IL-23 and IL-17: function, disease and therapy

Transcription

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

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

3 IL-23

4 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

5 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 Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 421:

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

7 IL 17

8 Function of Th17 cells David C. Wraith, Anti-cytokine vaccines and immunotherapy of autoimmune diseases, Eur. J. Immunol :

9 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 IL-17A and IL-17F have role in airway hyper responsiveness and other pathological changes including metaplasia and airway remodeling Kawaguchi M et al., IL-17 cytokine family. J Allergy Clin Immunol 2004;114:

10 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:

11 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:

12 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 The role of T cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res. Ther. 7: Komiyama, Y. Et al., IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol :

13 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: Linden A, Adachi M: Neutrophilic airway inflammation and IL- 17. Allergy 2002, 57: 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:

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

15 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:

16 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.

17 IL-17 in tumorigenesis: conclusion increased growth in nude mice IL-17 is pleiotropic a cytokine with opposite activities in the regulation of tumor growth 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.

18 Immunotherapy of autoimmune diseases with Anti-cytokine vaccines

19 Autoimmune myocardits: IL17VLP 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 : DOI: /eji

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

21 auto-immune encephalomyelitis IL17 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 : DOI: /eji

22 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.

23 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: Langowski, J. L. et al., IL-23 promotes tumour incidence and growth. Nature, : Chia-Hui Lo et al., Antitumor and antimetastatic activity of IL-23. J. Immunol. 171: Jing-Sheng Hao and Bao-En Shan, 2006, Immune enhancement and anti-tumor activity of IL-23, Cancer Immunol Immunother, 55: David C. Wraith, Anti-cytokine vaccines and immunotherapy of autoimmune diseases, Eur. J. Immunol : 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: Kawaguchi M et al., IL-17 cytokine family. J Allergy Clin Immunol 2004;114: 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 Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev. 202: Lankford, C. S. R. and Frucht, D. M., A unique role for IL-23 in promoting cellular immunity. J. Leukoc. Biol : Sonderegger, I. et al., Neutralization of IL-17 by active vaccination inhibits IL-23-mediated autoimmune myocarditis. Eur. J. Immunol : DOI: /eji Rhn, T. A. et al., Vaccination against IL 17 suppresses autoimmune arthritis and encephalomyelitis Eur. J. Immunol : DOI: /eji Uyttenhove, C. and Van Snick, J., Development of an anti-il 17A autovaccine that prevents experimental auto-immune encephalomyelitis Eur. J. Immunol : DOI: /eji Numasaki, M. et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood 101, (2003). Lubberts, E., M. I. Koenders, and W. B. van den Berg The role of T cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res. Ther. 7:

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

25 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 Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev. 202: Lankford, C. S. R. and Frucht, D. M., A unique role for IL-23 in promoting cellular immunity. J. Leukoc. Biol :

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

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

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