In Vivo Ablation of Plasmacytoid Dendritic Cells Inhibits Autoimmunity through Expansion of Myeloid-Derived Suppressor Cells

Ιωάννου, Μαριάννα; Alissafi, Themis; Boon, Louis; Boumpas, Dimitrios T.; Verginis, Panayotis

doi:10.4049/jimmunol.1201897

Cited by 32 publications

(26 citation statements)

References 54 publications

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“…Increasingly, however, it is appreciated that deficient MDSC induction may play a role in autoimmunity 71,72. Induction of MDSCs can inhibit autoimmunity, most likely by interacting and suppressing T-cell effector responses 73,74. Notably, this is highly consistent with the studies by Ghazarian et al75 who showed that while Coxsackievirus B4 virus can accelerate T1D, natural killer T cell induced MDSCs that infiltrated into the islet, downregulated effector T cells, and prevented T1D.…”

Section: Novel Approaches To Immunotherapy For T1d: Targeting Innate supporting

confidence: 70%

Targeting innate immunity to downmodulate adaptive immunity and reverse type 1 diabetes

Itoh¹,

Ridgway²

2017

ITT

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Type 1 diabetes (T1D) is characterized by specific destruction of pancreatic insulin-producing beta cells accompanied by evidence of beta-cell-directed autoimmunity such as autoreactive T cells and islet autoantibodies (IAAs). Currently, T1D cannot be prevented or reversed in humans. T1D is easy to prevent in the nonobese diabetic (NOD) spontaneous mouse model but reversing new-onset T1D in mice is more difficult. Since the discovery of the T-cell receptor in the 1980s and the subsequent identification of autoreactive T cells directed toward beta-cell antigens (eg, insulin, glutamic acid decarboxylase), the dream of antigen-specific immunotherapy has dominated the field with its promise of specificity and limited side effects. While such approaches have worked in the NOD mouse, however, dozens of human trials have failed. Broader immunosuppressive approaches (originally cyclosporine, subsequently anti-CD3 antibody) have shown partial successes (e.g., prolonged C peptide preservation) but no major therapeutic efficacy or disease reversal. Human prevention trials have failed, despite the ease of such approaches in the NOD mouse. In the past 50 years, the incidence of T1D has increased dramatically, and one explanation is the “hygiene hypothesis”, which suggests that decreased exposure of the innate immune system to environmental immune stimulants (e.g., bacterial products such as Toll-like receptor (TLR) 4-stimulating lipopolysaccharide [LPS]) dramatically affects the adaptive immune system and increases subsequent autoimmunity. We have tested the role of innate immunity in autoimmune T1D by treating acute-onset T1D in NOD mice with anti-TLR4/MD-2 agonistic antibodies and have shown a high rate of disease reversal. The TLR4 antibodies do not directly stimulate T cells but induce tolerogenic antigen-presenting cells (APCs) that mediate decreased adaptive T-cell responses. Here, we review our current knowledge and suggest future prospects for targeting innate immunity in T1D immunotherapy.

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Section: Novel Approaches To Immunotherapy For T1d: Targeting Innate supporting

confidence: 70%

Targeting innate immunity to downmodulate adaptive immunity and reverse type 1 diabetes

Itoh¹,

Ridgway²

2017

ITT

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“…A reciprocal relationship has been shown to exist between pDCs and myeloid-derived suppressor cells (MDSC) (25). Because pDCs appear to be significantly elevated in the absence of galectin-3, we determined if there was a corresponding decrease in the number of immature myeloid cells, which have the potential to develop into MDSCs.…”

Section: Resultsmentioning

confidence: 99%

Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells

Kouo

Huang

Pucsek

et al. 2015

Cancer Immunology Research

413

331

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Galectin-3 is a 31 kD lectin that modulates T-cell responses through several mechanisms including apoptosis, T-cell receptor (TCR) cross-linking, and TCR down-regulation. We found patients with pancreatic ductal adenocarcinoma (PDA) responding to a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic PDA vaccine developed post immunization neutralizing antibodies to galectin-3. We show that galectin-3 binds activated antigen-committed CD8+ T cells only in the tumor microenvironment (TME). Galectin-3-deficient mice exhibit improved CD8+ T-cell effector function, and increased expression of several inflammatory genes. Galectin-3 binds to LAG-3, and LAG-3 expression is necessary for galectin-3-mediated suppression of CD8+ T cells in vitro. Lastly, galectin-3-deficient mice have elevated levels of circulating plasmacytoid dendritic cells (pDC), which are superior to conventional dendritic cells (cDC) in activating CD8+ T cells. Thus, inhibiting galectin-3 in conjunction with CD8+ T cell-directed immunotherapies should enhance the tumor-specific immune response.

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“…Similarly, BTZ protection was lost in Ido1 −/− NOD mice (Figure 4B). In vivo depletion of pDCs (23) occurring at the time of BTZ administration negated the protective effect of the proteasomal inhibitor against diabetes development (Figure 4C), whereas depletion of pDCs occurring before BTZ treatment would not ablate its anti-diabetic effect (data not shown). Of interest, administration of anti-PDCA1 in the absence of BTZ also significantly reduced the percentage of animals that developed diabetes over time (Figure 4D).…”

Section: Resultsmentioning

confidence: 91%

The Proteasome Inhibitor Bortezomib Controls Indoleamine 2,3-Dioxygenase 1 Breakdown and Restores Immune Regulation in Autoimmune Diabetes

et al. 2017

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Bortezomib (BTZ) is a first-in-class proteasome inhibitor approved for the therapy of multiple myeloma that also displays unique regulatory activities on immune cells. The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan metabolizing enzyme exerting potent immunoregulatory effects when expressed in dendritic cells (DCs), the most potent antigen-presenting cells capable of promoting either immunity or tolerance. We previously demonstrated that, in inflammatory conditions, IDO1 is subjected to proteasomal degradation in DCs, turning these cells from immunoregulatory to immunostimulatory. In non-obese diabetic (NOD) mice, an experimental model of autoimmune diabetes, we also identified an IDO1 defect such that the DCs do not develop tolerance toward pancreatic islet autoantigens. We found that BTZ rescues IDO1 protein expression in vitro in a particular subset of DCs, i.e., plasmacytoid DCs (pDCs) from NOD mice. When administered in vivo to prediabetic mice, the drug prevented diabetes onset through IDO1- and pDC-dependent mechanisms. Although the drug showed no therapeutic activity when administered alone to overtly diabetic mice, its combination with otherwise suboptimal dosages of autoimmune-preventive anti-CD3 antibody resulted in disease reversal in 70% diabetic mice, a therapeutic effect similar to that afforded by full-dosage anti-CD3. Thus, our data indicate a potential for BTZ in the immunotherapy of autoimmune diabetes and further underline the importance of IDO1-mediated immune regulation in such disease.

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In Vivo Ablation of Plasmacytoid Dendritic Cells Inhibits Autoimmunity through Expansion of Myeloid-Derived Suppressor Cells

Cited by 32 publications

References 54 publications

Targeting innate immunity to downmodulate adaptive immunity and reverse type 1 diabetes

Targeting innate immunity to downmodulate adaptive immunity and reverse type 1 diabetes

Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells

The Proteasome Inhibitor Bortezomib Controls Indoleamine 2,3-Dioxygenase 1 Breakdown and Restores Immune Regulation in Autoimmune Diabetes

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