Antisense Oligonucleotides Down-Regulating Costimulation Confer Diabetes-Preventive Properties to Nonobese Diabetic Mouse Dendritic Cells

Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
The Journal of Immunology (Impact Factor: 4.92). 11/2004; 173(7):4331-41. DOI: 10.4049/jimmunol.173.7.4331
Source: PubMed


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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    • "Indeed, it is now very clear that DC stabilized into a state that promotes immunosuppression (directly or indirectly) can prevent and reverse a number of organ-specific autoimmune diseases in the relevant animal models, including T1D47484950515253. In fact, we first demonstrated that autologous DC generated in the presence of antisense oligonucleotides (AS-ODN) targeting the CD40, CD80 and CD86 costimulation protein primary transcripts could prevent and reverse T1D in the NOD strain via upregulation of Foxp3+ Tregs and novel IL-10+ B-regulatory cells (Bregs)54555657 and that human embodiments of these cell products were safe and potentially of some benefit in humans, in a phase I clinical trial [58]. In spite of these promising approaches, a strategy more attractive than ex vivo DC manipulation to stabilize a tolerogenic state can be the in vivo targeting of DC with biologics or chemical drugs that facilitate and confer this stabilized state. "
    [Show abstract] [Hide abstract] ABSTRACT: We have developed novel antisense oligonucleotide-formulated microspheres that can reverse hyperglycemia in newly-onset diabetic mice. Dendritic cells taking up the microspheres adopt a restrained co-stimulation ability and migrate to the pancreatic lymph nodes when injected into an abdominal region that is drained by those lymph nodes. Furthermore, we demonstrate that the absolute numbers of antigen-specific Foxp3+ T regulatory cells are increased only in the lymph nodes draining the site of administration and that these T-cells proliferate independently of antigen supply in the microspheres. Taken together, our data add to the emerging model where antigen supply may not be a requirement in "vaccines" for autoimmune disease, but the site of administration - subserved by lymph nodes draining the target organ - is in fact critical to foster the generation of antigen-specific regulatory cells. The implications of these observations on "vaccine" design for autoimmunity are discussed and summarized. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Clinical Immunology
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    • "In addition to suppression of inflammatory cytokine synthesis, the activated DCs would provide an element of safety because they have a limited lifetime of approximately 5 days and therefore would have only a transient effect on the immune response [139]. Additional studies have demonstrated prevention and reversal of type 1 diabetes in NOD mice using costimulation impaired, immunosuppressive bone marrow-derived DCs generated ex vivo with a mixture of antisense oligonucleotides targeting the primary transcripts of DC costimulatory factors CD40, CD80, and CD86 [140]. Phase 1 clinical trials show that the vaccine is well tolerated in patients [141]. "
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    Full-text · Article · Apr 2014 · Research Journal of Immunology
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    • "We now add suppressive B-cells/Bregs to the list. RA production by iDC can explain, in part, our observations of increased CD4+ CD25+ T-cell frequency in successfully-treated NOD mice [23] as well as the increased frequency of suppressive B-cells, which express, as we have shown herein, RA receptors. The seminal findings of Clare-Salzer and colleagues [102], who showed that B-cells were increased in frequency in NOD mice injected DC from syngeneic pancreatic lymph nodes, could represent an a process of DC-induced suppressive B-cell expansion, as part of a therapeutic mechanism as they originally reported. "
    [Show abstract] [Hide abstract] ABSTRACT: The objective of the study was to identify immune cell populations, in addition to Foxp3+ T-regulatory cells, that participate in the mechanisms of action of tolerogenic dendritic cells shown to prevent and reverse type 1 diabetes in the Non-Obese Diabetic (NOD) mouse strain. Co-culture experiments using tolerogenic dendritic cells and B-cells from NOD as well as transgenic interleukin-10 promoter-reporter mice along with transfer of tolerogenic dendritic cells and CD19+ B-cells into NOD and transgenic mice, showed that these dendritic cells increased the frequency and numbers of interleukin-10-expressing B-cells in vitro and in vivo. The expansion of these cells was a consequence of both the proliferation of pre-existing interleukin-10-expressing B-lymphocytes and the conversion of CD19+ B-lymphcytes into interleukin-10-expressing cells. The tolerogenic dendritic cells did not affect the suppressive activity of these B-cells. Furthermore, we discovered that the suppressive murine B-lymphocytes expressed receptors for retinoic acid which is produced by the tolerogenic dendritic cells. These data assist in identifying the nature of the B-cell population increased in response to the tolerogenic dendritic cells in a clinical trial and also validate very recent findings demonstrating a mechanistic link between human tolerogenic dendritic cells and immunosuppressive regulatory B-cells.
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