title: 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.
authors: Department of Chemical and Biological Engineering, McCormick School of Engineering, Northwestern University, Evanston, Illinois, USA.
authors: John G
authors: JG
authors: Graham
authors: Xiaomin
authors: X
authors: Zhang
authors: Ashley
authors: A
authors: Goodman
authors: Kathryn
authors: K
authors: Pothoven
authors: Josetta
authors: J
authors: Houlihan
authors: Shusen
authors: S
authors: Wang
authors: R Michael
authors: RM
authors: Gower
authors: Xunrong
authors: X
authors: Luo
authors: Lonnie D
authors: LD
authors: Shea
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000941:Antigens / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000628:therapy*; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D019344:Lactic Acid / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D011100:Polyglycolic Acid / Q000494:pharmacology*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000637:transplantation*; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D000941:Antigens; D007328:Insulin; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid