title: CD26/DPPIV inhibition alters the expression of immune response-related genes in the thymi of NOD mice.
abstract: The transmembrane glycoprotein CD26 or dipeptidyl peptidase IV (DPPIV) is a multifunctional protein. In immune system, CD26 plays a role in T-cell function and is also involved in thymic maturation and emigration patterns. In preclinical studies, treatment with DPPIV inhibitors reduces insulitis and delays or even reverses the new -onset of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. However, the specific mechanisms involved in these effects remain unknown. The aim of the present study was to investigate how DPPIV inhibition modifies the expression of genes in the thymus of NOD mice by microarray analysis. Changes in the gene expression of β-cell autoantigens and Aire in thymic epithelial cells (TECs) were also evaluated by using qRT-PCR. A DPPIV inhibitor, MK626, was orally administered in the diet for 4 and 6 weeks starting at 6-8 weeks of age. Thymic glands from treated and control mice were obtained for each study checkpoint. Thymus transcriptome analysis revealed that 58 genes were significantly over-expressed in MK626-treated mice after 6 weeks of treatment. Changes in gene expression in the thymus were confined mainly to the immune system, including innate immunity, chemotaxis, antigen presentation and immunoregulation. Most of the genes are implicated in central tolerance mechanisms through several pathways. No differences were observed in the expression of Aire and β-cell autoantigens in TECs. In the current study, we demonstrate that treatment with the DPPIV inhibitor MK626 in NOD mice alters the expression of the immune response-related genes in the thymus, especially those related to immunological central tolerance, and may contribute to the prevention of T1D.
authors.affiliation: Department of Endocrinology and Nutrition, Germans Trias i Pujol Health Sciences Research Institute and Hospital, 08916, Badalona, Spain; Department of Medicine, Autonomous University of Barcelona, 08193, Barcelona, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Julián
authors.affiliation: Department of Endocrinology and Nutrition, Germans Trias i Pujol Health Sciences Research Institute and Hospital, 08916, Badalona, Spain; Department of Medicine, Autonomous University of Barcelona, 08193, Barcelona, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Alonso
authors.affiliation: Immunology Division, Vall d'Hebron Research Institute (VHIR), Vall d'Hebron University Hospital, 08035, Barcelona, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Colobran
authors.affiliation: Statistics Department, Faculty of Biology, University of Barcelona, 08028, Barcelona, Spain; Statistics and Bioinformatics Unit, Vall d'Hebron Research Institute (VHIR), 08035, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: Statistics Department, Faculty of Biology, University of Barcelona, 08028, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Miñarro
authors.affiliation: Immunology Department, Germans Trias i Pujol Health Sciences Research Institute, 08916, Badalona, Autonomous University of Barcelona, Spain.
authors.forename: Irma
authors.initials: I
authors.lastname: Pujol-Autonell
authors.affiliation: Immunology Department, Germans Trias i Pujol Health Sciences Research Institute, 08916, Badalona, Autonomous University of Barcelona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Carrascal
authors.affiliation: Immunology Department, Germans Trias i Pujol Health Sciences Research Institute, 08916, Badalona, Autonomous University of Barcelona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rodríguez-Fernández
authors.affiliation: Immunology Department, Germans Trias i Pujol Health Sciences Research Institute, 08916, Badalona, Autonomous University of Barcelona, Spain.
authors.forename: Rosa María
authors.initials: RM
authors.lastname: Ampudia
authors.affiliation: Immunology Department, Germans Trias i Pujol Health Sciences Research Institute, 08916, Badalona, Autonomous University of Barcelona, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Vives-Pi
authors.affiliation: Department of Endocrinology and Nutrition, Germans Trias i Pujol Health Sciences Research Institute and Hospital, 08916, Badalona, Spain; Department of Medicine, Autonomous University of Barcelona, 08193, Barcelona, Spain; CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain; CIBER of Rare Diseases (CIBERER), Instituto de Salud Carlos III (ISCIII), 28029, Madrid, Spain. Electronic address: mpuigd@igtp.cat.
authors.forename: Manel
authors.initials: M
authors.lastname: Puig-Domingo
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D053263:Gene Regulatory Networks; D056747:Immunomodulation / Q000235:genetics; D019469:Indinavir / Q000494:pharmacology*; D016688:Mice, Inbred NOD; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism; D059467:Transcriptome
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D019469:Indinavir; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse
keywords: DNA microarray analysis; DPPIV/CD26 inhibition; Gene expression; NOD mice; Type 1 diabetes prevention; β-cell autoantigens expression