 products that have been modified for specific purposes. Liston’s team is working on developing IL-2 therapies that target just one part of the body (10). He adds, “We’d like to only provide extra IL-2 in the brain so that we can just treat neuroinflammatory diseases without shutting down immune responses in the rest of the body.”

Tolerogenic Dendritic Cell Therapy

Another type of therapy, tolerogenic dendritic cells, attempts to reinstate tolerance specifically towards self-antigens. This therapy is based on the fact that dendritic cells normally display antigens to T cells. The outcome of this interaction depends on the environment it occurs in. Within an inflammatory setting, these T cells become activated while in a steady state or anti-inflammatory environment, the dendritic cells either lead to the deletion of pro-inflammatory T cells or the generation of regulatory T cells that suppress the immune response.

Martínez-Cáceres says that tolerogenic dendritic cells can be generated in the lab by taking monocytes (a precursor to dendritic cells) from patients, differentiating them in the lab, adding a tolerogenic environment, and loading them with the target antigen before they are introduced back into the patient (11). The challenge here is that it’s difficult to identify the self-antigen that should be introduced. “In most autoimmune diseases, we don’t know the antigens that are causing the disease,” says Martínez-Cáceres. She added that epitope spreading, a process where damaged tissues reveal different self-antigens, makes it even more challenging to pinpoint specific self-antigens to generate tolerogenic dendritic cells (12). Beyond epitope spreading, there are additional challenges for tolerogenic dendritic cells to work effectively. First, this therapy would require multiple doses (similar to allergy shots), but it’s not known how long a patient would have to continue therapy for. Martínez-Cáceres says this could take years, with treatment every one to two months, for example.

There are multiple tolerogenic dendritic cell therapies in clinical trials (11).

Stem Cell Therapies for Autoimmune Disease

A specific type of stem cells called mesenchymal stromal cells (MSCs) have an immunosuppressive and regenerative feature that make them useful in treating autoimmune disease. They can migrate to damaged tissues and regulate inflammation, promoting immune tolerance. For more information on stem cells and how they can help treat autoimmune diseases, see this article here.

The Future of Immune Tolerance Research

Being able to apply principles of immune tolerance to therapies that target autoimmune diseases requires first understanding how immune tolerance works and then translating these findings into therapies that give patients tangible, beneficial outcomes. Liston thinks that scientists currently have a “very good understanding” of how immune tolerance works, but it’s more difficult to restore it clinically. For Martínez-Cáceres, she noted that “the challenge in autoimmunity is that you want to induce tolerance to the antigens that are self, but you want to keep the immune competence of the immune system towards dangerous illnesses.”

Sources

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