Modify the body’s immune system to help treat type 1 diabetes

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In a new study, a team of researchers from the University of Missouri, Georgia Tech and Harvard University have demonstrated the successful use of a new type 1 diabetes treatment in a large animal model. Their approach involves transplanting insulin-producing pancreatic cells – called pancreatic islets – from a donor to a recipient, without the need for long-term immunosuppressive drugs.

In people with type 1 diabetes, their immune system can malfunction, causing it to attack itself, said Haval Shirwan, professor of child health and molecular microbiology and immunology at the MU School of Medicine, and one of the main authors of the study.

“The immune system is a tightly controlled defense mechanism that ensures the well-being of individuals in an environment full of infections,” Shirwan said. “Type 1 diabetes develops when the immune system mistakenly identifies insulin-producing cells in the pancreas as infections and destroys them. Normally, once a perceived danger or threat is removed, the control mechanism and control of the immune system comes into play to eliminate everything. However, if this mechanism fails, diseases such as type 1 diabetes can manifest.

Diabetes affects the body’s ability to produce or use insulin, a hormone that helps regulate how blood sugar is used in the body. People with type 1 diabetes do not make insulin and are therefore unable to control their blood sugar levels. This loss of control can lead to life-threatening complications such as heart disease, kidney damage, and eye damage.

Over the past two decades, Shirwan and Esma Yolcu, professor of child health and molecular microbiology and immunology at MU School of Medicine, have targeted a mechanism, called apoptosis, that destroys “rogue” immune cells by causing diabetes or rejection of transplant recipients. pancreatic islets by attaching a molecule called FasL to the surface of the islets.

“A type of apoptosis occurs when a molecule called FasL interacts with another molecule called Fas on rogue immune cells, and it causes them to die,” said Yolcu, one of the study’s first authors. “Therefore, our team pioneered a technology that enabled the production of a new form of FasL and its presentation on transplanted pancreatic islet cells or microgels to avoid rejection by rogue cells. . Following transplantation of insulin-producing pancreatic islet cells, the rogue cells engraft for destruction but are eliminated by FasL engaging Fas on their surface.”

One of the benefits of this new method is the ability to potentially forgo a lifetime of taking immunosuppressive drugs, which neutralize the immune system’s ability to seek out and destroy a foreign object when introduced into the body, such as that an organ, or in this case, a cell, transplant.

“The major problem with immunosuppressive drugs is that they are not specific, so they can have many adverse effects, such as high incidences of cancer development,” Shirwan said. “So using our technology, we found a way to modulate or train the immune system to accept, not reject, these transplanted cells.”

Their method uses technology included in a US patent filed by the University of Louisville and Georgia Tech, and has since been licensed by a commercial company that plans to seek FDA approval for human testing. To develop the commercial product, MU researchers collaborated with Andres García and the Georgia Tech team to attach FasL to the surface of microgels with evidence of efficacy in a small animal model. Next, they joined Jim Markmann and Ji Lei from Harvard to evaluate the effectiveness of FasL-microgel technology in a large animal model, which is published in this study.

Integrate the power of NextGen

This study represents an important step in the laboratory-to-bedside research process, or how laboratory results are directly integrated into patient use to help treat different diseases and disorders, a hallmark of the MU’s most ambitious research initiative, the NextGen Precision Health Initiative.

Highlighting the promise of personalized healthcare and the impact of large-scale interdisciplinary collaboration, the NextGen Precision Health initiative brings together innovators like Shirwan and Yolcu from across UM and the three other research universities in the UM system in the pursuit of life-changing advances in precision health. This is a collaborative effort to build on MU’s research strengths toward a better future for the health of Missourians and beyond. The Roy Blunt NextGen Precision Health building at MU anchors the overall initiative and expands collaboration between researchers, clinicians and industry partners in the cutting-edge research center.

“I believe that by being in the right institution with access to a large facility like the Roy Blunt NextGen Precision Health building, it will allow us to build on our existing findings and take the necessary steps to further our research and make the improvements needed, faster.” Yolcu said.

Shirwan and Yolcu, who joined the MU faculty in the spring of 2020, are among the first group of researchers to begin work in the NextGen Precision Health building, and after working at MU for nearly two years, they are now among the first NextGen investigators to have a research paper accepted and published in a high-impact, peer-reviewed academic journal.

“FasL microgels induce immune acceptance of islet allografts in non-human primates”, was published in Scientists progress, a journal published by the American Association for the Advancement of Science (AAAS). Funding was provided by grants from the Juvenile Diabetes Research Foundation (2-SRA-2016-271-SB) and the National Institutes of Health (U01 AI132817), as well as a postdoctoral fellowship from the Juvenile Diabetes Research Foundation and a graduate of the National Science Foundation. Fellowship. The content is the sole responsibility of the authors and does not necessarily represent the official views of the funding bodies.

Other study authors include Ji Lei, Hongping Deng, Zhihong Yang, Kang Lee, Alexander Zhang, Cole Peters, Zhongliang Zou, Zhenjuan Wang, Ivy Rosales, and James Markmann at Harvard; Michael Hunckler and Andrés J. García of the Georgia Institute of Technology (Georgia Tech); Hao Luo at Western Theater Command General Hospital in Chengdu, China; Tao Chen of Xiamen University School of Medicine in Xiamen, China; and Colleen McCoy of the Massachusetts Institute of Technology. The study authors would also like to thank Jessica Weaver, Lisa Kojima, Haley Tector, Kevin Deng, Rudy Matheson, and Nikolaos Serifis for their technical contributions.

Potential conflicts of interest are also disclosed. Three of the study authors, García, Shirwan and Yolcu, are the inventors of a U.S. patent application filed by the University of Louisville and Georgia Tech Research Corporation (16/492441, filed February 13, 2020). Additionally, García and Shirwan are co-founders of iTolerance, and García, Shirwan and Markmann serve on iTolerance’s Scientific Advisory Board.

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