Ridgway, William , M.D.
Soluble CD137 in Type one diabetes
General Research Subject: Type 1 Diabetes
Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Genetics\Type 1 Diabetes, Immunology
Type of Grant: Clinical Scientist Training Award
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Diabetes Type: Type 1 diabetes
Despite much progress in understanding the immune and genetic basis of Type one diabetes (T1D), new therapies and new experimental approaches to therapy are still needed. An ideal approach would deliver disease-suppressive immunotherapy directly to the pancreatic islets, thus preventing or reversing disease and minimizing systemic immunosuppression and its associated risks. My lab focuses on genetically defined pathways producing T1D in nonobese diabetic (NOD) mice and tests therapeutic agents directed to those aberrant pathways. CD137 is a powerful immune costimulatory molecule implicated in the pathogenesis of diabetes in NOD mice. We previously prevented T1D in NOD mice by treating with antibodies to CD137.
Our further research into CD137 shows that a highly immunosuppressive soluble form of this protein is produced by T regulatory cells. Here, we propose to use a cellular-based therapy to deliver soluble CD137 directly to the site of disease, the inflamed pancreatic islet. By delivering this immunosuppressive molecule to the islet, we will avoid systemic immune suppression. Thus this grant tests the therapeutic efficacy of a novel immune molecule, soluble CD137. Moreover, the lentiviral gene ontology system we propose to use is a novel tool for testing many different gene products, using a modular approach to gene expression and cellular tracking in which different genes can quickly be expressed and followed using several different fluorescent markers. Thus our novel approach will become a valuable tool for the T1D research community. Both our approach and our novel immunosuppressive molecule should open new directions in T1D research and therapy.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My research on soluble CD137 is intended to lead to a new therapy directed towards autoreactive T cells in new onset Type one diabetes. We have known for over 25 years that T1D is caused by autoreactive T cells, yet progress has been slow in using this knowledge to treat disease. Our approach is to target a different aspect of T cell biology, a different (untested) signaling pathway that could be used to downregulate autoreactive T cell activation. This therapy could be used alone or in combination with existing therapies that target the T cell receptor (e.g. anti-CD3 therapy).
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our work is dedicated to finding new approaches to treating new onset T1D. In addition, however, we believe the CD137 immunogenetic pathway is genetically implicated in both humans and mice. Therefore increased knowledge of this pathway could help both new onset diabetics and help understand the genetically imposed risks leading to T1D. Understanding the genetic risks is relevant to diabetes patients who want to try to understand the risk their children face.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have dedicated my career to researching and treating autoimmune diseases. Our work suggests that many autoimmune diseases have common underlying genetic mechanisms that may manifest as different autoimmune diseases. I believe that basic research can discover the cause and cure for autoimmune diseases including T1D and I am very excited to be able to contribute to help individuals with this devastating disease.
In what direction do you see the future of diabetes research going?
We need to continue the difficult process of identifying genetic risk factors so that we can screen and monitor children at high risk for T1D, in order to immediately identify them at the earliest possible time when they develop the disease.
In addition, we need to continue to understand the biology of the disease in order to identify novel immune pathways that are acting to cause the disease. Ultimately it may require a combination-therapy approach to treat site-specific autoimmunity. This means that we will need multiple drugs directed to different but synergistic immune pathways.
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