Article

Antisense oligonucleotides down-regulating costimulation confer diabetes-preventive properties to nonobese diabetic mouse dendritic cells.

Diabetes Institute, Department of Pediatrics, University of Pittsburgh School of Medicine, PA 15213, USA.
The Journal of Immunology (Impact Factor: 5.36). 11/2004; 173(7):4331-41. DOI: 10.4049/jimmunol.173.7.4331
Source: PubMed

ABSTRACT Phenotypically "immature" dendritic cells (DCs), defined by low cell surface CD40, CD80, and CD86 can elicit host immune suppression in allotransplantation and autoimmunity. Herein, we report the most direct means of achieving phenotypic immaturity in NOD bone marrow-derived DCs aiming at preventing diabetes in syngeneic recipients. CD40, CD80, and CD86 cell surface molecules were specifically down-regulated by treating NOD DCs ex vivo with a mixture of antisense oligonucleotides targeting the CD40, CD80, and CD86 primary transcripts. The incidence of diabetes was significantly delayed by a single injection of the engineered NOD DCs into syngeneic recipients. Insulitis was absent in diabetes-free recipients and their splenic T cells proliferated in response to alloantigen. Engineered DC promoted an increased prevalence of CD4(+)CD25(+) T cells in NOD recipients at all ages examined and diabetes-free recipients exhibited significantly greater numbers of CD4(+)CD25(+) T cells compared with untreated NOD mice. In NOD-scid recipients, antisense-treated NOD DC promoted an increased prevalence of these putative regulatory T cells. Collectively, these data demonstrate that direct interference of cell surface expression of the major costimulatory molecules at the transcriptional level confers diabetes protection by promoting, in part, the proliferation and/or survival of regulatory T cells. This approach is a useful tool by which DC-mediated activation of regulatory T cells can be studied as well as a potential therapeutic option for type 1 diabetes.

0 Followers
 · 
74 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The use of immunosuppressive (IS) drugs to treat transplant recipients has markedly reduced the incidence of acute rejection and early graft loss. However, such treatments have numerous adverse side effects and fail to prevent chronic allograft dysfunction. In this context, therapies based on the adoptive transfer of regulatory cells are promising strategies to induce indefinite transplant survival. The use of tolerogenic dendritic cells (DC) has shown great potential, as preliminary experiments in rodents have demonstrated that administration of tolerogenic DC prolongs graft survival. Recipient DC, Donor DC, or Donor Ag-pulsed recipient DC have been used in preclinical studies and administration of these cells with suboptimal immunosuppression increases their tolerogenic potential. We have demonstrated that autologous unpulsed tolerogenic DC injected in the presence of suboptimal immunosuppression are able to induce Ag-specific allograft tolerance. We derived similar tolerogenic DC in different animal models (mice and non-human primates) and confirmed their protective abilities in vitro and in vivo. The mechanisms involved in the tolerance induced by autologous tolerogenic DC were also investigated. With the aim of using autologous DC in kidney transplant patients, we have developed and characterized tolerogenic monocyte-derived DC in humans. In this review, we will discuss the preclinical studies and describe our recent results from the generation and characterization of tolerogenic monocyte-derived DC in humans for a clinical application. We will also discuss the limits and difficulties in translating preclinical experiments to theclinic.
    Frontiers in Immunology 01/2012; 3:218. DOI:10.3389/fimmu.2012.00218
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: We determined the ability of tolerogenic dendritic cells (tDC) derived from type 1 diabetes mellitus (T1D) patients to inactivate their autoreactive T cells recognizing the pancreatic islet antigens insulin and glutamic acid decarboxylase 65 -GAD65-. 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 effector/memory CD4+ T lymphocytes (primary culture), and then rechallenged with insulin- or GAD65-pulsed cDC (secondary culture). In the primary cultures, tDC induced lower lymphocyte proliferation and IL-2 and IFN-γ secretion than cDC, but higher IL-10 production. Lymphocytes from 60% of patients proliferated specifically against insulin or GAD65 (group 1), whereas 40% did not (group 2). Tolerance to insulin or GAD65 was induced in 14 and 10 patients, respectively. 70-80% of these patients belonged to group 1, suggesting that tDC therapy might be useful in a subset of T1D patients.
    Clinical Immunology 06/2014; DOI:10.1016/j.clim.2014.06.009 · 3.99 Impact Factor

Preview

Download
2 Downloads
Available from