Upregulation of Interleukin-12 and -17 in Active Inflammatory Bowel Disease

Nielsen, Ole Haagen; Kirman, Irena; Rüdiger, Niels; Hendel, Jakob; Vainer, Ben

doi:10.1080/00365520310000672

Cited by 221 publications

(151 citation statements)

References 39 publications

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“…It offers great hope for potential treatment of diseases where IL-17 is recognized as the key inducer of inflammation, as is now Highlights 2871 well documented in arthritis [29], asthma [30], inflammatory bowel disease [31,32] and intra-abdominal abscesses [33]. In multiple sclerosis, little is known about the actual importance of IL-17, although increased numbers of IL-17 mRNA-expressing cells were found to correlate with disease exacerbation [34].…”

Section: Discussionmentioning

confidence: 99%

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

2006

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IL-17 has been associated with multiple inflammatory disorders such as rheumatoid arthritis, asthma and multiple sclerosis. As these diseases require long-term treatment we turned to an auto-vaccine strategy for IL-17 neutralization in vivo. Mouse IL-17A was covalently linked to ovalbumin and used to immunize C57BL/6 mice. This vaccine induced the production of antibodies that blocked IL-17A bioactivity in vitro but did not react with the other IL-17 isoforms, including IL-17F. As the half-life of the Ab titers after the last immunogen administration was approximately 4 months, the vaccine provides for long lasting and selective inhibition of IL-17A activity in vivo. A monoclonal Ab (mAb) derived from these mice showed the same specificity for IL-17A. To test the ability of the vaccine to confer protection against an IL-17-dependent disorder, SJL mice were vaccinated with IL-17-OVA and encephalomyelitis (EAE) was induced by proteolipid protein (PLP) peptide 139-151. Vaccinated mice were completely protected against the disease. The above-mentioned anti-IL-17A mAb also prevented EAE development. The absence of clinical symptoms contrasted with unaltered PLP-induced cytokine production in vitro and unmodified anti-PLP IgG titers and isotypes. These results suggest that an anti-IL-17A auto-vaccine offers new perspectives for therapy of autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

2006

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“…6,7,[20][21][22][23][24][25] The murine intestine harbours a large proportion of CD4 + Th17 cells in steady-state, 26 possibly reflecting the constitutive IL-23 expression found in the terminal ileum of healthy mice. 27 Moreover, specific constituents of the gut microbiota, e.g.…”

Section: Interleukin-23 Has Broad Effects On Both T Cells and Non-t Cmentioning

confidence: 99%

Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity

2011

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Summary Interleukin‐23 (IL‐23) plays an essential role in driving intestinal pathology in experimental models of both T‐cell‐dependent and innate colitis. Furthermore, genome‐wide association studies have identified several single‐nucleotide polymorphisms in the IL‐23 receptor (IL‐23R) gene that are associated with either susceptibility or resistance to inflammatory bowel disease in humans. Although initially found to support the expansion and maintenance of CD4+ T helper 17 (Th17) cells, IL‐23 is now recognized as having multiple effects on the immune response, including restraining Foxp3+ regulatory T‐cell activity and inducing the expression of Th17‐type cytokines from non‐T‐cell sources. Here we focus on Th17 cells and their associated cytokines IL‐17A, IL‐17F, IL‐21 and IL‐22. We review studies performed in mouse models of colitis where these effector cytokines have been shown to have either a pathogenic or a tissue‐protective function. We also discuss the heterogeneity found within the Th17 population and the phenomenon of plasticity of Th17 cells, in particular the ability of these lymphocytes to extinguish IL‐17 expression and turn on interferon‐γ production to become Th1‐like ‘ex‐Th17’ cells. Interleukin‐23 has been identified as a key driver in this process, and this may be an additional mechanism by which IL‐23 promotes pathology in the intestinal tract. These ‘ex‐Th17’ cells may contribute to disease pathogenesis through their secretion of pro‐inflammatory mediators.

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“…Excessive production of IL-12 or IL-23 has been linked to a number of diseases including arthritis [13,14], psoriasis [15], glomerulonephritis [16], Crohn's disease [17,18] and multiple sclerosis [19][20][21][22] as well as its mouse model experimental autoimmune encephalomyelitis (EAE) [23,24]. The multiplicity of these chronic and severe diseases makes these factors attractive targets for immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Development of an anti‐IL‐12 p40 auto‐vaccine: protection in experimental autoimmune encephalomyelitis at the expense of increased sensitivity to infection

et al. 2004

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IL‐12 and IL‐23, which share the IL‐12 p40 subunit, have been ascribed central roles in many autoimmune disorders. We describe here an anti‐IL‐12 (αIL‐12) auto‐vaccine that potentially blocks both factors in vivo. Immunization of mice with mouse IL‐12 coupled to OVA or Pan DR epitope (PADRE) peptide induced Ab directed against the IL‐12 p40 subunit, which prevented IFN‐γ production in response to IL‐12 administration in vivo. Experimental autoimmune encephalomyelitis, an IL‐23‐dependent disease model, induced in SJL mice with a proteolipid protein (PLP) peptide was almost undetectable after αIL‐12 vaccination. Myelin oligodendrocyte glycoprotein (MOG)‐induced disease in C57BL/6 mice was also significantly inhibited. This protection correlated with inhibited Th1 cytokine responses in vitro and with an increase in the IgG1/IgG2a anti‐PLP Ab balance. Detrimental consequences of αIL‐12 vaccination were evaluated in C57BL/6 mice infected with Leishmania major (L.m.). While delayed‐type hypersensitivity (DTH) suppression and immunoglobulin as well as interleukin production patterns reflected a major shift toward a Th2‐type response, L.m. growth was still significantly retarded as compared to that seen in susceptible BALB/c mice. However, vaccinated animals ultimately failed to control parasite expansion. These results suggest that some chronic autoimmune diseases may benefit from αIL‐12 vaccination at the expense of reduced, but not completely abrogated, cell‐mediated immunity.

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Upregulation of Interleukin-12 and -17 in Active Inflammatory Bowel Disease

Abstract: The expression of both IL-12 and IL-17 mRNA is induced in active UC and CD and may thus be involved in sustaining the intestinal inflammation in IBD. Inhibition of IL-12 or IL-17 might be future therapeutic targets in IBD.

Cited by 221 publications

References 39 publications

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

Development of an anti‐IL‐17A auto‐vaccine that prevents experimental auto‐immune encephalomyelitis

Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity

Development of an anti‐IL‐12 p40 auto‐vaccine: protection in experimental autoimmune encephalomyelitis at the expense of increased sensitivity to infection

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