title: Combination Therapy Reverses Hyperglycemia in NOD Mice With Established Type 1 Diabetes.
abstract: An increasing number of therapies have proven effective at reversing hyperglycemia in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D), yet situations of successful translation to human T1D are limited. This may be partly due to evaluating the effect of treating immediately at diagnosis in mice, which may not be reflective of the advanced disease state in humans at disease onset. In this study, we treated NOD mice with new-onset as well as established disease using various combinations of four drugs: antithymocyte globulin (ATG), granulocyte-colony stimulating factor (G-CSF), a dipeptidyl peptidase IV inhibitor (DPP-4i), and a proton pump inhibitor (PPI). Therapy with all four drugs induced remission in 83% of new-onset mice and, remarkably, in 50% of NOD mice with established disease. Also noteworthy, disease remission occurred irrespective of initial blood glucose values and mechanistically was characterized by enhanced immunoregulation involving alterations in CD4+ T cells, CD8+ T cells, and natural killer cells. This combination therapy also allowed for effective treatment at reduced drug doses (compared with effective monotherapy), thereby minimizing potential adverse effects while retaining efficacy. This combination of approved drugs demonstrates a novel ability to reverse T1D, thereby warranting translational consideration.
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Amanda
authors.initials: A
authors.lastname: Posgai
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Courtney
authors.initials: C
authors.lastname: Myhr
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Todd
authors.initials: T
authors.lastname: Brusko
authors.affiliation: Sanford Research, University of South Dakota, Sioux Falls, SD.
authors.forename: Alex
authors.initials: A
authors.lastname: Rabinovitch
authors.affiliation: Sanford Research, University of South Dakota, Sioux Falls, SD.
authors.forename: Alexei
authors.initials: A
authors.lastname: Savinov
authors.affiliation: San Raffaele Diabetes Research Institute, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Battaglia
authors.affiliation: Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Desmond
authors.initials: D
authors.lastname: Schatz
authors.affiliation: Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL.
authors.forename: Michael
authors.initials: M
authors.lastname: Haller
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL atkinson@ufl.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
mesh_terms: D000818:Animals; D000961:Antilymphocyte Serum / Q000494:pharmacology / Q000627:therapeutic use*; D002096:C-Peptide / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D054328:Proton Pump Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000961:Antilymphocyte Serum; D002096:C-Peptide; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D054328:Proton Pump Inhibitors; D016179:Granulocyte Colony-Stimulating Factor