Optimizing PLG nanoparticle-peptide delivery platforms for transplantation tolerance using an allogeneic skin transplant model

Biomaterials. 2019 Jul:210:70-82. doi: 10.1016/j.biomaterials.2019.04.030. Epub 2019 May 1.

Abstract

A robust regimen for inducing allogeneic transplantation tolerance involves pre-emptive recipient treatment with donor splenocytes (SP) rendered apoptotic by 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide(ECDI) treatment. However, such a regimen is limited by availability of donor cells, cost of cell procurement, and regulatory hurdles associated with cell-based therapies. Nanoparticles (NP) delivering donor antigens are a promising alternative for promoting transplantation tolerance. Here, we used a B6.C-H-2bm12(bm12) to C57BL/6(B6) skin transplant model involving a defined major histocompatibility antigen mismatch to investigate design parameters of poly(lactide-co-glycolide) (PLG) NPs delivering peptides containing the donor antigen for optimizing skin allograft survival. We showed that an epitope-containing short peptide (P1) was more effective than a longer peptide (P2) at providing graft protection. Importantly, the NP and P1 complex (NP-ECDI-P1) resulted in a significant expansion of graft-infiltrating Tregs. Interestingly, in comparison to donor ECDI-SP that provided indefinite graft protection, NP-ECDI-P1 targeted different splenic phagocytes and skin allografts in these recipients harbored significantly more graft-infiltrating CD8+IFN-γ+ cells. Collectively, the current study provides initial engineering parameters for a cell-free and biocompatible NP-peptide platform for transplant immunoregulation. Moreover, it also provides guidance to future NP engineering endeavors to recapitulate the effects of donor ECDI-SP as a goal for maximizing tolerance efficacy of NP formulations.

Keywords: Nanoparticles; Poly(lactide-co-glycolide) (PLG); Skin transplantation; Transplantation tolerance; bm-12.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens / metabolism
  • Cell Proliferation
  • Cytokines / biosynthesis
  • Epitopes / metabolism
  • Ethyldimethylaminopropyl Carbodiimide / chemistry
  • Graft Survival
  • Male
  • Mice, Inbred C57BL
  • Nanoparticles / chemistry*
  • Peptides / administration & dosage*
  • Peptides / chemistry
  • Polylactic Acid-Polyglycolic Acid Copolymer / chemistry*
  • Skin Transplantation*
  • T-Lymphocytes / cytology
  • Tissue Distribution
  • Transplantation Tolerance*
  • Transplantation, Homologous

Substances

  • Antigens
  • Cytokines
  • Epitopes
  • Peptides
  • Polylactic Acid-Polyglycolic Acid Copolymer
  • Ethyldimethylaminopropyl Carbodiimide