Objective
The Tse lab demonstrated that islet encapsulation with immunomodulatory coatings can delay islet graft rejection following transplantation in mouse models, but the protection observed was not complete as some recipients were not able to maintain euglycemia long-term. In addition, the Haskins lab has used nanoparticles to suppress autoreactive T cell responses effectively in mouse models of islet transplantation, but this approach alone was also not able to elicit sustained immunoprotection. Therefore, we have decided to combine both strategies and determine if we can delay both also- and autoimmune responses involved in islet graft destruction.
Background Rationale
Type 1 diabetes (T1D) is an autoimmune disease resulting in β-cell destruction. Transplantation of islets can restore euglycemia in patients with T1D. However, a major hurdle for the clinical application of islet transplantation is immune rejection. Leukocytes that infiltrate islet grafts generate proinflammatory effector responses to destroy islet transplants. Technologies that delay islet allograft rejection are lacking. The challenge is to develop combinatorial strategies that stabilize islet function, ensure transplant survival, and provide immunoprotection.
Description of Project
Islet transplantation is a cure for Type 1 diabetes, but transplanted islets are susceptible to immune-mediated destruction. Encapsulation of islets with a protective biomaterial that retains insulin secretion, but also prevents recognition by the immune system is highly desired. We will determine if combinatorial strategies with nanoparticles that can suppress T cell responses in conjunction with islet encapsulation with a novel antioxidant and immune system modulator, tannic acid and CTLA-4-Ig, respectively, can mediate immune suppression and prolong islet function after transplantation.
Anticipated Outcome
We anticipate that the use of immunosuppressive nanoparticles and islet encapsulation will provide long-term immune protection without compromising islet function following transplantation into diabetic NOD mice. The combined use will be more efficacious than each individual strategy alone. In the event that we do not observe long-term immunoprotection, we will analyze specific immune cell populations that are involved in islet graft destruction and will develop novel strategies to target these immune cell(s). The advantages of our encapsulation technology is that we can conjugate additional immune inhibitors on the outside coating to target other cell types involved in islet graft destruction.
Relevance to T1D
Islet transplantation is effective in properly restoring euglycemia in patients with Type 1 diabetes, but unfortunately, systemic immunosuppression is needed for islet transplant recipients. Our research proposal will determine if combining our two novel approaches of delaying islet graft destruction may be efficacious in future human translational studies. One approach will target the T cells involved in mediating islet graft destruction and the other approach will involve islet encapsulation to provide a physical barrier against immune interactions.