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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.

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    • "Three patients received control DC generated in the presence of GM- CSF and IL-4 and seven patients received immunosuppressive DC generated in the presence of GM-CSF, IL-4, and antisense oligonucleotides targeting CD40, CD80, and CD86 transcripts. Use of tolerogenic DC generated with these antisense oligonucleotides was shown previously by the same team to have a preventive and curative effect on diabetes in NOD mice (Machen et al., 2004). This Phase I study demonstrated that intradermal injections of autologous TolDC (both control and immunosuppressive DC) are well-tolerated and safe in diabetic patients; no adverse effects or toxicity was observed. "
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    • "One such example is the use of immunoregulatory dendritic cells (iDC), autologous monocytederived DCs in which the CD40, CD80 and CD86 co-stimulatory molecules are downregulated by antisense molecules before reintroduction . An approved clinical safety study (NCT00445913) will evaluate the success achieved in NOD mice [40] [41]. Second, from a clinical standpoint it will prove useful to pre-screen patients for a specific type of treatment based on the presence or absence of certain 'biomarkers', for example autoreactive T cells. "
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