Biological activity of IL 23 and IL 17

IL-23 and IL-17:
function, disease and
therapy
Daniele Conte
a.a. 2006/2007

IL-23/IL-17 axis in inflammation and infection
Yoichiro Iwakura and Harumichi Ishigame, 2006, IL-23/IL-17 axis in inflammation, jci, 116

IL-23

Preferential action of IL-23 on Memory T Cells
Frucht DM. IL-23: a cytokine that acts on memory T cells. Sci STKE 2002;2002:PE1.
IL-23 promote cellular immune response

IL-23 in diseases:
IL-23 in autoimmune inflammation
IL-23 plays a central role in the establishment and maintenance of organ-specific
inflammatory autoimmune diseases.
IL-23p19 KO mice are resistant to
EAE, CIA
Cua, D.J., et al. 2003. Interleukin-23 rather than interleukin-12 is
the critical cytokine for autoimmune inflammation of the brain.
Nature. 421:744–748.

IL-23 in diseases:
Pro-tumour activity of IL-23
Langowski, J. L. et al., IL-23 promotes tumour incidence and growth. Nature, 2006. 442: 461–465.
IL-17, G.CSF, granulocytes and macrophages are decreased in IL-23 KO
IL-12 and IL-23 antagonize each other in tumour surveillance

IL 17

Function of Th17 cells
David C. Wraith, Anti-cytokine vaccines and immunotherapy of autoimmune diseases, Eur. J.
Immunol. 2006. 36: 2844–2848

The IL-17 super family
Pleiotropic activity of the IL 17-family
Major function of IL-17A/F/E
Major function is chemoattractant
activity through the induction of
cytokines and chemokines:
IL-17A and IL-17F: neutrophili
IL-17E : eosinophili
Kawaguchi M et al., IL-17 cytokine family. J Allergy Clin Immunol
2004;114:1265-73
IL-17A and IL-17F have role in
airway hyper responsiveness and
other pathological changes
including metaplasia and airway
remodeling

IL-17 synergize to other cytokines
• with IL-1 and TNF-α to drive expression of numerous
infiammatory effector
• with IFN-γ to promote chemokine gene expression
IL-17 is in the midst of a complex network that amplifies
inflammation
IL-17 play during adaptive or memory immune responses.
IL-17 may be to trigger innate immune responses shortly after a
second encounter with antigen, when the memory response is
activated but when concentrations of antigen are still too low to
trigger a full-scale innate immune response.
Sarah L Gaffen, Biology of recently discovered cytokines: Interleukin-17 – a unique inflammatory cytokine with roles in bone biology
and arthritis, Arthritis Res Ther 2004, 6:240-247

IL 17 in diseases:
IL 17 in bone metabolism and arthritic process
M I Koenders et al., Potential new target in arthritis therapy:interleukin (IL)-17 and its relation to
tumour necrosis factor and IL-1 in experimental arthritis , Ann Rheum Dis 2006;65;29-33
Sarah L Gaffen, Biology of recently discovered cytokines: Interleukin-17 – a unique inflammatory cytokine with roles in bone biology
and arthritis, Arthritis Res Ther 2004, 6:240-247

IL 17 in diseases:
RA, CIA and EAE
In RA IL-17 is upregulated in early disease
IL-17 knockout mice are resistant to CIA
Development of EAE is reduced in IL-17 knockout mice
Lubberts, E., et al. 2005. The role of T cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis
Res. Ther. 7: 29–37.
Komiyama, Y. Et al., IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol.
2006. 177: 566–573.

IL 17 in diseases:
IL-17 in other diseases
Possible pathogenic role in viral infections
(tropic Herpes virus saimiri)
Elevated levels in bacterial infections
Important role in immune response in the lung
•Patera AC, et al. : Interleukin 17 modulates the immune response to vaccinia virus infection. Virology 2002, 299:56-63.
• Linden A, Adachi M: Neutrophilic airway inflammation and IL- 17. Allergy 2002, 57:769-775.
•Sarah L Gaffen, Biology of recently discovered cytokines: Interleukin-17 – a unique inflammatory cytokine with roles in bone biology
and arthritis, Arthritis Res Ther 2004, 6:240-247

IL 17 in diseases:
in tumorigenesis
The role played by IL-17 in tumorigenesis is complex

IL 17 in diseases: in tumorigenesis
IL-17 promote growth and tumorigenicity of human cervical tumors
in nude mice
•Tartour E, et al.: Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer
Res 1999, 59:3698- 3704.

IL 17 in diseases: in tumorigenesis
IL-17 inhibited the growth of hematopoietic tumors (mastocytoma
P815 and lymphoma J558L in immunocompetent mice
Benchetrit F, et al., Tartour E: Interleukin-17 inhibits tumor cell growth by means of a T-cell- dependent mechanism. Blood 2002, 99.

IL-17 in tumorigenesis:
conclusion
IL-17 is pleiotropic a
cytokine with opposite
activities in the regulation
of tumor growth
increased growth in nude
mice
Inhibition of immunogenic
tumors in immunocompetent
mice by T-cell-dependent
mechanism
Other cytokines have this feature
These antagonistic activities of cytokines in the regulation of tumor growth,
which often depends on the immunogenicity of the tumor model, must be
taken into consideration when these molecules are used in trials of
immunotherapy.

Immunotherapy of autoimmune diseases with
Anti-cytokine vaccines

Autoimmune myocardits: IL17-
VLP vaccination
IL-12 p35 KO and WT mice developed myocarditis
p40 KO mice show low level of disease.
Injection of anti-p19 antibody reduced the disease
Sonderegger, I. et al., Neutralization of IL-17 by active vaccination inhibits IL-23-mediated autoimmune myocarditis. Eur. J. Immunol.
2006. 36: DOI: 10.1002/eji.200636484

Autoimmune arthritis:
IL17-VLP vaccination
CIA
Rhn, T. A. et al., Vaccination against IL 17 suppresses autoimmune arthritis and encephalomyelitis Eur. J. Immunol. 2006. 36:
DOI: 10.1002/eji.200636658

auto-immune encephalomyelitis IL-
17 chemically coupled to ovalbumin
Uyttenhove, C. and Van Snick, J., Development of an anti-IL 17A autovaccine that prevents experimental auto-immune
encephalomyelitis Eur. J. Immunol. 2006. 36: DOI: 10.1002/eji.200636662

Conclusion
Central role of IL-17 and 23 in certain organ specific inflammatory autoimmune diseases.
Inhibition of IL-17 activity with anti-cytokine vaccines in mouse
More extensive human studies to define the precise role of IL-17
IL-17 have displayed both pro- and anti-tumour activities.
IL-12 and IL-23 antagonize each other in tumour surveillance.
IL-17 was shown to enhance the cytotoxic T cell response to murine haematopoietic tumours
It is difficult to predict the effect that IL-17 inhibition will have on the susceptibility of an individual
to different types of cancer.

References
• Yoichiro Iwakura and Harumichi Ishigame, 2006, IL-23/IL-17 axis in inflammation, jci, 116
• Frucht DM. IL-23: a cytokine that acts on memory T cells. Sci STKE 2002;2002:PE1.
• Lankford CS and Frucht DM. A unique role for IL-23 in promoting cellular immunity. J Leukoc Biol 2003;73:49–56.
• Langowski, J. L. et al., IL-23 promotes tumour incidence and growth. Nature, 2006. 442: 461–465.
• Chia-Hui Lo et al., 2003. Antitumor and antimetastatic activity of IL-23. J. Immunol. 171:600–607.
• Jing-Sheng Hao and Bao-En Shan, 2006, Immune enhancement and anti-tumor activity of IL-23, Cancer Immunol
Immunother, 55: 1426-143
• David C. Wraith, Anti-cytokine vaccines and immunotherapy of autoimmune diseases, Eur. J. Immunol. 2006. 36: 2844–2848
• Sarah L Gaffen, Biology of recently discovered cytokines: Interleukin-17 – a unique inflammatory cytokine with roles in bone
biology and arthritis, Arthritis Res Ther 2004, 6:240-247
• Kawaguchi M et al., IL-17 cytokine family. J Allergy Clin Immunol 2004;114:1265-73
• M I Koenders et al., Potential new target in arthritis therapy:interleukin (IL)-17 and its relation to tumour necrosis factor and
IL-1 in experimental arthritis , Ann Rheum Dis 2006;65;29-3
• Watford, W. T., et al. 2004. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev. 202: 139–
156.
• Lankford, C. S. R. and Frucht, D. M., A unique role for IL-23 in promoting cellular immunity. J. Leukoc. Biol. 2003. 73: 49–56.
• Sonderegger, I. et al., Neutralization of IL-17 by active vaccination inhibits IL-23-mediated autoimmune myocarditis. Eur. J.
Immunol. 2006. 36: DOI: 10.1002/eji.200636484
• Rhn, T. A. et al., Vaccination against IL 17 suppresses autoimmune arthritis and encephalomyelitis Eur. J. Immunol. 2006. 36:
DOI: 10.1002/eji.200636658
• Uyttenhove, C. and Van Snick, J., Development of an anti-IL 17A autovaccine that prevents experimental auto-immune
encephalomyelitis Eur. J. Immunol. 2006. 36: DOI: 10.1002/eji.200636662
• Numasaki, M. et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood 101, 2620–-2627 (2003).
• Lubberts, E., M. I. Koenders, and W. B. van den Berg. 2005. The role of T cell interleukin-17 in conducting destructive
arthritis: lessons from animal models. Arthritis Res. Ther. 7: 29–37.

• Komiyama, Y. Et al., IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J.
Immunol. 2006. 177: 566–573.
• Tartour E, et al.: Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice.
Cancer Res 1999, 59:3698- 3704.
• Benchetrit F, et al., Tartour E: Interleukin-17 inhibits tumor cell growth by means of a T-cell- dependent mechanism. Blood
2002, 99:2114-2121.
• Patera AC, et al. : Interleukin 17 modulates the immune response to vaccinia virus infection. Virology 2002, 299:56-63.
• Linden A, Adachi M: Neutrophilic airway inflammation and IL- 17. Allergy 2002, 57:769-775.
• Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201,
233–-240 (2005).
• Cua, D.J., et al. 2003. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the
brain. Nature. 421:744–748.
• Murphy, C.A., et al. 2003. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J.
.
Exp. Med. 198:1951–1957.

IL-23 promoting cellular immunity
its production in hematopoietic cells is critical.
its biological activity requires cell-specific expression
Its important in indirectly control of infections
IL-23 modulates DC costimulatory function
pathways of IL-12 and IL-23 are very similar
IL-23could act to down-regulate Stat4-dependent actions of IL-12
unique role for IL-23 in promoting cellular immune responses
Watford, W. T., et al. 2004. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev. 202: 139–156.
Lankford, C. S. R. and Frucht, D. M., A unique role for IL-23 in promoting cellular immunity. J. Leukoc. Biol. 2003. 73: 49–56.

IL-17 promotes angiogenesis and tumor growth
Numasaki, M. et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood 101, 2620–-2627 (2003).

IL-23 in diseases:
IL-23 Promoting tumor incidence or anti-tumour activity
27

Anti-tumour activity of IL-23
Chia-Hui Lo et al., 2003. Antitumor and antimetastatic activity of IL-23. J. Immunol. 171:600–607.