By Thania Benios
In this first installment of a two-part series, Countdown takes you on a tour of your immune system and how it can turn against your body. In the second, we will give you a panoramic view of how JDRF is propelling the search for vaccines that can reset your immune system and prevent, treat, or halt type 1 diabetes.
Fine-Tuning Our Defenses
Type 1 diabetes affects individuals of all ages and the rate of incidence has increased dramatically in the past two decades. This marked increase, especially in children between the ages of one to five years, has made the need for preventing type 1 diabetes all the more imperative. That’s why JDRF has prioritized vaccine research, not only to prevent type 1 diabetes, but also to arrest or reverse its progression in people who have been newly diagnosed or have been living with the disease for years. In this effort, JDRF has been funding discovery research and its translation, and has been bringing together scientific efforts from universities, biotechnology companies, and pharmaceutical companies, to drive this research forward.
In the first installment of this two-part series, we will describe how the immune system protects our body from the universe of pathogens—the bacteria, viruses, fungi and parasites that would, if they could, harm us. It will also address the ways the immune system has evolved to protect the body from this destructive response while not turning against itself.
Part two will describe the research that has gained traction, and how JDRF and others leveraging these findings to open up new avenues for better treatments and a cure.
The Basics of Balance
To understand balance, think of tuning in to your favorite radio station. When you balance the right frequency signals, you can hear the station clearly. When you turn the dial a little bit to the right or left, the station becomes less clear. This fine-tuning allows you to hone in on the proper balance of signals so that your favorite station comes in clearly.
Instead of balancing frequency signals to tune into a station, the immune system balances communication signals—in this case, regulatory and effector T cells—to keep it from turning against the body’s own cells. Effector T cells attack and destroy anything that the immune system perceives as dangerous. Regulatory T cells, on the other hand, reign in the destructive power of effector T cells so that they do not attack the body’s own tissues. This balance between a destructive response against pathogens and a tolerant response toward the body has to be just right. Otherwise, it can lead the body to attack its own healthy tissues-a condition known as autoimmunity.
T cells learn to recognize and tolerate the body’s healthy tissues in an organ called the thymus, the hub of the immune system. This training is important because ultimately T cells will have to distinguish between what is part of the body and what is foreign tissue that needs to be destroyed.
So, how does it do this?
Located just above and in front of the heart, the thymus holds billions of protein fragments, called peptides, which are expressed throughout the human body. As T cells mature in the thymus, they develop the ability to recognize these peptides using a detection device on their surface, known as a receptor. Each T cell randomly expresses a receptor, which is designed to recognize only one particular peptide. When this receptor comes into contact with its matching peptide, it will bind to its surface.
T cells that bind too strongly to these peptides are considered a risk and destroyed. In this case, the thymus signals these T cells to self-destruct immediately because if they were allowed to mature into effector T cells, they would have the potential to kill healthy cells in the body. On the other hand, T cells that bind weakly to the peptides survive. The thymus selects them because they are the most likely to guard us from the universe of pathogens that we will encounter the moment we are born without turning against and attacking our own body. After these potentially useful T cells mature, the thymus releases them into the bloodstream where they may or may not encounter a foreign invader they can detect and destroy.
Unlike T cells that bind weakly to peptides, T cells that bind strongly to them are so dangerous and have such potential to do harm that if they are not eliminated in the thymus, the body has evolved a backup system to suppress them. People without an autoimmune disease are able to keep these potential troublemakers in check—and keep them in check in the face of the pathogens and substances in our environment that could awaken them.
In people with type 1 diabetes, this selection process is not as stringent as in those without an autoimmune disease. People with type 1 diabetes are thought to be born with a balance skewed toward immune attack; not only is there an increase in the number of potentially dangerous effector T cells, but also a decrease in the number of regulatory T cells that prevent these effector T cells from turning against the body—as well as a progressive decrease in this ability over time. This means that type 1 diabetes, like most autoimmune diseases, arises because of a defect in what is known as immunoregulation.
Out of Balance
In the past five years, researchers have found more than 40 regions on a type 1 diabetes person’s genetic map that set the balance between immune attack and tolerance. People with type 1 have different sequences of letters in one or more of these genes compared to individuals not at risk for an autoimmune disease. In fact, people with type 1 are more genetically similar to people who have a different autoimmune disease, such as rheumatoid arthritis and multiple sclerosis, than to their type 2 diabetes counterparts.
A balance that is set off-kilter can lead to any number of defects in immunoregulation. Especially in the case of people with established type 1 diabetes, effector T cells can become resistant to signals from regulatory T cells that would signal them to stop attacking. The result is that regulatory T cells are blocked from doing their job: protecting the body from attack.
This deficiency in T cell function may also change how strongly a T cell and its matching peptide communicate with each other. For instance, a T cell that could be very intensely bound to a peptide may appear as one that is weakly bound. In this case, the thymus mistakes a potentially dangerous T cell for one that is potentially useful. These T cells escape the thymus and roam the body via the bloodstream; but instead of having the potential to only attack a foreign invader, it actively searches for the healthy cells that harbor the self-peptide it is designed to attack.
Everybody has a few of these dangerous T cells roaming the body. That’s precisely why the immune system built itself a safety net. But people with type 1 diabetes may not be able to suppress these T cells in the face of an environmental challenge, such as a viral infection. A virus, for example, may awaken a suppressed T cell that is designed to target a self-peptide. If that T cell succeeds, autoimmunity can develop.
Resetting the Balance
Ideally, a vaccine to combat type 1 diabetes would have a two-pronged approach. First, it would actively tamp down the specific effector T cells that attack beta cells in the pancreas or enhance their response to regulatory signals. Second, the vaccine would promote self-tolerance through the activation of more beta-cell specific regulatory T cells. This would help prevent beta-cell specific effector cells from turning against the body’s own tissues.
Individually, each approach could right the imbalance between the activity of effector and regulatory T cells in people who have recently been diagnosed with type 1 diabetes. But a two-pronged approach could also help people who have been living with type 1 for years or who are at risk for developing the disease.
“Our goals is to support as many different and unique diabetes vaccines as possible, and fully explore their potential in animal models, and then conduct proof-of-concept clinical trials,” says JDRF Scientific Officer Richard Insel, M.D. “Our hope is that one or more of these prove to be successful in regulating and resetting the autoimmune response associated with type 1 diabetes.”