title: Type 1 Diabetes Prevention in NOD Mice by Targeting DPPIV/CD26 Is Associated with Changes in CD8⁺T Effector Memory Subset.
abstract: CD26 is a T cell activation marker consisting in a type II transmembrane glycoprotein with dipeptidyl peptidase IV (DPPIV) activity in its extracellular domain. It has been described that DPPIV inhibition delays the onset of type 1 diabetes and reverses the disease in non-obese diabetic (NOD) mice. The aim of the present study was to assess the effect of MK626, a DPPIV inhibitor, in type 1 diabetes incidence and in T lymphocyte subsets at central and peripheral compartments. Pre-diabetic NOD mice were treated with MK626. Diabetes incidence, insulitis score, and phenotyping of T lymphocytes in the thymus, spleen and pancreatic lymph nodes were determined after 4 and 6 weeks of treatment, as well as alterations in the expression of genes encoding β-cell autoantigens in the islets. The effect of MK626 was also assessed in two in vitro assays to determine proliferative and immunosuppressive effects. Results show that MK626 treatment reduces type 1 diabetes incidence and after 6 weeks of treatment reduces insulitis. No differences were observed in the percentage of T lymphocyte subsets from central and peripheral compartments between treated and control mice. MK626 increased the expression of CD26 in CD8+ T effector memory (TEM) from spleen and pancreatic lymph nodes and in CD8+ T cells from islet infiltration. CD8+TEM cells showed an increased proliferation rate and cytokine secretion in the presence of MK626. Moreover, the combination of CD8+ TEM cells and MK626 induces an immunosuppressive response. In conclusion, treatment with the DPPIV inhibitor MK626 prevents experimental type 1 diabetes in association to increase expression of CD26 in the CD8+ TEM lymphocyte subset. In vitro assays suggest an immunoregulatory role of CD8+ TEM cells that may be involved in the protection against autoimmunity to β pancreatic islets associated to DPPIV inhibitor treatment.
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Germans Trias i Pujol, Badalona, Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain.|CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM). Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Alonso
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Germans Trias i Pujol, Badalona, Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Julián
authors.affiliation: Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Carrascal
authors.affiliation: Service of Immunology, Vall d'Hebron Research Institute, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Colobran
authors.affiliation: Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
authors.forename: Irma
authors.initials: I
authors.lastname: Pujol-Autonell
authors.affiliation: Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rodriguez-Fernández
authors.affiliation: Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.
authors.forename: Aina
authors.initials: A
authors.lastname: Teniente
authors.affiliation: Cytometry Unit, Germans Trias i Pujol Research Institute, Badalona, Spain.
authors.forename: Marco Antonio
authors.initials: MA
authors.lastname: Fernández
authors.affiliation: Department of Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Miñarro
authors.affiliation: Department of Statistics, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Ruiz de Villa
authors.affiliation: Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain.|CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM). Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Vives-Pi
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Germans Trias i Pujol, Badalona, Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain.|CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM). Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Puig-Domingo
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D000068900:Sitagliptin Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000097:blood
chemical_list: D001324:Autoantigens; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000608431:MK-626; D016212:Transforming Growth Factor beta; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000068900:Sitagliptin Phosphate