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: Jane Bryant, Kelan A Hlavaty, Xiaomin Zhang, Woon-Teck Yap, Lei Zhang, Lonnie D Shea, Xunrong Luo
• Journal: Biomaterials (Biomaterials) Vol. 35 Issue 31 Pg. 8887-8894 (Oct 2014) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 25066477 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antigens
• Drug Carriers
• Immunosuppressive Agents
• Polyglactin 910
• Ethyldimethylaminopropyl Carbodiimide
• Sirolimus

Topics

• Animals
• Antigens (administration & dosage, therapeutic use)
• Drug Carriers (chemistry)
• Ethyldimethylaminopropyl Carbodiimide (chemistry)
• Immune Tolerance (drug effects)
• Immunosuppressive Agents (administration & dosage, therapeutic use)
• Islets of Langerhans Transplantation (methods)
• Male
• Mice, Inbred BALB C
• Nanoparticles (chemistry)
• Polyglactin 910 (chemistry)
• Sirolimus (administration & dosage, therapeutic use)
• Transplantation, Homologous