Delayed graft rejection in autoimmune islet transplantation via biomaterial immunotherapy

María M Coronel; Stephen W Linderman; Karen E Martin; Michael D Hunckler; Juan D Medina; Graham Barber; Kayle Riley; Esma S Yolcu; Haval Shirwan; Andrés J García

doi:10.1016/j.ajt.2023.07.023

Delayed graft rejection in autoimmune islet transplantation via biomaterial immunotherapy

Am J Transplant. 2023 Nov;23(11):1709-1722. doi: 10.1016/j.ajt.2023.07.023. Epub 2023 Aug 3.

Authors

Affiliations

¹ Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
² Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA; Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia, USA.
³ Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA.
⁴ Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA; Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA.
⁵ Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
⁶ Department of Child Health and Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri, USA.
⁷ Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA; Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA. Electronic address: andres.garcia@me.gatech.edu.

Abstract

The induction of operational immune tolerance is a major goal in beta-cell replacement strategies for the treatment of type 1 diabetes. Our group previously reported long-term efficacy via biomaterial-mediated programmed death ligand 1 (PD-L1) immunotherapy in islet allografts in nonautoimmune models. In this study, we evaluated autoimmune recurrence and allograft rejection during islet transplantation in spontaneous nonobese diabetic (NOD) mice. Graft survival and metabolic function were significantly prolonged over 60 days in recipients of syngeneic islets receiving the biomaterial-delivered immunotherapy, but not in control animals. The biomaterial-mediated PD-L1 immunotherapy resulted in delayed allograft rejection in diabetic NOD mice compared with controls. Discrimination between responders and nonresponders was attributed to the enriched presence of CD206+ program death 1+ macrophages and exhausted signatures in the cytotoxic T cell compartment in the local graft microenvironment. Notably, draining lymph nodes had similar remodeling in innate and adaptive immune cell populations. This work establishes that our biomaterial platform for PD-L1 delivery can modulate immune responses to transplanted islets in diabetic NOD mice and, thus, can provide a platform for the development of immunologic strategies to curb the allo- and autoimmune processes in beta-cell transplant recipients.

Keywords: autoimmunity; bioengineering; immunomodulation; islet transplantation.

Publication types

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

MeSH terms

Animals
B7-H1 Antigen
Diabetes Mellitus, Type 1* / therapy
Graft Rejection / etiology
Graft Survival
Immunotherapy
Islets of Langerhans Transplantation*
Mice
Mice, Inbred NOD

Substances

B7-H1 Antigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding