Targeting Immune Cell Protein May Prevent Type 1 Diabetes

Immune cells are so clever. They can detect any foreign material that they encounter. They have memory and will remember past invaders. But they can also be destructive, harming the body’s own tissues, and memory is a known culprit.

Repeated encounters with a known molecule—called an antigen—in the body are a key feature of autoimmunity, including type 1 diabetes (T1D).

But what if you could halt immune cell memory? Meaning that you can present the immune cell to an antigen that it’s already seen, and it remains inactive.

Breakthrough T1D-funded researchers have discovered a protein on immune cells that, when it is disabled, might just do that. It’s called OCA-B.

Normally, OCA-B helps ensure that immune cells can easily be reactivated if they reencounter the same antigens at a later date. But blocking the activity of OCA-B put the immune cells in a non-responsive state. What’s more: Those that were prone to developing T1D were protected from the disease if they lacked OCA-B!

These results were published in the Journal of Experimental Medicine. Breakthrough T1D-funded researchers who were involved include the lead author, Dean Tantin, Ph.D., Brian D. Evavold, Ph.D., Danny H.-C. Chou, Ph.D., three of whom have received grants from Breakthrough T1D, and all based at the University of Utah.

When Breakthrough T1D was founded in 1970, there were no types of diabetes. There was no type 1, no type 2, no gestational (which, as we now know, happens when you are pregnant). It was all diabetes.

Until 1974. Two teams showed—for the first time—that insulin-dependent diabetes is associated with the development of antibodies directed against insulin-producing beta cells in the pancreas.1,2 This was instrumental in establishing type 1 diabetes (T1D) as an autoimmune disease.

Using this, investigators were able to:

1. Describe the presence of more antibodies, besides the islet cell antibodies, that were associated with type 1 diabetes. There are now 5 antibodies connected with the disease.

 What’s more, studies have shown that T1D begins well before its symptoms appear—and it includes the presence of 2 or more T1D-specific antibodies. This allowed us to conduct clinical trials before the presence of symptoms, to prevent or delay the progression to clinical onset of the disease.

2. Refine the tests for T1D-related antibodies, for more widespread study. This led to TrialNet—an international NIH-funded and Breakthrough T1D-supported network of leading academic institutions, endocrinologists, physicians, scientists, and healthcare teams dedicated to finding cures for T1D—who began its Pathway to Prevention study in 2004. This study identifies people at risk for T1D with the aim to conduct clinical trials to stop the disease.

3. Conduct clinical trials targeting several immune pathways and mechanisms, including teplizumab—a drug that blocks CD3, a blood marker that helps activate immune cells. In a clinical trial conducted by TrialNet, it was the first study to significantly delay the onset of T1D, for nearly 3 years, in individuals at-risk of developing the disease.

Recently, Breakthrough T1D also launched a community-based education and awareness program to expand screening to the general population. The program’s aim is to make people understand what type 1 diabetes is, how screening is advantageous to the public, how they can be involved, and what to do if you are positive for T1D-specific antibodies.

Learn more about the Breakthrough T1D Early Detection Program.

  1. Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974 Nov 30; 2 (7892): 1279-83. PMID: 4139522.
  2. MacCuish AC, Irvine WJ, Barnes EW, Duncan LJ. Antibodies to pancreatic islet cells in insulin-dependent diabetics with coexistent autoimmune disease. Lancet. 1974 Dec 28; 2 (7896): 1529-31. PMID: 4140978.

In the words of Colin Dayan, M.D., Ph.D., professor of clinical diabetes and metabolism at Cardiff University: “Type 1 diabetes is almost the only major autoimmune disease now that does not have a licensed immunotherapy.” And he’s going to change that.

Dr. Dayan conducts clinical trials in the development of immune therapies, which aims to re-train the immune system to stop the attack on insulin-producing beta cells. These therapies could be given to people when they are first diagnosed with type 1 diabetes (T1D), and still have surviving insulin-producing cells, or when they have a high risk of T1D, before their insulin-producing cells have been destroyed, to try and stop the condition from developing (as is the case with the immune therapy teplizumab, which was able to delay T1D for nearly 3 years).

Dr. Dayan set up the Type 1 Diabetes UK Immunotherapy Consortium (T1D UK), backed by Diabetes UK and Breakthrough T1D, to coordinate immunotherapy trials and improve the way in which they are carried out. So far, the consortium has increased the number of people with T1D taking part in vital clinical trials ten-fold, and is paving the way toward cures.

But what keeps him motivated as a scientist? People with T1D.

“Just one hour in the clinic reminds me why this work is important,” says Dr. Dayan, “and when I meet a person who has just heard that they have been diagnosed, I long to be able to offer something different from the treatments we already have.”

So do we.

Find out from his video why being a clinician is both challenging and gratifying in T1D research:

Breakthrough T1D’s funding enables promising scientists, like Colin, to focus their talent, ambition and passion on improving life with T1D. Learn more about the researchers we fund, and learn how you can support their work to prevent, treat and—one day—find cures for T1D.

Last year, at the American Association for Diabetes (ADA) Scientific Sessions, a drug, called teplizumab, was able to significantly delay—for over two years—the onset of type 1 diabetes (T1D) in participants with a high risk of developing the disease. This was the first ever study in humans to show a delay in the onset of T1D. But it doesn’t stop there. Breakthrough T1D has updated results, and this is big. The investigators were able to follow up on the individuals who didn’t develop clinical diabetes, and the effect of teplizumab had been sustained: 50% of those treated with teplizumab remain diabetes-free, compared to only 22% of those taking placebo, and the delay in diabetes onset was close to 3 years (35 months). These were presented by Emily Sims, M.D., an assistant professor of pediatrics at Indiana University and a Breakthrough T1D-funded investigator, at ADA’s Scientific Sessions.

Additionally, the participants, both the teplizumab and placebo groups, had a progressive decline in the biomarker that measure’s the body’s ability to produce insulin—C-peptide—preceding the trial. But the teplizumab team found that production of C-peptide actually went up following treatment with teplizumab, especially in the first 6 months after treatment. Like, teplizumab could reverse the downward trajectory of C-peptide loss that was there before the trial.* Um, wow. And there’s more: the increases in C-peptide were correlated with induction of a state of “exhaustion” in “bad” immune cells. Like, they literally took a punch and lost the ammo to keep on attacking the beta cells. Wow (again).

So, could the exhaustion of “bad” immune cells result in not getting T1D or significantly slowing down the time to getting it? Well, we’re not there yet, but we’re close, and closer to a day when T1D might be prevented, forever.

Breakthrough T1D Leadership: Breakthrough T1D funded one of the first clinical trials of this drug, results of which were integral to the teplizumab prevention trial. The study in this report was conducted by TrialNet, a T1D trial consortium funded by NIDDK and by the NIH’s Special Diabetes Program for which Breakthrough T1D is the leading advocate. Multiple studies involving samples and data from teplizumab trials have continued to receive Breakthrough T1D funding. Teplizumab (now called PRV-031) is currently being tested in a phase 3 clinical trial in people recently diagnosed with T1D, headed by Provention Bio, a company with an investment from the Breakthrough T1D T1D Fund. If successful, this could become the first immune therapy approved for T1D.

*In the placebo group, C-peptide still declined.

In this time of great uncertainty, there is some exciting news out of Europe. Innodia, a partnership between public and private entities working together to fund research aimed at biomarker discovery and the prevention of type 1 diabetes (T1D), received an additional €12 million in funding from the European Commission, Breakthrough T1D and the Helmsley Charitable Trust. Led by Breakthrough T1D-funded researcher, Professor Chantal Mathieu, M.D., Ph.D., this funding means this critical project, called Innodia Harvest, can begin.

Innodia began in 2015 as a collaboration between the leading charitable funders of T1D research, Breakthrough T1D, the Helmsley Charitable Trust, The European Commission, and several pharmaceutical companies. In the years since, the consortium has grown to include 40 partners from around Europe and the world.

“Innodia Harvest will build on the success of Innodia and leverage Innodia’s network of clinical trial centers and world-renowned experts to expand on previous biomarker work and conduct clinical trials in close collaboration with people with T1D and family members,” said Jeannette Soderberg, Ph.D., Breakthrough T1D Associate Director, European Research. “In this very important public private partnership, we will be able to test new therapies on large European platform using an EMA endorsed trial protocol, ultimately in the hope to provide the T1D community with a preventive therapy.”

Delaying and preventing the onset of T1D is a key part of Breakthrough T1D’s research portfolio, and identifying biomarkers that indicate T1D in at-risk individuals is paramount to achieving that goal. Innodia Harvest will build on the work that began in 2016 through biomarker validation.

Additionally, this new tranche of funding allows Innodia Harvest to start clinical trials in 2020, bringing preventative therapies one step closer to fruition. These two clinical trials take different approaches to arresting the progression of T1D; one is an immune therapy led by industry and the other is a beta cell therapy driven by academia. This diverse approach exemplifies Breakthrough T1D’s strategy of pursuing several plans of attack to make the biggest impact in the shortest amount of time.

Learn more about the additional funding at the Innodia website.

Carla Greenbaum, M.D., chair of TrialNet—an international Breakthrough T1D-supported network that is dedicated to finding cures for type 1 diabetes (T1D)—and a professor at Benaroya Research Institute, discussed T1D research in the time of COVID-19, including what TrialNet is up to, on Breakthrough T1D’s Facebook Live event. She chats about:

Watch the full, recorded livestream below:

The idea of heterogeneity—a disease having different or diverse pathways to the same disease type—has been gaining ground in type 1 diabetes (T1D). It was iterated by almost all of the presenters at the 12th Network for Pancreatic Organ Donors with Diabetes (nPOD) Annual Meeting (February 23-26), and a new publication gives further support to the concept as a way to better understand T1D. In the paper, Breakthrough T1D-funded researchers—including Sarah Richardson, Ph.D., and Richard Oram, MBBCh, of the University of Exeter—found that T1D is comprised of two different subtypes, called endotypes by the scientific community, which are dependent upon the age at diagnosis.

The researchers used samples from nPOD and the Exeter Archival Diabetes Biobank (EADB), and looked at co-localization of insulin and proinsulin—the precursor to insulin—in the pancreas. They found that people under the age of 7 do not process proinsulin properly, leading to a highly aggressive attack on beta cells. The investigators propose this aggressive subtype should be defined as “type 1 diabetes endotype 1” or T1DE1. People diagnosed at 13+ years of age have lower levels of infiltrating immune cells and they retain more insulin-containing islets. Investigators call this subtype “type 1 diabetes endotype 2” or T1DE2. The field is now working hard to figure out which T1D pathways govern this.

In clinical research, the authors say, it will be important to design future immune therapies based on the distinct endotypes of T1D.

Breakthrough T1D funded other authors of the study, as well, including Andrew T. Hattersley, FRS, Noel G. Morgan, Ph.D., Bart O. Roep, Ph.D., and Timothy I. Tree, Ph.D.

Reza Abdi, M.D., has a reason to care about type 1 diabetes research—he has a father and a brother with the disease. Dr. Abdi, of Brigham and Women’s Hospital in Boston, is an expert in immune therapy research, specifically nanotechnologies—miniscule therapies that can deliver immune treatments to specific regions in the body. His goal: To bring new therapies to people with type 1 diabetes (T1D).

“Immunotherapy represents probably the most promising routes or ways of treating type 1 diabetes.”

– Reza Abdi, M.D., Brigham and Women’s Hospital

Please join us for an inside look, as we present the fifth video in our seven-part series Inside the Lab at Boston. See as Dr. Abdi gives a first-hand overview of the passion, the obstacles and the hope that immune therapies may have for the T1D community, and how he and Breakthrough T1D are helping to advance.

If you haven’t seen the other featured videos in this series already, don’t miss out. See how scientists are collaborating to expedite the process of finding cures:

Don’t forget to check back next week, when we highlight Kidney Complications Research in Boston, featuring Monika Niewczas, M.D., Ph.D., M.P.H., and Manoj Gupta, Ph.D. A week later, be on the lookout for Eye Complications Research in Boston, featuring Jennifer Sun, M.D., M.P.H.

Funding immune therapy research is one of Breakthrough T1D’s most critical undertakings, essential in our mission to find cures for type 1 diabetes. Please consider donating today, and we’ll turn Type 1 into Type None, with your support.

Breakthrough T1D today launched its first Center of Excellence, a new research and funding model aimed at accelerating leading type one diabetes (T1D) research.

The new Breakthrough T1D Northern California Center of Excellence will unite the work being done at Stanford University and the University of California, San Francisco, focusing on beta cell therapies and immune therapies.

“We’re excited that the Northern California center is our first Center of Excellence,” said Aaron J. Kowalski, Ph.D., President and CEO of Breakthrough T1D. “The scientists at Stanford and UCSF are leaders in driving true innovation as they advance research into the immune system, beta cells and stem cells.”

Centers of Excellence are a new concept aiming to tap into and accelerate critical T1D research being done around the world.

The new model gives researchers the stability that will enable longer-term projects, while also allowing the flexibility to be nimble as new science emerges.

The innovative model also promotes collaboration and provides longer-term stability to institutions that have demonstrated excellence in T1D research. Each Center will be initially funded for five years through the generous support of Breakthrough T1D donors.

The Northern California Center of Excellence will focus on the interaction of immune cells with insulin-producing beta cells; generating islets and immune cells from stem cells for next-generation therapies; and developing ways to transplant insulin-producing cells into people with T1D without requiring immunosuppression.

It brings together experts in the fields of stem cells, T1D immunology, gene editing, transplant immunology and technology. Many of the scientists have received Breakthrough T1D early-career grants that prompted them to make T1D research the focus of their life’s work.

The Breakthrough T1D Northern California Center of Excellence is made possible with initial contributions from Karen and Jeff Jordan, Michelle Griffin and Tom Parker, and Karen and Joe Niehaus.

To learn more, read our press release here.

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to teplizumab, an anti-CD3 monoclonal antibody, for the prevention or delay of type 1 diabetes (T1D) in individuals at-risk of developing the disease. CD3 is a blood marker that helps to activate the immune cells—called T cells—which are thought to be responsible for the disease.

Kevan Herold, M.D., of Yale University and a longtime Breakthrough T1D grantee, presented the results of the clinical trial at the American Diabetes Association’s Scientific Sessions in June. For the first time ever, an immune therapy treatment was able to significantly delay—for over two years—the onset of T1D in participants with a high risk of developing the disease. The FDA’s decision to provide Breakthrough Designation recognizes the importance of these results to the T1D community, and those at risk of developing it, and is intended to lead to an interactive and efficient drug development process. Breakthrough T1D will continue to fight for the development of teplizumab and other type 1 diabetes treatments that show the potential to make a significant difference to people with—and at risk for—T1D.

Breakthrough T1D funded one of the first clinical trials of this drug, results of which were integral to the teplizumab prevention trial. This study was conducted by TrialNet, also funded by Breakthrough T1D and by the NIH’s Special Diabetes Program for which Breakthrough T1D is the leading advocate.

Teplizumab (also called PRV-301) is now being tested in a phase III clinical trial in people recently diagnosed with T1D, sponsored by Provention Bio, a company with an investment from the T1D Fund.

If successful, this could become an approved therapy that modifies the disease course of T1D, instead of only treating the symptoms.