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

Abstract

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.

Considerations and challenges of islet transplantation and future therapies on the horizon

“…Modulation of the liver niche with growth factors [109] and anti-inflammatory agents [110] have been used with some success and polymer properties may be exploited to regulate release of such factors when islets are immediately transplanted and particularly vulnerable to apoptosis [109,111], but these are still at a very early pre-clinical stage. Accelerating the vascularisation of transplanted islets with a number of approaches including gene therapy methods [112] may be a relevant strategy to accelerate islet engraftment and may improve transplantation outcomes.…”

Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal.

“…Various local immunomodulation strategies for islet transplantation have been explored recently, including protein immobilization on biomaterial surface, chemical modi cation of the material, use of drug-releasing biomaterials, and co-transplantation with immunomodulatory cell types 40,41 . However, although promising, biomaterial and cell-based strategies have the remaining challenges of being limited duration, di cult to replenish, and often rely on supplementation with systemic immunosuppression to effectively abrogate the allogeneic response 42 . To overcome these challenges, the NICHE was speci cally designed for long-acting release, minimally invasive, transcutaneous re lling (every 6 months) via integrated silicone ports.…”

Islet transplantation into brown adipose tissue can delay immune rejection

“…In addition, transplantation studies incorporating engraftment into BAT with other therapeutic strategies could further enhance islet graft survival. These approaches include induction of localized immunosuppression by encapsulating islets with antioxidant-containing nanothin coatings to decrease oxidative stress (46), incorporating dexamethasone-eluting micelles to suppress inflammatory responses (47), or by co-transplanting BAT-derived mesenchymal stem cells (MSC) to further induce Treg differentiation (42). Additionally, BAT is a promising extra-hepatic transplant site for other sources of insulin-producing β-cells such as stem cell-derived β-cells (48)(49)(50)(51) or genetically modified xenogeneic porcine islets (52)(53)(54)(55)(56)(57), both of which have demonstrated promise.…”