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The enemy within? New perspectives on autoimmune disease

New knowledge generated by original basic science takes an average of 17 years to reach the clinic. That’s the conclusion reached by a number of authors who have sought to quantify what some have called the translational research time lag.

That may be a depressing thought for PhD students motivated by a desire to rapidly improve the lot of patients. For those working in autoimmunity (the study of how the body’s immune system can attack its own cells to cause disease), however, the figure underlines the feeling in the field that significant clinical returns on the investment in basic research going back 30 years are imminent.

The dawn of a golden age?

Our understanding of the immune system and autoimmune conditions, such as type 1 diabetes, rheumatoid arthritis and inflammatory bowel disease, has grown rapidly in the last 30 years or so. Of particular importance has been research that has revealed the fundamental part played by T cells in a range of essential roles to regulate immune responses. 

Over this time better treatments have been developed, yet some are disappointed that lasting cures have not been found. “There’s been a lot of progress, but the really important progress of getting patients close to cures is still to come,” says Professor Sir Marc Feldmann, who in 2014 was awarded the Canada Gairdner International Award, which in many cases has been a precursor to a Nobel Prize, for the discovery of anti-TNF therapy, a treatment now used for a range of inflammatory autoimmune conditions such as rheumatoid arthritis. Many in the field believe we are at the dawn of a golden age which will see major benefits for patients in the form of both treatments and cures.

Anti-inflammatory breakthroughs

While science is a highly collaborative and international endeavour, few would dispute that UK-based immunologists have made major contributions to this field, including for example the elucidation of the central roles of T cells. In the early 1980s, research from various groups showed that human leukocyte antigen (HLA) genes, which encode major histocompatibility complex (MHC) cell surface proteins, are upregulated in autoimmune disease-affected tissue. Feldmann, who was studying the role of HLA in triggering T cell activity, hypothesised in a 1983 paper that cell signalling molecules called cytokines, which upregulate MHC, were key to understanding the triggering of autoimmunity. 

Fingers with rheumatoid arthritis

Together with Professor Sir Ravinder Maini, then at the Kennedy Institute of Rheumatology in Oxford, Feldmann began to look at the cytokines expressed in joint tissue from patients with rheumatoid arthritis. “The dilemma was there were about a dozen proinflammatory cytokines present, all at levels capable of upregulating inflammation,” says Feldmann. “Most researchers in the field concluded they were not good targets for therapy because if you blocked one cytokine, the others that were present would still drive the biology so you would be wasting your time.”

Feldmann and Maini disagreed with this view, and went on to show that excessive production of one cytokine called tumour necrosis factor alpha (TNF-α) causes the inflammation that occurs in inflammatory joint disease by demonstrating that blocking it prevents the production of the other proinflammatory cytokines in their model of human disease tissue in culture. They further went on to lead clinical trials which demonstrated impressive anti-inflammatory effects. This eventually led to the approval of the first widely used monoclonal antibodies, the anti-TNF-α drugs, in 1998. These have gone on to become the treatments of choice to stop inflammation in rheumatoid arthritis and other autoimmune conditions including ulcerative colitis, psoriasis, Crohn’s disease and ankylosing spondylitis.

Regulatory T cells on the map

The 1990s saw important advances in the discovery and description of cells that suppress immune reactions. Work by both Professor Shimon Sakaguchi, of Osaka University and Professor Fiona Powrie in Oxford helped identify the roles of regulatory T cells in self-tolerance, and how their malfunction could cause autoimmune diseases. In 1990, Powrie showed that injecting one set of T cells into rats could cause inflammatory disease; however if regulatory T cells were injected at the same time the rats were protected. “Between them, Powrie and Sakaguchi put regulatory T cells and immune regulation on the map,” says Lucy Walker, Professor of Immune Regulation at University College London. “That was really important in advancing our understanding of autoimmunity, and what prevents autoimmunity normally.”

Around this time Professor Herman Waldmann, at the University of Oxford, was developing his idea of infectious tolerance. In a key paper published in the journal Science , he demonstrated that courses of CD4 antibodies could stimulate long-term immune system tolerance to foreign proteins, and that this tolerance could be transferred from one animal to another by transplanting the right immune cells. Waldmann went on to demonstrate that the regulatory T cells Powrie had described were required for infectious tolerance.

Helper T cells, also known as CD4 cells, play a crucial role in protecting the body from pathogens by triggering the release of cytokines that suppress or moderate immune responses. It was initially thought they could differentiate into just two subsets. These were type 1 (Th1) to fight viruses and other intracellular pathogens, eliminate cancer cells and stimulate delayed type hypersensitivity skin reactions, and type 2 (Th2) to stimulate antibody production to combat extracellular organisms. In fact, recent research has shown they can turn into other types as well. Professor Gitta Stockinger, now at the Francis Crick Institute in London, for example, has been instrumental in the discovery of Th17 cells that produce the proinflammatory cytokine interleukin-17, which in turn has been found to play an important role in autoimmunity.

A finely balanced system

The growth in our knowledge about the different types of T cells has greatly improved our understanding of the causes of autoimmune diseases. “It has made us think about autoimmunity in terms of both the cells that induce disease and the cells that protect from disease,” says Walker. “In thinking about therapies, we traditionally thought about trying to block dangerous cells to stop them working. More recently there has been much more emphasis on trying to boost the protective cells in the regulatory arm of the immune system.”

Work by Stockinger on Th17 cells and others on the wide variety of ways that T cells can become activated has stimulated many in the field to investigate the types of T cell activation involved in different autoimmune diseases. In work published last year, for example, Walker’s group identified a central role of follicular helper T (Tfh) cells, which help B cells in the development of humoral immunity, in type 1 diabetes. Humoral immunity is the element of the immune system associated with antibodies found in extracellular fluids. Walker found that memory T cells from type 1 diabetes patients exhibited enrichment of Tfh cells and greater secretion of the soluble protein interleukin-21. “This may provide a way to track levels of Tfh cells in patients following therapy to see if treatment is working, and inspire ideas about different pathways to target to combat the disease,” says Walker.

Following on from the identification of regulatory T cells and their roles, researchers have sought to identify the mechanisms by which they act to suppress immune responses. A key way they do this is through the CTLA-4 protein. In collaboration with the laboratory of Professor David Sansom, Walker’s group identified a novel molecular mechanism for CTLA4 function and, together with colleagues at the Royal Free Hospital in London, reported in 2014 that patients with CTLA4 gene mutations exhibit a wide variety of autoimmune symptoms. Samples of regulatory T cells taken from their blood cannot perform their normal immune regulation function. A soluble version of CTLA-4 called abatacept is used to treat some rheumatoid arthritis patients and other autoimmune diseases, and may prove a useful therapy in CTLA4 deficiency.

Helper T cells lend a hand

The central role of helper T cells in autoimmune disease was revealed by research during the 1980s and 1990s. Professor David Wraith, now at the University of Birmingham, believed that finding ways to desensitise helper T cells could offer new therapies. He was intrigued by the idea of adopting the ‘antigen-specific immunotherapy’ approach that has been used against allergies since the time of John Freeman and Leonard Noon, of St Mary’s Hospital, London, who published a trial on it in The Lancet in 1911.

Others had tried this approach in autoimmune diseases before using whole or intact antigens, however the mechanisms involved were not fully understood. Such efforts proved largely ineffective and some triggered harmful autoimmune responses. An important clue to a way forward lay in research showing associations between autoimmune diseases and genes that encode protein receptors for small fragments of antigens called peptides. Further work showed it was these rather than the whole antigen that helper T cells were responding to.

Wraith set about demonstrating it was possible to suppress immune reactions in autoimmunity using synthetic versions of these peptides. Some warned this could make things worse. “That’s not how it turned out,” says Wraith. “What we came to realise was we weren’t just switching these cells off. We were turning them from potentially aggressive cells that could promote autoimmune disease into ones that could police the immune system and protect against autoimmune disease.”

Clinical trials

Getting funding to carry out clinical trials of peptide immunotherapy proved difficult. Wraith set up a company called Apitope in 2002. A phase I trial published in 2015 found injections of ATX-MS-1467, a treatment based on this approach, to be safe and well-tolerated in six patients with secondary progressive multiple sclerosis. Merck Serono has licensed the treatment and has provided backing for two more trials. Wraith says that initial MRI scans have shown the approach can significantly reduce the inflammation and scarring to the protective myelin sheaths that surround nerves that are characteristic of multiple sclerosis.
“Current therapies for autoimmune diseases tend to rely on immunosuppressive drugs that have to be given long-term and make patients susceptible to infections and cancers,” says Wraith. “We want to get away from non-specific immune suppression and help the immune system correct itself. What I want to see in the last part of my working career is this approach being rolled out into as many diseases as possible.”

While science is a highly collaborative and international endeavour few would dispute that UK-based immunologists have made major contributions to this field.   

Apitope is working on therapeutic peptides for the thyroid condition Graves’ disease, uveitis (which can cause vision loss) and the rare chronic bleeding disorder Factor VIII intolerance. Professor Mark Peakman, at King’s College London, completed a trial of a peptide-based treatment for type 1 diabetes last year, and began a trial of a more powerful version called MultiPepT1De in 24 patients at Guy’s Hospital, London, in March. A phase III trial of Lupuzor, a potential therapy for the autoimmune condition lupus, was launched by the UKbased pharmaceutical company ImmuPharma last year.

Micrograph showing the thyroid gland in the autoimmune condition Graves’ disease 

Boosting regulatory processes

Various groups around the world are pursuing another approach widely seen as promising – boosting regulatory T cell activity to counter autoimmunity, either by growing them in the lab or finding other ways to increase their activity. The soluble protein interleukin-2 (IL-2) is known to increase the number of regulatory T cells naturally and there is considerable interest in using this as a therapy.

Dr Frank Waldron-Lynch, Professor John Todd and Professor Linda Wicker of the University of Cambridge have completed a trial of synthetic IL-2 to determine the optimal dose in patients with type 1 diabetes and are carrying out another to find out the optimal treatment frequency, in preparation for a phase II trial.

Professor Giovanna Lombardi, of King’s College London, adopted the other approach of taking regulatory T cells from 13 patients with Crohn’s disease and growing them to increase their number in the lab using IL-2. In research published in 2014, her group showed that, in vitro at least, the regulatory T cells they had grown could modulate immune responses seen in the inflamed tissue of Crohn’s patients.

Millions of rheumatoid arthritis patients already benefit from anti-TNF drugs. There are other treatments for autoimmune conditions that work by dampening immune system responses based on targeting the interleukin 6 receptor (IL6R) and B-lymphocyte antigen CD20. These are known as ‘biologics’ – genetically-engineered protein therapies derived from human proteins. The recent success of immune checkpoint inhibitor-based cancer immunotherapy in boosting the immune system’s response to certain forms of cancer leads many to believe there is potential for major clinical improvements for those with autoimmune conditions based on doing the reverse, especially for treatments that target T cells.

“There’s a real sense that immunology is coming of age,” says Walker. “Biologics have been seen as highly successful in augmenting the immune system to fight cancer. The hope is that in autoimmunity we can develop further treatments that do the opposite to suppress the immune system to the real benefit of patients. It’s a hugely exciting time.”

This article was written by Nic Fleming as part of the BSI's report '60 years of immunology: past, present and future'. This article is licensed under Creative Commons Attribution-NoDerivative Licence (CC BY-ND 4.0). Additional permissions may need to be sort from image licence owners.