Immune-Protective Formulations and Process Strategies for Improved Survival and Function of Transplanted Islets

Abstract

Type 1 diabetes (T1D) is an autoimmune disease caused by the immune system attacking and destroying insulin-producing β cells in the pancreas. Islet transplantation is becoming one of the most promising therapies for T1D patients. However, its clinical use is limited by substantial cell loss after islet infusion, closely related to immune reactions, including instant blood-mediated inflammatory responses, oxidative stress, and direct autoimmune attack. Especially the grafted islets are not only exposed to allogeneic immune rejection after transplantation but are also subjected to an autoimmune process that caused the original disease. Due to the development and convergence of expertise in biomaterials, nanotechnology, and immunology, protective strategies are being investigated to address this issue, including exploring novel immune protective agents, encapsulating islets with biomaterials, and searching for alternative implantation sites, or co-transplantation with functional cells. These methods have significantly increased the survival rate and function of the transplanted islets. However, most studies are still limited to animal experiments and need further studies. In this review, we introduced the immunological challenges for islet graft and summarized the recent developments in immune-protective strategies to improve the outcomes of islet transplantation.

Advances in the Use of Biologics and Biomaterials toward the Improvement of Pancreatic Islet Graft Survival in Type 1 Diabetes

“…Significant allogeneic islet loss is provoked by surgical trauma, as a result of either the instant blood-mediated inflammatory response (IBMIR) or stress/ hypoxia-induced apoptosis. [27] Trauma at the local site of implantation triggers the recruitment of inflammatory-mediating cells to the area. The acute blood coagulation, platelet, and complement activation of C5a and C3a proteins during the IBMIR trigger the innate immune system as shown in Figure 3.…”

“…[33] Clinical islet transplantation is often accompanied with systemic immunosuppressive therapy to prevent islet allo-rejection, leading to side effects such as nephrotoxicity, and increased risk of infections. [27] Researchers are exploring the possibility of creating biocompatible encapsulation devices to protect donor islets from HIR, while avoiding the administration of systemic immunosuppressive drugs. Encapsulation devices are designed to provide a physical barrier between allogeneic islets and the recipient immune system.…”

“…Enzymatic dissociation during pancreas isolation, followed by islet retrieval and purification, can drastically reduce functionality and lead to low cell survival rate. [27] Islet recovery and β-cell stimulation in culture media prior to transplantation have been shown to improve outcomes of islets replacement therapy. [56] Several therapeutic strategies (summarized in Table 1) have been exploited to expand the β-cell mass and preserve viability while stimulating insulin from freshly isolated islets.…”

“…[85] Induction strategies involve methods to inhibit and deplete activated T-cells with the most commonly used drug being anti-thymocyte globulin (ATG), also known as thymoglobulin. [27,86] Other drug candidates explored as an induction agent, include alemtuzumab (anti-CD52), which was paired with lower levels of maintenance drugs to examine its potential in a long-term immunosuppression strategy. [85] IL-2 receptor antagonists (such as daclizumab), TNF-α inhibitors (such as etanercept), and IL-1 receptor antagonists (such as anakinra) have also been explored for this application.…”

Biomaterial-assisted strategies to improve islet graft revascularization and transplant outcomes

“…2 Islet transplantation offers a promising alternative that is expected to achieve stable long-term metabolic control while circumventing the complexities and associated complications of conventional treatment. 3 The Edmonton protocol, the first systematic clinical protocol for islet transplantation, was introduced in 2000 and is regarded as the most significant milestone. 4 The Edmonton protocol involves the infusion of donor islet cells into beneficiaries through the hepatic portal vein, eliminating the need for glucocorticoids as immunosuppressants.…”