Shirwan, Haval , PhD
Immunomodulation with SA-FasL-engineered pancreatic islets for the treatment of type 1 diabetes
General Research Subject: Type 1 Diabetes
Focus: Immunology, Transplantation
Type of Grant: Basic Science
Project Start Date: January 1, 2012
Project End Date: December 31, 2014
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and or/curing diabetes?
This project focuses on pancreatic islet transplantation as an effective means of treating type 1 diabetes (T1D). T1D is an autoimmune disease where the patient's immune system sees insulin-producing beta cells in the pancreas as foreign and destroys them, which culminates in the development of T1D. Although standard insulin treatment is effective and saves lives, it does not prevent long-term complications of T1D due to its inability to regulate the blood glucose at levels achieved in healthy individuals. Extensive research in animals as well as humans has demonstrated that the transplantation of allogeneic (from another individual) pancreatic islets can establish minute-to-minute control of blood glucose levels seen in healthy individuals, and as such overcome complications of exogenous insulin treatment for T1D. Unfortunately, allogeneic islet grafts are faced with rejection by the recipient's immune system that destroys the insulin producing beta cells in the first place. A white blood cell type, designated as T cells, is the major culprit of the destruction of patient's own beta cells as well as those grafted from another individual. Therefore, controlling the destructive function of these pathogenic T cells is key to the long-term survival of pancreatic islet grafts. This is presently being achieved in the clinic using immunosuppressive drugs that are not only ineffective, but also have major side effects on the graft as well as on the patient. The challenge in the field is to control the destructive function of T cells without the use of chronic immunosuppression, i.e., inducing immune tolerance to foreign pancreatic islets. This proposal is designed to induce immune tolerance by engineering allogeneic pancreatic islets with a protein that has the ability to specifically destroy graft-reactive T cells without compromising the ability of the recipient immune system to respond to infections. This will be achieved by modifying the surface of allogeneic pancreatic islets with a B-complex vitamin, called biotin, which binds strongly to a bacterial protein called streptavidin. Modified islets will then be decorated with a recombinant protein genetically engineered to have streptavidin fused to another molecule called FasL. Following transplantation, FasL on the surface of engineered islets will protect them from destruction by sending a death signal through its receptor, Fas, expressed on the attacking T cells.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The proposed approach will first be tested for the prevention of allogeneic islet graft rejection in a mouse model of human T1D called non-obese diabetic (NOD) mouse. If shows efficacy in the NOD model, we will next test the efficacy and feasibility of this approach for the treatment of diabetes in monkeys as a prelude to the translation of this approach into the clinic for the treatment of T1D.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Type 1 diabetes inflicts a significant portion of population in the worldwide, including US. Importantly, this disease can be treated with allogeneic islet transplantation, provided that graft rejection is controlled. I have devoted significant research effort over a few decades to understand graft rejection, and as a result gained significant expertise and know-how that may help the use of allogeneic pancreatic islet transplantation to treat T1D. In particular, I have pioneered a practical and effective approach to engineer cells, tissues, and organs with proteins of interest and use the engineered cells, tissues, and organs to control rejection. This award will allow us to test if engineering of allogeneic islets with an immunomodulatory protein of interest called FasL is effective in preventing rejection and treating T1D in the NOD mouse model.
In what direction do you see the future of diabetes research going?
Exogenous insulin treatment has been the major treatment option for patients with T1D irrespective its inability to tightly regulate blood glucose levels that result in long-term complications. Irrespective of intense efforts over the past several decades to develop a curative approach, pancreatic islet transplantation remains the most viable approach. However, graft rejection persists as a major barrier that significantly limits the therapeutic utility of pancreatic islet transplantation. Recent important progresses in the biomedical field in general and autoimmunity and transplantation in particular raise hope for the development of effective approaches to control allograft rejection and cure T1D.
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