In a new study, a team of researchers from Missouri, Georgia Tech, and Harvard University demonstrate the successful use of a new treatment for type 1 diabetes in a large animal model. Their approach involves transplanting insulin-producing pancreatic cells – called pancreatic islets – from donor to 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 Sherwan, professor of child health, molecular microbiology and immunology at MU School of Medicine and one of the study’s lead authors.
“The immune system is a tightly controlled defense mechanism that ensures the well-being of individuals in an environment full of infection,” Shirwan said. Type 1 diabetes develops when the immune system misidentifies and destroys the insulin-producing cells in the pancreas as an infection. Usually, once the perceived danger or threat is eliminated, the command and control mechanism of the immune system begins to eliminate any rogue cells. However, if this mechanism fails, diseases such as type 1 diabetes can emerge.”
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 therefore cannot control their blood sugar levels. Loss of control can lead to life-threatening complications such as heart disease, kidney damage, and eye damage.
Over the past two decades, Shirvan and Esma Yolko, professor of child health, molecular microbiology and immunology at MU School of Medicine, have targeted a mechanism called apoptosis, which destroys “rogue” immune cells from causing diabetes or rejecting transplanted pancreatic islets by A molecule called FasL binds to the surface of the islets.
“A type of programmed cell death occurs when a molecule called FasL interacts with another molecule called Fas on rogue immune cells, causing them to die,” said Yolko, one of the study’s first authors. “Therefore, our team pioneered technology that enabled a new form of FasL to be produced and presented to transplanted pancreatic islet cells or microgels to prevent their rejection by rogue cells. After transplantation of insulin-producing pancreatic islet cells, rogue cells move into the graft for destruction but are eliminated them by engaging FasL on their surface.”
One advantage of this new method is the opportunity to forgo lifelong immunosuppressive drugs, which nullify the immune system’s ability to seek out and destroy a foreign body when introduced into the body, such as an organ, or in this case, a cell, an organ transplant.
“The main problem with immunosuppressive drugs is that they are not specific, so they can have a lot of adverse effects, such as higher cases of cancer,” Sherwan said. “So, using our technology, we’ve found a way that we can modify or train the immune system to accept, not reject, these transplanted cells.”
Their method uses technology embedded in a US patent filed by the University of Louisville and Georgia Tech, and has since been licensed by a commercial company that has plans to pursue FDA approval for human testing. To develop the commercial product, MU researchers collaborated with Andres García and the team at Georgia Tech to attach FasL to the surface of microgels with demonstrated efficacy in a small animal model. Next, they joined forces with Jim Markmann and Ji Lei of Harvard University to evaluate the efficacy of the FasL-microgel technique in a large animal model, which is published in this study.
Incorporating the power of NextGen
This study represents a significant milestone in the bench-to-bed research process, or how laboratory results are directly integrated into their use by patients to help treat various diseases and disorders, a hallmark of MU’s most ambitious research initiative, the NextGen Precision Health Initiative.
Highlighting the promise of personalized healthcare and the impact of multidisciplinary collaboration at scale, the NextGen Precision Health initiative brings together innovators such as Shirwan and Yolcu from across MU and UM’s three other research universities in the pursuit of critical, life-changing health advances. . It is a collaborative effort to leverage MU’s research strengths toward a better future for the health of Missouri residents and beyond. The Roy Blunt NextGen Precision Health Building in MU anchors the overall initiative and expands collaboration between researchers, clinicians and industry partners in a state-of-the-art research facility.
“I believe that by being in the right organization with access to a fantastic facility like the Roy Blunt NextGen Precision Health building, it will allow us to build on our current findings and take the necessary steps to continue our research and make the necessary improvements faster,” said Yolko.
Shirwan and Yolko, who joined the faculty at MU in spring 2020, are part of the first group of researchers to begin work at the NextGen Precision Health Building, and after working at MU for nearly two years are now among the first researchers from NextGen to have a paper accepted research paper and published in a peer-reviewed, high-impact academic journal.
“FasL microgels for immune acceptance of islet allografts in non-human primates” are published in science progress, a journal published by the American Association for the Advancement of Science (AAAS). Funding was provided through grants from the Juvenile Diabetes Research Foundation (2-SRA-2016-271-SB) and the National Institutes of Health (U01 AI132817) as well as a Juvenile Diabetes Research Foundation Postdoctoral Fellowship and a National Science Foundation Graduate Research Fellowship. The content is the sole responsibility of the authors and does not necessarily represent the official views of the funding agencies.
Other study co-authors include Ji Li, Hong Bingding, Jihong Yang, Kang Li, Alexander Zhang, Cole Peters, Zhongliang Zhou, Zhengguan Wang, Ivy Rosales, and James Markman at Harvard University. Michael Honkler and Andres J. Garcia at Georgia Institute of Technology (Georgia Tech); Hao Lu at the Western Theater Command General Hospital in Chengdu, China; Tao Chen at Xiamen University College of Medicine in Xiamen, China; and Colin McCoy at the Massachusetts Institute of Technology. The study authors would also like to express their appreciation to Jessica Weaver, Lisa Kojima, Haley Tector, Kevin Ding, Rudi Matheson, and Nicholas Serevis for their artistic contributions.
Potential conflicts of interest were also noted. Three of the study’s authors, García, Shirwan, and Yolcu, are inventors in a US 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 the iTolerance Scientific Advisory Board.