Coacervates for Localized and Sustained Delivery of Immunomodulators to Prevent Islet Allograft Rejection
Abstract
Diabetes is the seventh leading cause of death in the U.S. Military personnel, Veterans, and their families are more prone to develop type 1 diabetes (T1D) due to job-related stress and operational and environmental conditions. According to the Veterans Administration, diabetes among the Veteran population is the third most common diagnosis with a prevalence rate of 25% as compared to 8.3% in the general population. The estimated annual cost of diabetes on the U.S. healthcare system is over $242 billion and is associated with multiple chronic conditions, including cardiovascular, stroke, and blindness. Individuals with T1D constitute approximately 10% of total diabetics. The current standard of care for T1D is insulin treatment, which is burdensome and only partially efficacious in preventing long-term complications. Insulin is made by pancreatic islets, which are destroyed by the T1D patients’ own immune system. Transplantation of pancreatic islets from cadaveric donors was effective in restoring normal blood glucose levels in a multicenter phase III clinical trial and emerged as a promising therapy for T1D. However, most islet transplant patients do not maintain long-term graft survival and function due to immune rejection and complications of chronic immunosuppression used to control rejection. Therefore, there is an urgent need for an immunomodulatory approach that effectively controls the rejection without the need for chronic immunosuppression. Two distinct and opposing immune mechanisms regulate rejection of transplanted pancreatic islets: destructive T effector (Teff) cells killing the islets and protective T regulatory (Treg) cells that control Teff cells and shield the transplanted islets from rejection. Thus, restoring the Teff and Treg cell balance is the key to transplant survival and has been the focus of intense translational research. Immunomodulatory approaches to date have targeted either Teff or Treg cells separately, but not both simultaneously, resulting in minimal clinical benefit. We will target both. Fas and IL-2R are two cell surface receptors (proteins) that regulate the balance between Treg and Teff cells under normal physiological conditions. Fas and IL-2R are triggered by their counter-receptors called, FasL and IL-2, respectively. Teff cells normally do not express Fas on their surface, but do so when interacting with grafted islets and perceive them as dangerous. The Principal Investigator (PI) of this proposal generated a recombinant protein designated as SA-FasL that kills the destructive Teff cells. The binding of IL-2 to IL-2R on protective Treg cells results in their expansion and improves their protective function. Thus, the combined use of these two reagents will kill the destructive Teff cells and expand the protective Treg cells, tilting the balance of towards protection of the transplanted islets. These two biologics will be loaded in a delivery vehicle invented by the Partnering PI to make them even more effective. The vehicle increases the safety of the reagents by reducing side effects and prolong their presence in the body. The proposed research addresses two of the FY20 PRMRP topics related to diabetes: (i) research on the transplantation of allogeneic or autologous pancreatic islet cells for long-term natural insulin production, and (ii) interventions to prevent or treat diabetes complications, including diabetic retinopathy, nephropathy, neuropathy, cardiomyopathy, and impaired wound healing. Furthermore, if effective for diabetes treatment, our approach can also be used for other autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel diseases, two other focus areas for FY20 PRMRP. Additionally, our approach combines a genuinely multidisciplinary group of researchers providing their respective expertise encompassing islet transplantation, T1D, protein engineering, immunology, and drug delivery. As this research develops and begins its translation tow
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110526
Entities
People
- Haval Shirwan
Organizations
- Curators of the University of Missouri
- United States Army