Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes

Yokoyama, Seiji; Watanabe, Nobumasa; Sato, Noriko; Perera, Pin-Yu; Filkoski, Lyvouch; Tanaka, Toshiyuki; Miyasaka, Masayuki; Waldmann, Thomas A.; Hiroi, Takachika; Perera, Liyanage P.

doi:10.1073/pnas.0908834106

Cited by 118 publications

(101 citation statements)

References 24 publications

(37 reference statements)

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“…In humans, activation of CTLs via TCRindependent NKG2D signaling pathway by IL-15 was suggested to be a pathogenic mechanism underlying celiac disease (12). Consistent with this report, transgenic mice expressing human IL-15 in enterocytes accumulated NK-like CD8 + lymphocytes, which caused autoimmune intestinal damage (13). Whereas the above studies implicated IL-6, IL-21, IL-7, and IL-15 in promoting survival, proliferation, and effector functions of autoreactive CD8 + T cells, whether these cytokines also contributed to the initial triggering of autoreactive CD8 + T cells was not addressed.…”

supporting

confidence: 82%

Exposure to IL-15 and IL-21 Enables Autoreactive CD8 T Cells To Respond to Weak Antigens and Cause Disease in a Mouse Model of Autoimmune Diabetes

Ramanathan

Dubois

Chen

et al. 2011

The Journal of Immunology

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Autoreactive CD8+ T lymphocytes play a key role in the pathogenesis of several autoimmune diseases. It is not yet well understood how autoreactive CD8+ T cells, which express TCRs with low reactivity toward self-Ags, gain the ability to respond to autoantigens to cause disease. Previously, we have shown that prior stimulation of CD8+ T cells with synergistic combinations of cytokines produced by the innate immune response, such as IL-21 and IL-15, induces Ag-independent proliferation. Such “cytokine-primed” CD8 T cells displayed increased responsiveness to limiting quantities of the cognate Ag. In this paper, we report that prior stimulation with IL-15 and IL-21 also enables CD8+ T cells to respond to weakly agonistic TCR ligands, resulting in proliferation, cytokine secretion, and cytolytic activity. Using a transgenic mouse model of autoimmune diabetes, we show that cytokine-primed autoreactive CD8+ T cells induce disease following stimulation by weak TCR ligands, but their diabetogenic potential is dependent on continuous availability of IL-15 in vivo. These findings suggest that inflammatory cytokines could facilitate the triggering of autoreactive CD8+ T cells by weak autoantigens, and this mechanism may have important implications for autoimmune diseases associated with microbial infections and chronic inflammation.

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supporting

confidence: 82%

Exposure to IL-15 and IL-21 Enables Autoreactive CD8 T Cells To Respond to Weak Antigens and Cause Disease in a Mouse Model of Autoimmune Diabetes

Ramanathan

Dubois

Chen

et al. 2011

The Journal of Immunology

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“…As a first step to test this concept, we demonstrated that AMG714 restored IEL apoptosis, thereby reducing the massive accumulation of IELs in transgenic mice overexpressing human IL-15 in their gut epithelium (31). Yokoyama et al have recently observed that an IL-2/IL-15Rβ Ab can reverse the inflammatory epithelial lesions that develop in this model after 6-8 months of age (54). Together, these data indicate that blocking IL-15 signaling may both alleviate epithelial damage and eradicate transformed IELs in RCDII.…”

Section: Figurementioning

confidence: 53%

IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease–associated inflammation and lymphomagenesis

Malamut¹,

Machhour²,

Montcuquet³

et al. 2010

J. Clin. Invest.

214

198

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“…Independent studies on the role of IL-15 in an animal model have been intriguing. Transgenic mice that overexpress IL-15 in enterocytes appear to develop a sprue-like small intestinal inflammatory process that can be reversed by antibody-mediated blockade of IL-15 [40]. Similar inhibition was noted in the same IL-15 transgenic mouse model with tofacitinib, a janus kinase inhibitor [41].…”

Section: International Journal Of Celiac Diseasementioning

confidence: 60%

Sprue-like Intestinal Disease

Freeman¹

2016

IJCD

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Recurrent symptoms in well-established celiac disease may result in further clinical evaluation. In most, poor diet compliance is present. Other considerations include an unidentified gluten source, an erroneous initial diagnosis, another or second and superimposed cause for symptoms, or a complication, including collagenous sprue or an intestinal lymphoma. Failure to define an initial gluten-free diet response, however, suggests that celiac disease may not be present. Instead, a distinctive enteropathic process, refractory to diet restrictions, including gluten, is evident. This "sprue-like" intestinal disorder or enteropathy remains unclassified, and probably, represents a heterogeneous entity. Molecular changes suggestive of early clonal expansion of an aberrant population of intraepithelial lymphocytes may be detected in some (with or without a prior gluten-free diet response), and these changes may signify an early or "cryptic" lymphoma. Other newly recognized lymphoproliferative disorders occurring in the setting of celiac disease have been recorded, including hepatosplenic delta-gamma T-cell lymphoma, an indolent CD4+ T-cell lymphoma, particularly in younger males, and large granular lymphocytic leukemia, a possibly treatable disorder characterized by the clonal expansion of T-cells in blood and small intestinal mucosa. Studies using IL-15 blockade in a transgenic mouse model with pathologic features of a sprue-like intestinal disease has led to human clinical trials with encouraging positive results.

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Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes

Cited by 118 publications

References 24 publications

Exposure to IL-15 and IL-21 Enables Autoreactive CD8 T Cells To Respond to Weak Antigens and Cause Disease in a Mouse Model of Autoimmune Diabetes

Exposure to IL-15 and IL-21 Enables Autoreactive CD8 T Cells To Respond to Weak Antigens and Cause Disease in a Mouse Model of Autoimmune Diabetes

IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease–associated inflammation and lymphomagenesis

Sprue-like Intestinal Disease

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