title: Nanoparticle delivery of donor antigens for transplant tolerance in allogeneic islet transplantation.
abstract: Human islet cell transplantation is a promising treatment for type 1 diabetes; however, long-term donor-specific tolerance to islet allografts remains a clinically unmet goal. We have previously shown that recipient infusions of apoptotic donor splenocytes chemically treated with 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide (donor ECDI-SP) can mediate long-term acceptance of full major histocompatibility complex (MHC)-mismatched murine islet allografts without the use of immunosuppression. In this report, we investigated the use of poly(lactide-co-glycolide) (PLG) particles in lieu of donor ECDI-SP as a synthetic, cell-free carrier for delivery of donor antigens for the induction of transplant tolerance in full MHC-mismatched murine allogeneic islet transplantation. Infusions of donor antigen-coupled PLG particles (PLG-dAg) mediated tolerance in ∼20% of recipient mice, and the distribution of cellular uptake of PLG-dAg within the spleen was similar to that of donor ECDI-SP. PLG-dAg mediated the contraction of indirectly activated T cells but did not modulate the direct pathway of allorecognition. Combination of PLG-dAg with a short course of low dose immunosuppressant rapamycin at the time of transplant significantly improved the tolerance efficacy to ∼60%. Furthermore, altering the timing of PLG-dAg administration to a schedule that is more feasible for clinical transplantation resulted in equal tolerance efficacy. Thus, the combination therapy of PLG-dAg infusions with peritransplant rapamycin represents a clinically attractive, biomaterials-based and cell-free method for inducing long-term donor-specific tolerance for allogeneic cell transplantation, such as for allogeneic islet transplantation.
authors: Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Jane
authors: J
authors: Bryant
authors: The Institute for BioNanotechnology in Medicine (IBNAM), Northwestern University, Chicago, IL 60611, USA; Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Rd/E310, Evanston, IL 60208, USA.
authors: Kelan A
authors: KA
authors: Hlavaty
authors: Department of Surgery, Division of Organ Transplantation, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors: Xiaomin
authors: X
authors: Zhang
authors: The Institute for BioNanotechnology in Medicine (IBNAM), Northwestern University, Chicago, IL 60611, USA; Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Rd/E310, Evanston, IL 60208, USA.
authors: Woon-Teck
authors: WT
authors: Yap
authors: Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Lei
authors: L
authors: Zhang
authors: The Institute for BioNanotechnology in Medicine (IBNAM), Northwestern University, Chicago, IL 60611, USA; Department of Chemical and Biological Engineering, Northwestern University, 2145 Sheridan Rd/E136, Evanston, IL 60208, USA; The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA. Electronic address: l-shea@northwestern.edu.
authors: Lonnie D
authors: LD
authors: Shea
authors: Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Surgery, Division of Organ Transplantation, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA. Electronic address: xunrongluo@northwestern.edu.
authors: Xunrong
authors: X
authors: Luo
mesh_terms: D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D005022:Ethyldimethylaminopropyl Carbodiimide / Q000737:chemistry; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry; D011098:Polyglactin 910 / Q000737:chemistry*; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use; D014184:Transplantation, Homologous
chemical_list: D000941:Antigens; D004337:Drug Carriers; D007166:Immunosuppressive Agents; D011098:Polyglactin 910; D005022:Ethyldimethylaminopropyl Carbodiimide; D020123:Sirolimus
keywords: 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (ECDI); Allogeneic cells; Islet; Poly(lactide-co-glycolide) (PLG); Tolerance; Transplantation