In a new study, a team of researchers from the University of Missouri, Georgia Institute of Technology and Harvard University demonstrated the successful application of a novel type 1 diabetes treatment in a large animal model. Their approach involves transplanting insulin-producing pancreatic cells — called islets — from a donor to a recipient without the need for long-term immunosuppressive drugs.
In people with type 1 diabetes, their immune system may malfunction, causing it to attack itself, said Haval Shirwan, professor of Child Health, Molecular Microbiology and Immunology at the MU School of Medicine and one of the study’s lead authors.
“The immune system is a tightly controlled defense mechanism that ensures an individual’s health in an infection-laden environment,” Shirwan said. “Type 1 diabetes occurs when the immune system mistakenly identifies the insulin-producing cells in the pancreas as an infection and destroys them. Usually, once the perceived danger or threat has been eliminated, the immune system’s command and control mechanisms kick in to eliminate any rogue cells. But if this mechanism fails, diseases such as type 1 diabetes develop.”
Diabetes affects the body’s ability to produce or use insulin, a hormone that helps regulate the way blood sugar is used in the body. People with type 1 diabetes do not make insulin and therefore cannot control their blood sugar levels. This loss of control can lead to life-threatening complications such as heart disease, kidney damage and eye damage.
For the past two decades, Shirwan and Esma Yolcu, professors of child health, molecular microbiology, and immunology at the MU School of Medicine, have studied a mechanism called apoptosis that destroys “rogue” immune cells leading to diabetes or transplant rejection. reaction. Islets are achieved by attaching a molecule called FasL to the surface of the islets.
“When a molecule called FasL interacts with another molecule called Fas on rogue immune cells, a form of apoptosis occurs, causing them to die,” said Yolcu, one of the study’s first authors. “Therefore, our team pioneered a technique that enables the production and presentation of a novel FasL on transplanted islet cells or microgels to prevent rejection by rogue cells. After insulin-producing islet cells are transplanted, rogue cells mobilize to the graft for destruction, but was eliminated by FasL binding to Fas on the surface.”
One advantage of this new approach is the possibility of forgoing a lifetime of immunosuppressive drugs that counteract the ability of the immune system to seek out and destroy foreign objects, such as organs, or in this case, cells, when introduced into the body.
“The main problem with immunosuppressive drugs is that they are not specific, so they can have a lot of side effects, such as a high chance of developing cancer,” Shirwan said. “So, using our technology, we found a way to modulate or train the immune system to accept, rather than reject, these transplanted cells.”
Their method utilizes technology contained in U.S. patents filed by the University of Louisville and Georgia Tech and has been licensed by a commercial company with plans to seek FDA approval for human testing. To develop a commercial product, the MU researchers worked with teams from Andres García and Georgia Tech to attach FasL to the surface of a microgel and demonstrate efficacy in a small animal model. They then, together with Jim Markmann and Ji Lei of Harvard University, evaluated the efficacy of the FasL microgel technology in a large animal model, which has been published in this study.
Combine the power of NextGen
This research represents a major milestone in the journey from lab to bedside research, or how lab results can be used directly by patients to help treat different diseases and conditions, a hallmark of MU’s most ambitious research initiative, NextGen Precision Health Initiative.
Emphasizing the promise of personalized healthcare and the impact of large-scale interdisciplinary collaborations, the NextGen Precision Health program brings together innovators such as Shirwan and Yolcu from three other research universities in the MU and UM System in pursuit of life-changing precision Health Advances. This is a collaborative effort to leverage MU’s research strengths to create a better future for health in Missouri and beyond. MU’s Roy Blunt NextGen Precision Health Building consolidates the overall program and expands collaboration among researchers, clinicians and industry partners in a state-of-the-art research facility.
“I think that by using a state-of-the-art facility like the Roy Blunt NextGen Precision Health Building at the right institution, we will be able to build on existing research findings and take the necessary steps to advance our research and make the necessary faster improvement,” Yorku said.
Shirwan and Yolcu, who joined the MU Faculty in Spring 2020, were among the first researchers to begin work at the NextGen Precision Health Building, and after nearly two years at MU, they are now among the first researchers at NextGen to make an article Research papers are accepted and published in high-impact, peer-reviewed academic journals.
“FasL microgel induces immune acceptance of islet allografts in non-human primates”, published in scientific progress, a journal published by the American Association for the Advancement of Science (AAAS). Funding was provided by the Juvenile Diabetes Research Foundation (2-SRA-2016-271-SB) and the National Institutes of Health (U01 AI132817) as well as Juvenile Diabetes Research Foundation Postdoctoral Fellowships and National Science Foundation Graduate Research Fellowships. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding body.
Additional authors of the study include Ji Lei, Hongping Deng, Zhihong Yang, Kang Lee, Alexander Zhang, Cole Peters, Zhongliang Zou, Zhenjuan Wang, Ivy Rosales and James Markmann of Harvard University; Michael Hunchler and James Markmann of Georgia Tech Andrés J. García; Luo Hao, Western Theater General Hospital, Chengdu, China; Chen Tao, Xiamen University School of Medicine, Xiamen, China; and Colleen McCoy, MIT. The authors of the study 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 were also pointed out. The three authors of the study, García, Shirwan and Yolcu, are inventors on US patent application (16/492441, filed February 13, 2020) filed by the University of Louisville and Georgia Tech Research. In addition, García and Shirwan are co-founders of iTolerance and García, Shirwan and Markmann are members of iTolerance’s Scientific Advisory Board.