Circulating PEG-indoleamine 2,3-dioxygenase ameliorates diverse inflammatory diseases without toxicity or compromising immunocompetence
Abstract
Indoleamine 2,3-dioxygenase (IDO), the enzyme responsible for tryptophan catabolism, is protective in many autoimmune and inflammatory diseases. We previously developed a localized immunomodulation approach through the fusion of IDO to a carbohydrate binding protein [E. Bracho-Sanchez et al. , Nat. Biomed. Eng. 7 , 1156–1169 (2023)]. Here we further develop IDO as a protein therapeutic for inflammation, investigating systemic delivery via conjugation of poly(ethylene glycol) (PEG) to IDO. PEGylation extended circulation time and treatment PEG-IDO demonstrated therapeutic efficacy in five autoimmune and inflammatory models. Treatment with a single dose of PEG-IDO resulted in reversal of hind limb paralysis in experimental autoimmune encephalomyelitis as model of multiple sclerosis; protected against hepatic damage in liver ischemia-reperfusion injury; prevention of abdominal aortic aneurysm; and decreased severity of imiquimod-induced psoriasis. Treatment with two doses of PEG-IDO provided maintenance of body weight and colon length in acute ulcerative colitis. PEG-IDO treatment increased regulatory T cell populations and reduced pathogenic Th17 cell populations and inflammatory cytokine production. Systemic delivery of PEG-IDO had little-to-no off-target effects. Mice maintained immunocompetency, clearing the Listeria monocytogenes infection, and had no observed toxicity. Additionally, PEG-IDO increased serum kynurenine, consistent with a kynurenine-mediated mechanism of action. These findings demonstrate systemic immunomodulation via circulating PEG-IDO ameliorates a breadth of disparate autoinflammatory diseases, protecting against inflammation-driven tissue destruction in spinal cord, liver, abdominal aorta, skin, and colon, while presenting a positive safety profile, and expanding the scope of potential applications for this therapeutic approach.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (27)
Jennifer A. Simonovich
J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida
Ryan A. Clark
J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida
Alexander J. Kwiatkowski
J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida
Madeline J. Fuchs
J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida
Mariana E. Viso
J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida
Chen Lu
Sabrina L. Macias
J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida
Isabella Pinto
J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida
Abhishek P. Shrestha
Department of Surgery, Division of Transplantation and Hepatobiliary Surgery, College of Medicine, University of Florida
Tran B. Ngo
J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida
Sergio Duarte
Department of Surgery, Division of Transplantation and Hepatobiliary Surgery, College of Medicine, University of Florida
Yong He
Department of Pathogen Biology, School of Basic Medical Sciences, Anhui Medical University
Qiongyao Hu
Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, College of Medicine, University of Florida
Guanyi Lu
Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, College of Medicine, University of Florida
Joseph B. Hartman
Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, College of Medicine, University of Florida
Gang Su
Salvatore T. Scali
Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, College of Medicine, University of Florida
Scott A. Berceli
Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, College of Medicine, University of Florida
Ashish K. Sharma
Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, College of Medicine, University of Florida
Gilbert R. Upchurch
Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, College of Medicine, University of Florida
Shamima Islam
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute
Arun Wanchoo
J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida
Gregory A. Hudalla
J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida
Scott T. Robinson
Department of Surgery, Division of Vascular Surgery and Endovascular Therapy, College of Medicine, University of Florida
Ali Zarrinpar
Department of Surgery, Division of Transplantation and Hepatobiliary Surgery, College of Medicine, University of Florida
Dorina Avram
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute
Benjamin G. Keselowsky
J. Crayton Pruitt Family Department of Biomedical Engineering, Herbert Wertheim College of Engineering, University of Florida