Co-localized immune protection using dexamethasone-eluting micelles in a murine islet allograft model.

The broad application of ß cell transplantation for type 1 diabetes is hindered by the requisite of lifelong systemic immunosuppression. This study examines the utility of localized islet graft drug delivery to subvert the inflammatory and adaptive immune responses. Herein, we have developed and characterized dexamethasone (Dex) eluting Food and Drug Administration-approved micro-Poly(lactic-co-glycolic acid) micelles and examined their efficacy in a fully major histocompatibility complex-mismatch murine islet allograft model. A clinically relevant dose of 46.6 ± 2.8 µg Dex per graft was confirmed when 2 mg of micelles was implemented. Dex-micelles + CTLA-4-Ig (n = 10) resulted in prolonged allograft function with 80% of the recipients demonstrating insulin independence for 60 days posttransplant compared to 40% in empty micelles + CTLA-4-Ig recipients (n = 10, P = .06). Recipients of this combination therapy (n = 8) demonstrated superior glucose tolerance profiles, compared to empty micelles + CTLA-4-Ig recipients (n = 4, P < .05), and significantly reduced localized intragraft proinflammatory cytokine expression. Histologically, increased insulin positive and FOXP3+ T cells were observed in Dex-micelles + CTLA-4-Ig grafts compared to empty micelles + CTLA-4-Ig grafts (P < .01 and P < .05, respectively). Localized drug delivery via micelles elution has the potential to alter the inflammatory environment, enhances allograft survival, and may be an important adjuvant approach to improve clinical islet transplantation outcomes.

Nanothin Conformal Coating with Poly(N-vinylpyrrolidone) and Tannic Acid (PVPON/TA) Preserves Murine and Human Pancreatic Islets Function.

Beta cell replacement therapies can restore glycemic control to select individuals living with type 1 diabetes. However, the obligation of lifelong immunosuppression restricts cell therapies from replacing exogenous insulin administration. Encapsulation strategies can reduce the inherent adaptive immune response; however, few are successfully translated into clinical testing. Herein, we evaluated if the conformal coating of islets with poly(N-vinylpyrrolidone) (PVPON) and tannic acid (TA) (PVPON/TA) could preserve murine and human islet function while conferring islet allograft protection. In vitro function was evaluated using static glucose-stimulated insulin secretion, oxygen consumption rates, and islet membrane integrity. In vivo function was evaluated by transplanting human islets into diabetic immunodeficient B6.129S7-Rag1tm1Mom/J (Rag-/-) mice. The immunoprotective capacity of the PVPON/TA-coating was assessed by transplanting BALB/c islets into diabetic C57BL/6 mice. Graft function was evaluated by non-fasting blood glucose measurements and glucose tolerance testing. Both coated and non-coated murine and human islets exhibited indistinguishable in vitro potency. PVPON/TA-coated and control human islets were able to restore euglycemia post-transplant. The PVPON/TA-coating as monotherapy and adjuvant to systemic immunosuppression reduced intragraft inflammation and delayed murine allograft rejection. This study demonstrates that PVPON/TA-coated islets may be clinically relevant as they retain their in vitro and in vivo function while modulating post-transplant immune responses.

Islet Biology During COVID-19: Progress and Perspectives.

The coronavirus-2019 (COVID-19) pandemic has had significant impact on research directions and productivity in the past 2 years. Despite these challenges, since 2020, more than 2,500 peer-reviewed articles have been published on pancreatic islet biology. These include updates on the roles of isocitrate dehydrogenase, pyruvate kinase and incretin hormones in insulin secretion, as well as the discovery of inceptor and signalling by circulating RNAs. The year 2020 also brought advancements in in vivo and in vitro models, including a new transgenic mouse for assessing beta-cell proliferation, a "pancreas-on-a-chip" to study glucose-stimulated insulin secretion and successful genetic editing of primary human islet cells. Islet biologists evaluated the functionality of stem-cell-derived islet-like cells coated with semipermeable biomaterials to prevent autoimmune attack, revealing the importance of cell maturation after transplantation. Prompted by observations that COVID-19 symptoms can worsen for people with obesity or diabetes, researchers examined how islets are directly affected by severe acute respiratory syndrome coronavirus 2. Herein, we highlight novel functional insights, technologies and therapeutic approaches that emerged between March 2020 and July 2021, written for both scientific and lay audiences. We also include a response to these advancements from patient stakeholders, to help lend a broader perspective to developments and challenges in islet research.

Current State and Evidence of Cellular Encapsulation Strategies in Type 1 Diabetes.

Islet cell replacement therapies represent an effective way to restore physiologic glycemic control in patients with type 1 diabetes (T1DM) and severe hypoglycemia. Despite being able to provide long-term insulin independence, patients still require lifelong immunosuppression, which has myriad detrimental effects including an increased risk for opportunistic infections and some types of cancer. This vital issue precludes widespread application of these therapies as a true cure for T1DM. Encapsulation of islets into immunoisolating/immunoprotective devices provides the potential of abrogating the requisite for lifelong immunosuppression. The field of cellular encapsulation lies at a complex intersection between the areas of chemistry, physics, bioengineering, cell biology, immunology, and clinical medicine. In diabetes, cellular encapsulation has existed for nearly 50 years, nevertheless, a resurgence of interest in the field has been motivated by promising results in small- and large-animal models. Recent studies have demonstrated that long-term diabetes reversal without immunosuppression is indeed routinely achievable. Future researchers interested in exploring cellular encapsulation strategies will require a clear understanding of the basic theoretical and practical principles, guiding this rapidly expanding field. This article will provide essential considerations concerning the physicochemical properties of the most commonly used biomaterials, relevant aspects of the immune response to bioencapsulation, current encapsulation strategies, potential implantation sites for encapsulated cell therapies and, finally, a comprehensive review on the current state of clinical translation. © 2020 American Physiological Society. Compr Physiol 10:839-878, 2020.