Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis

Vicari, Alain; Schoepfer, Alain; Meresse, Bertrand; Goffin, Laurence; Léger, Olivier; Josserand, Soheila; Guégan, Nicolas; Yousefi, Shída; Straumann, Alex; Cerf‐Bensussan, Nadine; Simon, Hans‐Uwe; Chvatchko, Yolande

doi:10.1080/19420862.2017.1332553

Cited by 34 publications

(22 citation statements)

References 79 publications

(144 reference statements)

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“…The results of our study demonstrate a considerable expression of IL-15 in AD that is similar to the expression of IL-15 in EoE [6]. Both AD and EoE are characterized by Th2 immune responses.…”

Section: Discussionsupporting

confidence: 75%

“…EoE is considered a Th2-driven disease [5], and indeed IL-15 has been shown to activate CD4 + T cells to produce IL-5 and IL-13 as well as to induce eotaxin gene expression in esophageal epithelial cells [4]. Neutralizing IL-15 with a monoclonal antibody resulted in a significant reduction of eosinophils in the esophagus in an Aspergillus fumigatus mouse model of EoE [6].…”

Section: Introductionmentioning

confidence: 99%

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IL-15 Expression Pattern in Atopic Dermatitis

Karlen

Yousefi

Simon

et al. 2020

Int Arch Allergy Immunol

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Background: An increased expression of interleukin (IL)-15, a cytokine with a key role in stimulating innate and adaptive immune cells, such as dendritic cells (DC), natural killer cells, and T cells, has been observed in infectious and inflammatory diseases, including autoimmune diseases as well as cancer. Atopic dermatitis (AD) is a common inflammatory skin disease characterized by a type 2 immune response. Objective: To explore the expression of IL-15 and its pattern in AD skin. Method: Immunofluorescence staining was performed on skin specimens of AD skin, nonlesional AD skin (AD NL), and normal skin (NS) using antibodies directed against IL-15 and CD3, mast cell tryptase, eosinophil cationic protein, CD68, CD11b, CD1a, and vimentin. Results: A significantly higher IL-15 expression in AD and AD NL was observed in both the epidermis (p = 0.0003) and the dermis (p = 0.0154) as compared to NS. Cells expressing IL-15 were mainly keratinocytes, CD1a + DC, CD11b + DC, CD68 + macrophages, and vimentin + fibroblasts. In AD, an increase in the relative numbers of IL-15 expressing CD1a + DC, macrophages, and fibroblasts was noted. Conclusion: Our results demonstrate an expression of IL-15 in AD similar to that of eosinophilic esophagitis which is also a type 2 disease. IL-15 may serve as a therapeutic target for AD.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

IL-15 Expression Pattern in Atopic Dermatitis

Karlen

Yousefi

Simon

et al. 2020

Int Arch Allergy Immunol

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“…Hence, there is an urgent need for treatments for CeD, RCeD, and associated lymphomas. Currently, IL-15 blocking antibodies are being investigated as a treatment strategy (Vicari et al, 2017), however, with limited success (Cellier et al, 2019;Lähdeaho et al, 2019), thus identification of new targets for small molecule inhibitors would be beneficial. Our data suggest that inhibitors against the PIM kinases may also be suitable targets for the treatment of CeD and RCeD.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive proteomics analyses identify PIM kinases as key regulators of IL-15 driven activation of intestinal intraepithelial lymphocytes

James

Vandereyken

Marchingo

et al. 2020

Preprint

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Intestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect the gut from pathogens and maintain intestinal homeostasis. The cytokine IL-15 is transpresented by epithelial cells to IEL in complex with the IL-15 receptor α chain (IL-15Rα). It plays essential roles both in maintaining IEL homeostasis, and in inducing IEL activation in response to epithelial stress. IL-15 overexpression also drives the gluten-induced enteropathy Coeliac disease, through cytotoxic activation of IEL. In order to better understand how IL-15 directly regulates both homeostatic and inflammatory functions of IEL, we set up quantitative proteomics of IL-15/Rα stimulated IEL. We reveal that high IL-15/Rα stimulation licenses cell cycle activation, upregulates the biosynthetic machinery in IEL, increases mitochondrial respiratory capacity and induces expression of cell surface immune receptors and adhesion proteins that potentially drive IEL activation. We find that high IL-15/Rα selectively upregulated the Ser/Thr kinases PIM1 and PIM2 and demonstrate that PIM1/2 are essential for IEL to proliferate, grow, and upregulate Granzyme B in response to high IL-15. Significantly, IEL from Coeliac disease patients express high levels of PIM kinases. These unexpected findings reveal PIM kinases to be key determinants of IEL responses to elevated levels of IL-15.3

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“…IL15 is a pleiotropic cytokine, functionally and structurally classified as a partial mimetic of the in vitro IL2 activity and a component of the 4-α-helix bundle cytokine family [ 200 ]. Thus, IL15 is involved in the proliferation and effector functions of NK and CD8 + T cells [ 200 , 201 , 202 ], while opposing to IL2, no activation-induced cell death or Treg expansion and activation has been reported for IL15 [ 203 , 204 ]. The IL15 heterotrimeric receptor is composed of a specific subunit α (IL15A), that upon high affinity intracellular ligand-binding and exporting to the cell surface can recruit the β and γ chains of the IL2 receptor (IL2RB and IL2RG) at the plasma membrane, or be cleaved after trans-presentation to neighbouring cells displaying the IL2R signalling chains [ 201 , 205 ].…”

Section: Cytokines: Immune Actors In Bat Activation and Browning Omentioning

confidence: 99%

Regulation of Energy Expenditure and Brown/Beige Thermogenic Activity by Interleukins: New Roles for Old Actors

García

Pazos

Lima

et al. 2018

IJMS

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Obesity rates and the burden of metabolic associated diseases are escalating worldwide Energy burning brown and inducible beige adipocytes in human adipose tissues (ATs) have attracted considerable attention due to their therapeutic potential to counteract the deleterious metabolic effects of nutritional overload and overweight. Recent research has highlighted the relevance of resident and recruited ATs immune cell populations and their signalling mediators, cytokines, as modulators of the thermogenic activity of brown and beige ATs. In this review, we first provide an overview of the developmental, cellular and functional heterogeneity of the AT organ, as well as reported molecular switches of its heat-producing machinery. We also discuss the key contribution of various interleukins signalling pathways to energy and metabolic homeostasis and their roles in the biogenesis and function of brown and beige adipocytes. Besides local actions, attention is also drawn to their influence in the central nervous system (CNS) networks governing energy expenditure.

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Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis

Cited by 34 publications

References 79 publications

IL-15 Expression Pattern in Atopic Dermatitis

IL-15 Expression Pattern in Atopic Dermatitis

Comprehensive proteomics analyses identify PIM kinases as key regulators of IL-15 driven activation of intestinal intraepithelial lymphocytes

Regulation of Energy Expenditure and Brown/Beige Thermogenic Activity by Interleukins: New Roles for Old Actors

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