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1.03.2012

With $10 Million Grant, Norma Sue Kenyon, Ph.D., Aims to Develop Co-Transplant Criteria

Years ago, before researchers knew much about the ability of mesenchymal stem cells to reduce inflammation, repair damaged tissue and promote blood vessel growth, Norma Sue Kenyon, Ph.D., the Martin Kleiman Professor of Surgery, Microbiology and Immunology, and Biomedical Engineering, discovered that delivering mesenchymal stem cells intravenously during islet transplantation more than doubled islet function, enhanced islet survival and reversed rejection episodes.

Now, armed with a new five-year, nearly $10 million grant from the NIH, and the knowledge that mesenchymal stem cells can enhance the use of cell-based therapies to treat type 1 diabetes, Kenyon, who is also director of the Wallace H. Coulter Center for Translational Research and Senior Associate Dean for Translational Science, is poised to reproduce those novel findings, this time with an eye on identifying the optimal source of mesenchymal stem cells and developing the protocols for enhancing and infusing them during and after islet cell transplants.

“Our long-term goal is to find ways to transplant islets so they take up residence in the liver, and function for a much longer period of time, hopefully for the life of the individual,” Kenyon said. “In addition, we’d like to be able to use less immune suppression, as the drugs we use are very potent and they have a lot of side effects. So, the new grant is to reproduce our novel findings – that is, to use mesenchymal stem cells to enhance engraftment of islets, prolong rejection-free survival and reverse islet cell rejection episodes – and then analyze the ideal source of mesenchymal stem cells. Is it from the donor, the recipient or an unrelated third party?

“We also will define the characteristics of the cells associated with enhanced graft survival and function and identify ways to up-regulate the immunomodulatory potential of mesenchymal stem cells, ensuring that cells from different donors have the required potency to be effective.”

Performed at the Diabetes Research Institute since the 1980s, successful islet cell transplants give patients the ability to naturally produce their own insulin. However, transplanted islets initially trigger an inflammatory response, often leading to the loss of about half the transplanted islets.

The new grant advances the research Kenyon and her DRI team initiated in 2001 to explore the hypothesis that mesenchymal stem cells could play a significant role in islet transplantation. In those earlier NIH-funded studies, she and her team attempted to use mesenchymal stem cells to achieve “chimerism,” a state in which donor and recipient blood cells coexist subsequent to bone marrow transplantation. Chimerism had been shown experimentally to allow for transplantation of other cells and tissues from bone marrow donors without the need for life-long immune suppression, an outcome known as immunological “tolerance.”

Based on the immunomodulatory and tissue regenerative properties of mesenchymal stem cells , Kenyon also hypothesized that transplanting mesenchymal stem cells into the liver with islets would limit early loss of islets and lead to enhanced function. Although she and her team did not achieve chimerism in those studies, they found that co-delivering mesenchymal stem cells into the liver with islets more than doubled islet function, improved rejection-free survival, and reversed rejection episodes.

The end goal of the new grant, “Immunomodulatory and Regenerative Effects of Mesenchymal Cells on Allografts,” is to begin clinical trials using the mesenchymal stem cell transplant criteria she and her research partner, Amelia Bartholomew, M.D., professor of surgery and molecular genetics at the University of Illinois at Chicago, develop over the next five years. Bartholomew is studying the benefits of co-transplanting mesenchymal stem cells in renal transplants and focusing on stimulation of the stem cells to enhance their immunomodulatory function. The results of the two projects will be put together to design optimal transplant protocols for kidneys and islets.

Funded by the NIH’s National Institute of Allergy and Infectious Diseases, the grant also includes Daniel Salomon, M.D., from the Genomic and Proteomics Core of Scripps Research Institute in La Jolla, California, and Kenton McHenry, Ph.D., of the Supercomputing and Multidimensional Data Analysis Core at the University of Illinois at Urbana-Champaign.

As the grant noted, “This team will provide a powerful mechanism for data mining and analysis, thereby resulting in acceleration of the discovery process, as compared to the outcome of a single PI working to put together genomic and proteomic data in the context of complex clinical, immunologic and metabolic outcomes.”

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