Advisory Committee Chair
Rakesh Patel
Advisory Committee Members
Chad S Hunter
Eugenia Kharlampieva
Gregory Korbutt
Hubert M Tse
Document Type
Dissertation
Date of Award
2021
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
A hallmark of Type 1 diabetes (T1D) is the autoimmune destruction of insulin-producing pancreatic β-cells. Once the β-cells are lost, patients are reliant on less efficient exogenous insulin therapies to maintain glycemic control, leaving them at risk for secondary complications. Islet transplantation can restore the ability to regulate glucose levels without the need for exogenous insulin, however long-term islet graft survival has proven challenging in part due to ongoing immune-mediated destruction. Systemic immunosuppression strategies have proven somewhat effective at preventing rejection, but chronic use leaves the patient susceptible to opportunistic infections and organ toxicity. Reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, can induce islet stress and enhance immune cell activation, ultimately contributing to β-cell destruction. Therefore, suppressing local ROS generation may improve islet graft survival without the need for systemic immunosuppression. We previously generated novel, nanothin encapsulation materials comprised of tannic acid, an antioxidant, and a biocompatible polymer, poly(N-vinylpyrrolidone) (PVPON), that demonstrated ROS scavenging capacity. Utilizing this material, we hypothesized that islet encapsulation with (PVPON/TA) layers would reduce local ROS generation and proinflammatory immune responses, ultimately improving islet graft survival. Islets isolated from NOD.Rag mice iv encapsulated with (PVPON/TA) layers demonstrated significant delays in islet graft rejection when transplanted into autoimmune prone syngeneic NOD and into allogeneic C57BL/6 mice. Investigation of immune populations displayed significant reductions in immune infiltration and enhanced anti-inflammatory M2 macrophage polarization measured by altered STAT signaling. Xenotransplantation of neonatal porcine islets (NPIs) represents another promising avenue to alleviate limited donor availability that plagues human islet transplantation. However, immune responses to xenogeneic tissue are even more aggressive, reducing viability of NPIs after transplantation. Transplantation of (PVPON/TA)-encapsulated NPIs into immunodeficient mice demonstrated enhanced anti-inflammatory macrophage populations and reduced proinflammatory innate immune subsets compared to controls. Further modification of (PVPON/TA) materials with recombinant CTLA-4-Ig, (CTLA-4-Ig/PVPON/TA), demonstrated enhanced islet allograft survival compared to (PVPON/TA) alone. In addition to the modified macrophage polarization seen with (PVPON/TA), (CTLA-4-Ig/PVPON/TA)-encapsulated islet grafts displayed increased regulatory T cell (Treg) populations and effector T cell anergy. These data and the ease of future modification suggest local immunosuppression with antioxidant-based encapsulation materials may be a promising technique to prolong islet graft function.
Recommended Citation
Barra, Jessie Marie, "Suppressing Islet Graft Rejection With Antioxidant-Based Encapsulation Materials" (2021). All ETDs from UAB. 542.
https://digitalcommons.library.uab.edu/etd-collection/542