title: The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model.
abstract: Islet transplantation is a promising therapy for Type 1 diabetes mellitus; however, host inflammatory and immune responses lead to islet dysfunction and destruction, despite potent systemic immunosuppression. Grafting of poly(ethylene glycol) (PEG) to the periphery of cells or tissues can mitigate inflammation and immune recognition via generation of a steric barrier. Herein, we sought to evaluate the complementary impact of islet PEGylation with a short-course immunotherapy on the survival of fully-MHC mismatched islet allografts (DBA/2 islets into diabetic C57BL/6J recipients). Anti-Lymphocyte Function-associated Antigen 1 (LFA-1) antibody was selected as a complementary, transient, systemic immune monotherapy. Islets were PEGylated via an optimized protocol, with resulting islets exhibiting robust cell viability and function. Following transplantation, a significant subset of diabetic animals receiving PEGylated islets (60%) or anti-LFA-1 antibody (50%) exhibited long-term (>100d) normoglycemia. The combinatorial approach proved synergistic, with 78% of the grafts exhibiting euglycemia long-term. Additional studies examining graft cellular infiltrates at early time points characterized the local impact of the transplant protocol on graft survival. Results illustrate the capacity of a simple polymer grafting approach to impart significant immunoprotective effects via modulation of the local transplant environment, while short-term immunotherapy serves to complement this effect.
  
  
  
  We believe this study is important and of interest to the biomaterials and transplant community for several reasons: 1) it provides an optimized protocol for the PEGylation of islets, with minimal impact on the coated islets, which can be easily translated for clinical applications; 2) this optimized protocol demonstrates the benefits of islet PEGylation in providing modest immunosuppression in a murine model; 3) this work demonstrates the combinatory impact of PEGylation with short-course immunotherapy (via LFA-1 blockage), illustrating the capacity of PEGylation to complement existing immunotherapy; and 4) it suggests macrophage phenotype shifting as the potential mechanism for this observed benefit.
authors.affiliation: Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Miami, Miami, FL, USA.
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Giraldo
authors.affiliation: Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Surgery, University of Miami, Miami, FL, USA.
authors.forename: R Damaris
authors.initials: RD
authors.lastname: Molano
authors.affiliation: Diabetes Research Institute, University of Miami, Miami, FL, USA.
authors.forename: Hernán R
authors.initials: HR
authors.lastname: Rengifo
authors.affiliation: Diabetes Research Institute, University of Miami, Miami, FL, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Fotino
authors.affiliation: Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.
authors.forename: Kerim M
authors.initials: KM
authors.lastname: Gattás-Asfura
authors.affiliation: Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Miami, Miami, FL, USA; Department of Surgery, University of Miami, Miami, FL, USA; Department of Microbiology & Immunology, University of Miami, Miami, FL, USA.
authors.forename: Antonello
authors.initials: A
authors.lastname: Pileggi
authors.affiliation: Diabetes Research Institute, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Miami, Miami, FL, USA; Department of Surgery, University of Miami, Miami, FL, USA; Department of Microbiology & Immunology, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA. Electronic address: cstabler@bme.ufl.edu.
authors.forename: Cherie L
authors.initials: CL
authors.lastname: Stabler
mesh_terms: D000818:Animals; D006085:Graft Survival / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000378:metabolism; D007167:Immunotherapy; D016381:Islets of Langerhans Transplantation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011092:Polyethylene Glycols / Q000737:chemistry*; D014022:Tissue Survival; D014184:Transplantation, Homologous
chemical_list: D006649:Histocompatibility Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D011092:Polyethylene Glycols
keywords: Anti-Lymphocyte Function-associated Antigen 1 (LFA-1); Encapsulation; Inflammation; Local immunomodulation; Poly(ethylene glycol) (PEG); Polymer grafting