Inhibition of effector antigen-specific T cells by intradermal administration of heme oxygenase-1 inducers

Simon, Thomas; Pogu, Julien; Remy, Séverine; Brau, Frédéric; Pogu, Sylvie; Maquigneau, Maud; Fonteneau, Jean-François; Poirier, Nicolas; Vanhove, Bernard; Blancho, Gilles; Piaggio, Eliane; Anegón, Ignacio; Blancou, Philippe

doi:10.1016/j.jaut.2017.03.005

Cited by 10 publications

(8 citation statements)

References 32 publications

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“…Recovery of HO-1 expression in DCs to levels comparable to NOR mice in DOX-treated pIi-tTA-tHO-1 NOD mice dramatically lowered T1D incidence. While the proportion of DCs expressing HO-1 in non-diabetic mice is low, their capacity to induce tolerogenic immune response may be very powerful, even with a small proportion of cells expressing HO-1 as previously shown [19]. Concerning the role of HO-1 negative DCs, we can hypothesize that these cells might be of physiological importance to induce inflammatory response upon detection of immune danger signals.…”

Section: Discussionmentioning

confidence: 53%

“…We also demonstrated previously that ex vivo treatment with CO conferred tolerogenic properties to DCs and inhibited the pathogenicity of naïve T-cells stimulated by those DCs in a T1D model [17]. Moreover, intradermal injection of HO-1 inducers promoted the accumulation of DCs overexpressing HO-1 in draining lymph nodes (LNs) [19]. These HO-1 high DCs exhibited antigen-specific tolerogenic properties as demonstrated by their ability to inhibit the diabetogenic potential of autoreactive cytotoxic T-cells.…”

Section: Discussionmentioning

confidence: 88%

“…We [19] and others [5] have previously shown the protective effect of upregulating HO-1 in T1D with chemical inducers or systemic HO-1 transduction. Here, we demonstrated for the first time that genetic induction of HO-1 limited to DCs was sufficient both to prevent T1D in non-diabetic NOD mice and to stabilize glycemia in some recently diabetic NOD mice.…”

Section: Discussionmentioning

confidence: 99%

“…In this respect, studies in both mice and humans have ruled out the possibility that HO-1 degradation products act directly on regulatory T-cells (Tregs) [13,14,15]. In contrast, other studies have suggested that HO-1 degradation products could promote the development of tolerogenic dendritic cells (DCs) [16,17,18], that could eventually inhibit T-cell responses either by inhibiting the migration of autoreactive CD8+ T-cells to the target organ [19] or by inducing Tregs cells [20].…”

Section: Introductionmentioning

confidence: 99%

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Genetic Restoration of Heme Oxygenase-1 Expression Protects from Type 1 Diabetes in NOD Mice

Pogu

Tzima

Kollias

et al. 2019

IJMS

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Antigen-presenting cells (APCs) including dendritic cells (DCs) play a critical role in the development of autoimmune diseases by presenting self-antigen to T-cells. Different signals modulate the ability of APCs to activate or tolerize autoreactive T-cells. Since the expression of heme oxygenase-1 (HO-1) by APCs has been associated with the tolerization of autoreactive T-cells, we hypothesized that HO-1 expression might be altered in APCs from autoimmune-prone non-obese diabetic (NOD) mice. We found that, compared to control mice, NOD mice exhibited a lower percentage of HO-1-expressing cells among the splenic DCs, suggesting an impairment of their tolerogenic functions. To investigate whether restored expression of HO-1 in APCs could alter the development of diabetes in NOD mice, we generated a transgenic mouse strain in which HO-1 expression can be specifically induced in DCs using a tetracycline-controlled transcriptional activation system. Mice in which HO-1 expression was induced in DCs exhibited a lower Type 1 Diabetes (T1D) incidence and a reduced insulitis compared to non-induced mice. Upregulation of HO-1 in DCs also prevented further increase of glycemia in recently diabetic NOD mice. Altogether, our data demonstrated the potential of induction of HO-1 expression in DCs as a preventative treatment, and potential as a curative approach for T1D.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genetic Restoration of Heme Oxygenase-1 Expression Protects from Type 1 Diabetes in NOD Mice

Pogu

Tzima

Kollias

et al. 2019

IJMS

Self Cite

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“…Judged by the high expression of CD11c, CD38, MHCII and the immunoregulatory cytokines IL-10 and TGFβ, HO-1 hi F4/80 int cells could constitute tolerogenic myeloid-derived DCs (55) or regulatory DCs that potentially participate in the induction of specific regulatory or anergic T cells (8, 56). Indeed, DCs conditioned with parasite-derived molecules can induce T cell anergy (8, 14, 56, 57).…”

Section: Discussionmentioning

confidence: 99%

Heme-Oxygenase-1 Expression Contributes to the Immunoregulation Induced by Fasciola hepatica and Promotes Infection

et al. 2017

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Fasciola hepatica, also known as the liver fluke, is a trematode that infects livestock and humans causing fasciolosis, a zoonotic disease of increasing importance due to its worldwide distribution and high economic losses. This parasite immunoregulates the host immune system by inducing a strong Th2 and regulatory T immune response by immunomodulating dendritic cell (DC) maturation and alternative activation of macrophages. In this paper, we show that F. hepatica infection in mice induces the upregulation of heme-oxygenase-1 (HO-1), the rate-limiting enzyme in the catabolism of free heme that regulates the host inflammatory response. We show and characterize two different populations of antigen presenting cells that express HO-1 during infection in the peritoneum of infected animals. Cells that expressed high levels of HO-1 expressed intermediate levels of F4/80 but high expression of CD11c, CD38, TGFβ, and IL-10 suggesting that they correspond to regulatory DCs. On the other hand, cells expressing intermediate levels of HO-1 expressed high levels of F4/80, CD68, Ly6C, and FIZZ-1, indicating that they might correspond to alternatively activated macrophages. Furthermore, the pharmacological induction of HO-1 with the synthetic metalloporphyrin CoPP promoted F. hepatica infection increasing the clinical signs associated with the disease. In contrast, treatment with the HO-1 inhibitor SnPP protected mice from parasite infection, indicating that HO-1 plays an essential role during F. hepatica infection. Finally, HO-1 expression during F. hepatica infection was associated with TGFβ and IL-10 levels in liver and peritoneum, suggesting that HO-1 controls the expression of these immunoregulatory cytokines during infection favoring parasite survival in the host. These results contribute to the elucidation of the immunoregulatory mechanisms induced by F. hepatica in the host and provide alternative checkpoints to control fasciolosis.

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Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis

Diebold¹,

Sievers²,

Bantug³

et al. 2018

Journal of Autoimmunity

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Inhibition of effector antigen-specific T cells by intradermal administration of heme oxygenase-1 inducers

Cited by 10 publications

References 32 publications

Genetic Restoration of Heme Oxygenase-1 Expression Protects from Type 1 Diabetes in NOD Mice

Genetic Restoration of Heme Oxygenase-1 Expression Protects from Type 1 Diabetes in NOD Mice

Heme-Oxygenase-1 Expression Contributes to the Immunoregulation Induced by Fasciola hepatica and Promotes Infection

Dimethyl fumarate influences innate and adaptive immunity in multiple sclerosis

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