Anti-Inflammatory Role of IL-17 in Experimental Autoimmune Uveitis

Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, University of Louisville, KY 40202, USA.
The Journal of Immunology (Impact Factor: 4.92). 04/2009; 182(5):3183-90. DOI: 10.4049/jimmunol.0802487
Source: PubMed


Previous studies have shown that IL-17 is a strong proinflammatory cytokine and that IL-17-producing autoreactive T cells play a major role in the pathogenesis of autoimmune diseases. In a previous study, we showed that injection of experimental autoimmune uveitis-susceptible mice with anti-IL-17 Abs blocked subsequent disease development. To determine whether administration of IL-17 to experimental autoimmune uveitis-susceptible Lewis rats and B10RIII mice injected with disease-inducing peptides enhanced disease susceptibility, we injected the recipient animals with various doses of human rIL-17 (hIL-17). Unexpectedly, the treated animals showed significant amelioration of disease; in addition, both the intensity of the autoreactive response and cytokine production by the autoreactive T cells induced by immunization with uveitogenic peptides were significantly decreased. Our results show that IL-17 has anti-inflammatory activity and that this cytokine can suppress the development of autoimmune disease.

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    • "In R14-induced relapsing EAU this population slightly decreased during the course of disease, but increased during monophasic, PDSAg-induced uveitis. We speculate that these cells might play a role in prohibiting recurrent inflammation in monophasic EAU, for it was previously shown that injection of IL-17 can ameliorate EAU [22]. A regulatory role of cells coexpressing two inflammatory cytokines seems to be unusual, but further experiments showed that although IFN-γ+/IL-17+ cells did not express Foxp3, a rather high percentage coexpressed IL-10, a cytokine typical for regulatory T cells [23]. "
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    ABSTRACT: A major limitation of most animal models of autoimmune diseases is that they do not reproduce the chronic or relapsing-remitting pattern characteristic of many human autoimmune diseases. This problem has been overcome in our rat models of experimentally induced monophasic or relapsing-remitting autoimmune uveitis (EAU), which depend on the inducing antigen peptides from retinal S-Antigen (monophasic EAU) or interphotoreceptor retinoid-binding protein (relapsing EAU). These models enable us to compare autoreactive and regulatory T cell populations. Intraocular, but not peripheral T cells differ in their cytokine profiles (IFN-γ, IL-17 and IL-10) at distinct time points during monophasic or relapsing EAU. Only intraocular T cells concomitantly produced IFN-γ, IL-17 and/or IL-10. Monophasic EAU presented rising numbers of cells expressing IFN-γ and IL-17 (Th1/Th17) and cells expressing IL-10 or Foxp3. During relapsing uveitis an increase of intraocular IFN-γ+ cells and a concomitant decrease of IL-17+ cells was detected, while IL-10+ populations remained stable. Foxp3+ cells and cells expressing IL-10, even in combination with IFN-γ or IL-17, increased during the resolution of monophasic EAU, suggesting a regulatory role for these T cells. In general, cells producing multiple cytokines increased in monophasic and decreased in relapsing EAU. The distinct appearance of certain intraocular populations with characteristics of regulatory cells points to a differential influence of the ocular environment on T cells that induce acute and monophasic or relapsing disease. Here we provide evidence that different autoantigens can elicit distinct and differently regulated immune responses. IFN-γ, but not IL-17 seems to be the key player in relapsing-remitting uveitis, as shown by increased, synchronized relapses after intraocular application of IFN-γ. We demonstrated dynamic changes of the cytokine pattern during monophasic and relapsing-remitting disease with strongly increasing IL-10 expression in intraocular T cells during monophasic uveitis.
    PLoS ONE 11/2012; 7(11):e49008. DOI:10.1371/journal.pone.0049008 · 3.23 Impact Factor
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    • "Th17 cells were recently described as crucial for the development of EAU [21–25]; however, it was not observed differences in IL-17 levels by splenocytes at day 21 after-immunization between the experimental groups. Thus, we may assume that, at this phase, the Th17 cells are in the eye. "
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    ABSTRACT: Experimental autoimmune uveitis (EAU) is a well established model for immune-mediated organ-specific disease. Our group has recently shown that the M. leprae Hsp65 aggravated the uveitis in mice; in the present study, we evaluated the action of M. leprae  K(409)A mutant protein and the synthetic peptides Leader pep and K(409)A pep (covering amino acids residues 352-371 of WT and K(409)A proteins of M. leprae Hsp65, resp.) on the pathogenesis of EAU. Mice received the 161-180 IRBP peptide and B. pertussis toxin followed by the intraperitoneal inoculation of K(409)A protein or the Leader pep or K(409)A pep. The Leader pep aggravated the disease, but mice receiving the K(409)A pep did not develop the disease and presented an increase in IL-10 levels by spleen cells and a decrease in the percentage of CD4+ IFN-γ+ T cells. Moreover, animals receiving the Leader pep presented the highest scores of the disease associated with increase percentage of CD4+ IFN-γ+ T cells. These results would contribute to understanding of the pathogenesis of EAU and support the concept that immune responses to Hsp are of potential importance in exacerbating, perpetuating, or even controlling organ-restricted autoimmune diseases, and it is discussed the irreversibility of autoimmune syndromes.
    08/2012; 2012(5):197648. DOI:10.1155/2012/197648
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    • "In fact, the exact role played by Th17 cells in autoimmunity has been under active discussion [32], specially after the publication of some interesting studies providing data that bring in question the pathogenic potential of IL17, the signature cytokine of Th17 cells. In one hand IL17 treatment has been shown to induce an amelioration of experimental autoimmune uveitis in Lewis rats [33] and, in the other hand, mice with a conditional deletion of IL17 develop EAE normally [34]. In agreement with this last statement, the analysis of IL17 protein levels in our study demonstrated that despite the high increase in Th17 lymphocytes during the recovery phase, protein levels of this cytokine remained unaltered along the different phases of EAE, suggesting that may be IL17 is not the key cytokine secreted by these lymphocytes in this acute model or that their function is not as relevant as though. "
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE), a well-established model of multiple sclerosis, is characterised by microglial activation and lymphocyte infiltration. Induction of EAE in Lewis rats produces an acute monophasic disease characterised by a single peak of disability followed by a spontaneous and complete recovery and a subsequent tolerance to further immunizations. In the current study we have performed a detailed analysis of the dynamics of different lymphocyte populations and cytokine profile along the induction, peak, recovery and post-recovery phases in this paradigm. MBP-injected rats were sacrificed attending exclusively to their clinical score, and the different populations of T-lymphocytes as well as the dynamics of different pro- and anti-inflammatory cytokines were analysed in the spinal cord by flow cytometry, immunohistochemistry and ELISA. Our results revealed that, during the induction and peak phases, in parallel to an increase in symptomatology, the number of CD3+ and CD4+ cells increased progressively, showing a Th1 phenotype, but unexpectedly during recovery, although clinical signs progressively decreased, the number and proportion of CD3+ and CD4+ populations remained unaltered. Interestingly, during this recovery phase, we observed a marked decrease of Th1 and an important increase in Th17 and T-reg cells. Moreover, our results indicate a specific cytokine expression profile along the EAE course characterized by no changes of IL10 and IL17 levels, decrease of IL21 on the peak, and high IL22 levels during the induction and peak phases that markedly decrease during recovery. In summary, these results revealed the existence of a specific pattern of lymphocyte infiltration and cytokine secretion along the different phases of the acute EAE model in Lewis rat that differs from those already described in chronic or relapsing-remitting mouse models, where Th17-cells were found mostly during the peak, suggesting a specific role of these lymphocytes and cytokines in the evolution of this acute EAE model.
    PLoS ONE 11/2011; 6(11):e27473. DOI:10.1371/journal.pone.0027473 · 3.23 Impact Factor
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