Novel antibodies that selectively block mouse IL‐12 enable the re‐evaluation of the role of IL‐12 in immune protection and pathology

Gaignage, Mélanie; Uyttenhove, Catherine; Jones, Lindsay L.; Bourdeaux, Christophe; Chéou, Paméla; Mandour, Mohamed; Coutelier, Jean‐Paul; Vignali, Dario A.A.; Snick, Jacques Van

doi:10.1002/eji.202048936

Cited by 5 publications

(3 citation statements)

References 64 publications

(89 reference statements)

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“…Although IL-12 alone had little effect on a multiple myeloma mouse model, it could enhance the efficiency of additional therapy (45). By using an antibody recognizing the complete heterodimeric cytokine, rather than a mere IL-12 p40 subunit, which is shared with IL-23 (23), our results strongly suggest the crucial role of this molecule in the enhancement of cancer immunosurveillance induced by ligation of TLR, and 10.3389/fmed.2022.1057252 especially of TLR9 prior to the occurrence of cancer cells. It is quite plausible that IL-12 is produced by dendritic cells or macrophages in response to CpG stimulation.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of IL-12 heterodimers impairs TLR9-mediated prevention of early mouse plasmacytoma cell growth

Mandour

Soe²,

Castonguay³

et al. 2023

Front. Med.

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IntroductionNatural prevention of cancer development depends on an efficient immunosurveillance that may be modulated by environmental factors, including infections. Innate lymphoid cytotoxic cells have been shown to play a major role in this immunosurveillance. Interleukin-12 (IL-12) has been suggested to be a key factor in the activation of innate cytotoxic cells after infection, leading to the enhancement of cancer immunosurveillance.MethodsThe aim of this work was to analyze in mouse experimental models by which mechanisms the interaction between infectious agent molecules and the early innate responses could enhance early inhibition of cancer growth and especially to assess the role of IL-12 by using novel antibodies specific for IL-12 heterodimers.ResultsLigation of toll-like receptor (TLR)9 by CpG-protected mice against plasmacytoma TEPC.1033.C2 cell early growth. This protection mediated by innate cytolytic cells was strictly dependent on IL-12 and partly on gamma-interferon. Moreover, the protective effect of CpG stimulation, and to a lesser extent of TLR3 and TLR7/8, and the role of IL-12 in this protection were confirmed in a model of early mesothelioma AB1 cell growth.DiscussionThese results suggest that modulation of the mouse immune microenvironment by ligation of innate receptors deeply modifies the efficiency of cancer immunosurveillance through the secretion of IL-12, which may at least partly explain the inhibitory effect of previous infections on the prevalence of some cancers.

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Section: Discussionmentioning

confidence: 99%

“…into mice at a dose of 500 µg 1 day before and 6 days after TLR9 ligation. MM12A1.6 mouse IgG2a anti-IL-12 mAb (22,23) was injected i.p. into mice at a dose of 500 µg 1 day before and 6 days after TLR9 ligation.…”

Section: Antibodies Nk Cell Depletion and Cytokine Neutralizationmentioning

confidence: 99%

Inhibition of IL-12 heterodimers impairs TLR9-mediated prevention of early mouse plasmacytoma cell growth

Mandour

Soe²,

Castonguay³

et al. 2023

Front. Med.

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“…The toxic effects of the proposed therapy with IL-12 were observed in mice, and therefore its use as therapy in humans is controversial. A study with different doses is still necessary, or its combined use with antimicrobials with other molecules or with antioxidants [68].…”

Section: Discussionmentioning

confidence: 99%

Impact of Treatment with Antioxidants as an Adjuvant to Standard Therapy in Patients with Septic Shock: Analysis of the Correlation between Cytokine Storm and Oxidative Stress and Therapeutic Effects

Pérez-Torres,

Aisa-Álvarez,

Casarez-Alvarado

et al. 2023

IJMS

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Cellular homeostasis is lost or becomes dysfunctional during septic shock due to the activation of the inflammatory response and the deregulation of oxidative stress. Antioxidant therapy administered alongside standard treatment could restore this lost homeostasis. We included 131 patients with septic shock who were treated with standard treatment and vitamin C (Vit C), vitamin E (Vit E), N-acetylcysteine (NAC), or melatonin (MT), in a randomized trial. Organ damage quantified by Sequential Organ Failure Assessment (SOFA) score, and we determined levels of Interleukins (IL) IL1β, Tumor necrosis factor alpha (TNFα), IL-6, monocyte chemoattractant protein-1 (MCP-1), Transforming growth factor B (TGFβ), IL-4, IL-10, IL-12, and Interferon-γ (IFNγ). The SOFA score decreased in patients treated with Vit C, NAC, and MT. Patients treated with MT had statistically significantly reduced of IL-6, IL-8, MCP-1, and IL-10 levels. Lipid peroxidation, Nitrates and nitrites (NO3− and NO2−), glutathione reductase, and superoxide dismutase decreased after treatment with Vit C, Vit E, NAC, and MT. The levels of thiols recovered with the use of Vit E, and all patients treated with antioxidants maintained their selenium levels, in contrast with controls (p = 0.04). The findings regarding oxidative stress markers and cytokines after treatment with antioxidants allow us to consider to future the combined use of antioxidants in a randomized clinical trial with a larger sample to demonstrate the reproducibility of these beneficial effects.

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Novel strategies exploiting interleukin-12 in cancer immunotherapy

Cirella¹,

Luri-Rey²,

Trani³

et al. 2022

Pharmacology & Therapeutics

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Novel antibodies that selectively block mouse IL‐12 enable the re‐evaluation of the role of IL‐12 in immune protection and pathology

Cited by 5 publications

References 64 publications

Inhibition of IL-12 heterodimers impairs TLR9-mediated prevention of early mouse plasmacytoma cell growth

Inhibition of IL-12 heterodimers impairs TLR9-mediated prevention of early mouse plasmacytoma cell growth

Impact of Treatment with Antioxidants as an Adjuvant to Standard Therapy in Patients with Septic Shock: Analysis of the Correlation between Cytokine Storm and Oxidative Stress and Therapeutic Effects

Novel strategies exploiting interleukin-12 in cancer immunotherapy

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