Elsevier

Cellular Immunology

Volume 237, Issue 2, October 2005, Pages 123-130
Cellular Immunology

Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis

https://doi.org/10.1016/j.cellimm.2005.11.002Get rights and content

Abstract

Experimental autoimmune encephalomyelitis (EAE) is widely regarded as an animal model of the human disease multiple sclerosis. A multitude of studies has investigated the neuroantigen-specific T-cell mediated cytokine pattern present in animals with EAE. In particular, the role of the so-called Th1- and Th2-cytokines has been addressed. In a recent study, it has been demonstrated that IL-23 rather than IL-12 is critical for modulating the character of the developing immune response towards a proinflammatory response and leading to EAE. IL-17 is a crucial effector cytokine, whose production is specifically triggered by IL-23, and it has been shown to be an essential inflammatory mediator in other autoimmune diseases and inflammatory conditions. This led us to investigate the role of IL-17 in EAE. Strong antigen-specific production of IL-17 was demonstrated both in peripheral immune organs and in the CNS in acute and chronic EAE, as demonstrated by ELISPOT and RT-PCR analysis. Therapeutic neutralization of IL-17 with IL-17-receptor-Fc-protein in acute EAE ameliorated clinical symptoms. Neutralization of IL-17 with a monoclonal antibody also ameliorated the disease course. We conclude that IL-17 is crucially involved in the cytokine network as an effector cytokine in EAE.

Introduction

Interleukin 17 (IL-17) is a proinflammatory cytokine mainly secreted by activated T cells. Its biologic actions and the associations with major human autoimmune diseases and their respective animal models suggest that this cytokine may have a critical role in inflammation in general [1]. IL-17 was first identified as a rodent cDNA transcript, which was named CTLA8. It has been demonstrated that it is able to induce the production of other cytokines and chemokines from a variety of cell types [2], [3], and that it coordinates the recruitment of myeloid cells like monocytes and neutrophils to the site of an inflammation [4]. Other actions of IL-17 such as the stimulation of IL-6 and chemokine production have been shown to further orchestrate the local inflammatory environment [5], [6], [7].

IL-17 as an effector cytokine has been associated with a broad variety of chronic disease conditions, suggesting a role in these diseases. In particular, several works have indicated a crucial role for IL-17 in rheumatoid arthritis and the corresponding animal models [8], [9], [10], [11]. An association between IL-17 and transplant rejection [12], pancreatitis [6], inflammatory bowel disease [13], allergic asthma [14], adhesion formation [15], systemic sclerosis [16], Behcet’s disease [17] or multiple sclerosis [18] has been described. Investigations performed to analyze whether IL-17 could be classified according to the Th1/Th2 paradigm [19] have so far not yielded a clear answer [20], [21]. Individual T-cell clones have been shown to produce IFN-γ and IL-17, but many IL-17-producing clones appear to produce neither IFN-γ nor IL-4 [20] and therefore seem to represent an entity of T cells not easy to classify along the common Th1/Th2 paradigm. In the memory T-cell compartment there seems to exist a specific population of T cells able to produce IL-17, which are activated by stimuli which are so far unknown. It has been demonstrated that this does not happen when cells are stimulated with the classic Th1-driver IL-12, on the contrary, IL-17-expressing cells under certain conditions seem to represent a T-cell population which is distinct from the traditional Th1 profile and are characterized by the selective production of IL-17 and GM-CSF [22].

In multiple sclerosis (MS) and its corresponding animal model, experimental autoimmune encephalomyelitis (EAE), limited information has been accumulated so far about the role of IL-17 in the pathogenesis [18]. It has been revealed that in MS lesions in situ IL-17 is the cytokine which is predominantly upregulated [23]. In addition, a recent study has claimed a crucial role for IL-17 producing T cells in EAE [24]. A multitude of studies has addressed the role of the so-called Th1- and Th2-cytokines in MS and EAE with IL-12 proposed as being the key upstream cytokine influencing the character of the developing immune response towards a proinflammatory, destructive autoimmune reaction. The general notion has included that a Th1-response is associated with a disease-enhancing reaction, whereas a Th2-response exerts a more modulatory function and can protect from disease in most cases. In several recent studies, however, it has been demonstrated that IL-23 rather than IL-12 is critical for the initiation of EAE [25]. IL-17 is a crucial effector cytokine, whose production is specifically triggered by IL-23 [18], [26], and it has been shown to be an essential inflammatory mediator in other autoimmune diseases and inflammatory conditions. This led us to further investigate the potential role of IL-17 in EAE.

Section snippets

Animals, antigens, and treatments

Wild-type C57.BL/6 mice were obtained from Charles River (Sulzfeld, Germany) and maintained at the local animal facilities under special pathogen-free conditions. Animals were injected at 2–4 months of age with 200 μg myelin oligodendrocyte glycoprotein (MOG) peptide amino acids 35–55 (MOGp 35–55, Biotrend, Cologne, Germany). Pertussis toxin (400 ng, Sigma, Deisenhofen, Germany) was injected twice i.p., in 500 μl saline, 24 and 72 h after the immunization. Incomplete Freund’s adjuvant (IFA) was

MOGp 35–55-specific production of IL-17 in the spleen during acute EAE after immunization with MOGp 35–55 in CFA

To investigate whether IL-17-producing T cells are present in EAE, IL-17 expression was measured in the spleen of animals immunized with MOGp 35–55. A representative disease curve of a group of 4 animals is shown in Fig. 1A. Cytokine measurements were conducted by ELISPOT and by RT-PCR on spleen cells, reflecting the response in the immune periphery concerning the effector cell mass building up in the body. In acute EAE (day 15 after immunization), a strong MOGp-specific IL-17 production was

Discussion

The principal goal of this study was to investigate the potential role of IL-17 in MOGp-induced EAE in C57.BL/6 mice by ELISPOT and RT-PCR. Strong MOGp-specific IL-17 production could be detected both in the spleen representing the immune periphery with the induction phase and the CNS as the target organ of the autoimmune T-cell response in acute EAE. The differences regarding some cytokines comparing the results obtained with ELISPOT and with RT-PCR may be explained by the fact that ELISPOT

Acknowledgments

We thank Gabi Köllner and R. Waterstraat for excellent technical assistance, and Helga Brünner and Dr. Bettina Holtmann for excellent animal care. The work was supported by a grant from the German Federal Ministry of Education and Research (BMBF) programme NBL3, 01 ZZ0108, to S.M.I.

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