title: Tolerogenic dendritic cells induce antigen-specific hyporesponsiveness in insulin- and glutamic acid decarboxylase 65-autoreactive T lymphocytes from type 1 diabetic patients.
abstract: Tolerogenic dendritic cells (tDC) constitute a promising therapy for autoimmune diseases, since they can anergize T lymphocytes recognizing self-antigens. Patients with type 1 diabetes mellitus (T1D) have autoreactive T cells against pancreatic islet antigens (insulin, glutamic acid decarboxylase 65 -GAD65-). We aimed to determine the ability of tDC derived from T1D patients to inactivate their insulin- and GAD65-reactive T cells. CD14+ monocytes and CD4+CD45RA- effector/memory lymphocytes were isolated from 25 patients. Monocyte-derived DC were generated in the absence (control, cDC) or presence of IL-10 and TGF-β1 (tDC), and loaded with insulin or GAD65. DC were cultured with T lymphocytes (primary culture), and cell proliferation and cytokine secretion were determined. These lymphocytes were rechallenged with insulin-, GAD65- or candidin-pulsed cDC (secondary culture) to assess whether tDC rendered T cells hyporesponsive to further stimulation. In the primary cultures, tDC induced significant lower lymphocyte proliferation and IL-2 and IFN-γ secretion than cDC; in contrast, tDC induced higher IL-10 production. Lymphocytes from 60% of patients proliferated specifically against insulin or GAD65 (group 1), whereas 40% did not (group 2). Most patients from group 1 had controlled glycemia. The secondary cultures showed tolerance induction to insulin or GAD65 in 14 and 10 patients, respectively. A high percentage of these patients (70-80%) belonged to group 1. Importantly, tDC induced antigen-specific T-cell hyporesponsiveness, since the responses against unrelated antigens were unaffected. These results suggest that tDC therapy against multiple antigens might be useful in a subset of T1D patients.
authors.affiliation: Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del I.P.N. (CINVESTAV-IPN). Av. I.P.N. 2508, C.P. 07360, Mexico City, Mexico.
authors.forename: Norma
authors.initials: N
authors.lastname: Segovia-Gamboa
authors.affiliation: Research Department, Hospital Regional "Lic. Adolfo López Mateos", ISSSTE, Av. Universidad 1321, Mexico City, Mexico.
authors.forename: Martha Eunice
authors.initials: ME
authors.lastname: Rodríguez-Arellano
authors.affiliation: Department of Endocrinology, Hospital Regional "Lic. Adolfo López Mateos", ISSSTE, Av. Universidad 1321, Mexico City, Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rangel-Cruz
authors.affiliation: Department of Pediatrics, Hospital Regional "Lic. Adolfo López Mateos", ISSSTE, Av. Universidad 1321, Mexico City, Mexico.
authors.forename: Moisés
authors.initials: M
authors.lastname: Sánchez-Díaz
authors.affiliation: Department of Pediatrics, Hospital Regional "Lic. Adolfo López Mateos", ISSSTE, Av. Universidad 1321, Mexico City, Mexico.
authors.forename: Julio César
authors.initials: JC
authors.lastname: Ramírez-Reyes
authors.affiliation: Medicina Interna, Asociación Médica, Centro Médico ABC, Sur 136 #116, Mexico City, Mexico.
authors.forename: Raquel
authors.initials: R
authors.lastname: Faradji
authors.affiliation: Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del I.P.N. (CINVESTAV-IPN). Av. I.P.N. 2508, C.P. 07360, Mexico City, Mexico.
authors.forename: Érika
authors.initials: É
authors.lastname: González-Domínguez
authors.affiliation: Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del I.P.N. (CINVESTAV-IPN). Av. I.P.N. 2508, C.P. 07360, Mexico City, Mexico. Electronic address: csanchez@cinvestav.mx.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez-Torres
mesh_terms: D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000187:drug effects; D001681:Biological Assay; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005968:Glutamate Decarboxylase / Q000494:pharmacology*; D006801:Humans; D007108:Immune Tolerance; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D001324:Autoantigens; D007328:Insulin; D010446:Peptide Fragments; C501056:glutamate decarboxylase 65 (202-221); D005968:Glutamate Decarboxylase
keywords: Dendritic cells; Effector/memory CD4+ T lymphocytes;; Tolerance;; Type 1 diabetes mellitus;