Tolerogenic dendritic cells induce antigen-specific hyporesponsiveness in insulin- and glutamic acid decarboxylase 65-autoreactive T lymphocytes from type 1 diabetic patients |
| |
Authors: | Norma Segovia-Gamboa,Martha Eunice Rodrí guez-Arellano,Rafael Rangel-Cruz,Moisé s Sá nchez-Dí az,Julio Cé sar Ramí rez-Reyes,Raquel Faradji,É rika Gonzá lez-Domí nguez,Carmen Sá nchez-Torres |
| |
Affiliation: | 1. 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;2. Research Department, Hospital Regional “Lic. Adolfo López Mateos”, ISSSTE, Av. Universidad 1321, Mexico City, Mexico;3. Department of Endocrinology, Hospital Regional “Lic. Adolfo López Mateos”, ISSSTE, Av. Universidad 1321, Mexico City, Mexico;4. Department of Pediatrics, Hospital Regional “Lic. Adolfo López Mateos”, ISSSTE, Av. Universidad 1321, Mexico City, Mexico;5. Medicina Interna, Asociación Médica, Centro Médico ABC, Sur 136 #116, Mexico City, Mexico |
| |
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. |
| |
Keywords: | Ab, antibody Ag, antigen AGE, advanced glycation end products APC, antigen presenting cells cDC, control dendritic cells CFSE, carboxy-fluorescein diacetate succinimidyl ester cTL, T cells cultured with cDC FCS, foetal calf serum GAD, glutamic acid decarboxylase GM-CSF, granulocyte/macrophage colony-stimulating factor Hb, haemoglobin LPS, lipopolysaccharide mAb, monoclonal antibody NOD, non-obese diabetic T1D, type 1 diabetes mellitus tDC, tolerogenic DC Th, T helper Treg, regulatory T cells tTL, T cells cultured with tDC. |
本文献已被 ScienceDirect 等数据库收录! |
|