PLG Scaffold Delivered Antigen-Specific Regulatory T Cells Induce Systemic Tolerance in Autoimmune Diabetes

Abstract

Islet transplantation is a promising treatment for human type 1 diabetes mellitus. Transplantation requires systemic immunosuppression, which has numerous deleterious side effects. Islet antigen-specific regulatory T cells (Tregs) have been shown to protect islet grafts from autoimmune destruction in the nonobese diabetic (NOD) model when co-localized in the kidney capsule. An extra-hepatic transplant site was established by transplanting islet-loaded microporous poly (lactide-co-glycolide) (PLG) scaffolds into abdominal fat. This study examined an autoimmune transplantation model and determined whether co-localized Tregs could protect islet grafts in an extra-hepatic and extra-renal transplant site. Normoglycemia was restored, and co-transplanted Tregs extended graft survival, including several instances of indefinite protection. Transplanted Tregs were replaced by recipient-derived Tregs over time, indicating that islet antigen-specific Tregs induce tolerance to islet grafts through host-derived Tregs. Thus, Tregs provided protection against a diverse repertoire of autoreactive T-cell-receptor specificities mediating diabetes in the NOD model, possibly through a phenomenon previously described as infectious tolerance. Interestingly, the infiltration by Tregs protected a second islet transplant, indicating systemic tolerance to islet antigens. In summary, PLG scaffolds can serve as an alternative delivery system for islet transplantation that allows for the co-localization of immunomodulatory cells within islet grafts and induces long-term graft survival in an autoimmune diabetes model. This method of co-localizing immunomodulatory cells with islets in a clinically translatable transplant site to affect the immune system on a local and systemic level has potential therapeutic implications for human islet transplantation.

A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids

“…Thus, while all of these highly vascular sites have been utilized for engraftment in other contexts (Finkbeiner et al, 2015b; Watson et al., 2014; Pepper et al, 2013; Bartholomeus et al, 2013; Smink et al, 2013), HLOs did not thrive in these environments. We turned to microporous poly(lactide-co-glycolide) (PLG) scaffolds in order to create an alternative niche for the HLOs during transplantation since PLG scaffolds have led to improved survival and function of pancreatic beta cells following transplantation (Gibly et al, 2013; Blomeier et al, 2006; Hlavaty et al, 2014; Graham et al, 2013; Kheradmand et al, 2011). …”

Take a deep breath and digest the material: organoids and biomaterials of the respiratory and digestive systems

“…These scaffolds have been used previously for islet transplantation, with islets filing the pores of the scaffold while allow for vasculature to infiltrate and integrate with the islets. [62][63][64][65][66]129] Lung spheroids similarly fit within the pores of the scaffold and were vascularized from the host (Fig. 4).…”

“…3). [49,57,[62][63][64][65][66] A number of encapsulation materials have been investigated, [49] and a recent report involved the transplantation of hPSC-derived beta-like cell clusters encapsulated with non-degradable alginate triazole-thiomorpholine dioxide (TMTD). The encapsulated beta-like cells established normoglycemia in diabetic mice.…”

Immune Tolerance for Autoimmune Disease and Cell Transplantation

“…To further increase suppressor cell populations locally, scaffolds could be directly loaded with cells with immune-inhibitory capacity. In this regard, loading of ex vivo–expanded antigen-specific T reg s onto the scaffolds provided a significant survival advantage for transplanted islet grafts (129). …”