title: Repurposed JAK1/JAK2 Inhibitor Reverses Established Autoimmune Insulitis in NOD Mice.
abstract: Recent advances in immunotherapeutics have not yet changed the routine management of autoimmune type 1 diabetes. There is an opportunity to repurpose therapeutics used to treat other diseases to treat type 1 diabetes, especially when there is evidence for overlapping mechanisms. Janus kinase (JAK) 1/JAK2 inhibitors are in development or clinical use for indications including rheumatoid arthritis. There is good evidence for activation of the JAK1/JAK2 and signal transducer and activator of transcription (STAT) 1 pathway in human type 1 diabetes and in mouse models, especially in β-cells. We tested the hypothesis that using these drugs to block the JAK-STAT pathway would prevent autoimmune diabetes. The JAK1/JAK2 inhibitor AZD1480 blocked the effect of cytokines on mouse and human β-cells by inhibiting MHC class I upregulation. This prevented the direct interaction between CD8+T cells and β-cells, and reduced immune cell infiltration into islets. NOD mice treated with AZD1480 were protected from autoimmune diabetes, and diabetes was reversed in newly diagnosed NOD mice. This provides mechanistic groundwork for repurposing clinically approved JAK1/JAK2 inhibitors for type 1 diabetes.
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|The University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Prerak M
authors.initials: PM
authors.lastname: Trivedi
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|The University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Graham
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|The University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Scott
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.|The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
authors.forename: Misty R
authors.initials: MR
authors.lastname: Jenkins
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.
authors.forename: Suktilang
authors.initials: S
authors.lastname: Majaw
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Sutherland
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.
authors.forename: Stacey
authors.initials: S
authors.lastname: Fynch
authors.affiliation: The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
authors.affiliation: The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burns
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|The University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Krishnamurthy
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|The University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Brodnicki
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|The University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Stuart I
authors.identifier: 0000-0003-3497-3559
authors.initials: SI
authors.lastname: Mannering
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia.|The University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kay
authors.affiliation: St. Vincent's Institute, Fitzroy, Victoria, Australia hthomas@svi.edu.au.|The University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D054357:Chemokine CXCL10 / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D051379:Mice; D016688:Mice, Inbred NOD; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C545606:AZD 1480; D001786:Blood Glucose; D054357:Chemokine CXCL10; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D011720:Pyrazoles; D011743:Pyrimidines; D053613:Janus Kinase 1; D053614:Janus Kinase 2