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Evaluating the Effect of Specific T Cells on Type 1 Diabetes Risk and Treatment

As researchers delve more deeply into trying to understand the origins of type 1 diabetes (T1D), they become increasingly aware that there is not a single disease pathogenesis, but rather multiple paths that vary from person to person. While they know that T1D results from the immune system attacking and destroying insulin-producing beta cells in the pancreas, there may be several different factors that contribute to this risk.

A recent study examined a variety of T cells, T cell receptors, antigens, and autoantibodies that may play a role in the development of T1D. One common factor they found was that individuals with an elevated level of islet autoantibodies in the peripheral blood are at increased risk of developing T1D within their lifetime. Researchers also know that in addition to risk genes, human leukocyte antigen (HLA) genes and the autoantibody glutamic acid decarboxylase (GAD) could vary from person to person and impact the effectiveness of targeted therapies. Children who possess two or more islet autoantibodies have around an “85% chance of developing T1D within 15 years and nearly a 100% lifetime risk for disease development.”

However, the mere presence of islet autoantibodies does not demonstrate disease state, because it could be years before clinical T1D presentation. In its early stage (stage 1), while the autoantibodies are present, beta cell function remains normal. As risk for T1D advances (stage 2), metabolic abnormalities develop. Finally, with T1D onset (stage 3), there is both a presence of autoantibodies and loss of beta cell function in regard to blood glucose. The staging paradigm was derived from data from the United States’ Diabetes AutoImmunity Study in the Young (DAISY), Finland’s Type 1 Diabetes Prediction and Prevention Study (DIPP), and Germany’s BABYDIAB studies.

Given the similarities of mouse models and human models when it comes to diabetes, mouse models are often used to study disease risk, evaluate pathogenesis, and assess potential treatment options. Researchers have found that specific antigens and T cells affect pancreatic islets differently. Understanding these antigen subsets could be critical in determining effective clinical therapeutics for prevention and treatment.

Thanks to the Network for Pancreatic Organ Donors (nPOD), more than 150 cases have been collected from organ donors with T1D since 2007, as well as more than 150 from non-diabetic donors and dozens of donors with autoantibodies but no clinical diabetes. These tissue donations have provided researchers with islets, cells, and data from multiple facets of the ody that contribute to T1D risk.

Understanding tissue specific T cells, antigens, and autoantibodies may help identify biomarkers of disease activity which could improve targeted therapeutic interventions. Eventually, this may help reduce risk of T1D by creating early intervention strategies.

While not involved with this study, Diabetes Research Connection (DRC) is focused on advancing understanding of T1D and improving prevention, diagnosis, and treatment options as well as progress toward a cure. Early career scientists receive critical funding to pursue novel, peer-reviewed research projects regarding multiple aspects of T1D. Learn more by visiting http://diabetesresearchconnection.org.

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Bystander T Cells May Play A More Active Role in Managing Type 1 Diabetes

There are many types of cells that all play a different role in how the body works. Some of these cell functions are very well known, while others are still somewhat mysterious. For years, scientists have thought that bystander T cells were just that – bystanders, since it was unclear what their exact purpose was. A team of researchers led by Matthias von Herrath, M.D., a professor in the La Jolla Institute for Allergy and Immunology’s Division of Developmental Immunology and a diabetes researcher, may have shed more light on what these cells actually do.

von Herrath and his team found that while the initial belief was that bystander T cells increased inflammation associated with type 1 diabetes and the destruction of insulin-producing islet cells, they may actually do quite the opposite. They found that these cells interfere with the destruction of pancreatic beta cells rather than supporting it. CD8+ cytotoxic T lymphocytes (CLTs) target specific protein fragments in islet cells and then destroy the cells. During this process, the pancreata are flooded with other T cells that do not detect protein fragments, which are referred to as the bystander T cells.

New studies by von Herrath and his team have discovered that in mouse models, the bystander T cells actually have an immunosuppressive effect and decrease the effect of cell-killing CLTs. When mice were injected with equal amounts of cell-killing and bystander CLTs, the researchers found that there was “little cell death, and the specific CLTs recruited to the pancreas became less harmful.” When decreased amounts of bystander cells were injected, there was more cell destruction as well as the occurrence of diabetes symptoms including hyperglycemia. Two possible theories are that bystander T cells limit access to beta cells as they flood the cell protecting them from cell-killing CLTs, or possibly that the bystanders interfered with the signals sent to cell-killing CLTs, so, therefore, the destruction is not as severe.

The study demonstrates that regulatory T cells are not the only cells that help counteract inflammation, though they are the most widely recognized for having this effect. With this new insight into bystander T cells, researchers may be able to leverage them in future treatment for type 1 diabetes. Additional research is necessary to explore this potential.

The Diabetes Research Connection, for which von Herrath is a member of the Scientific Review Committee, is committed to supporting novel research studies for type 1 diabetes. The DRC provides funding to support early career scientists in carrying out research projects geared toward preventing and curing type 1 diabetes as well as minimizing complications and improving quality of life for those living with the disease. Learn more about current projects and how to support these efforts by visiting http://diabetesresearchconnection.org.

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