Summary: Our understanding of the role of T cells in human disease is undergoing revision as a result of the discovery of T-helper 17 (Th17) cells, a unique CD4+ T-cell subset characterized by production of interleukin-17 (IL-17) IL-17 is a highly inflammatory cytokine with robust effects on stromal cells in many tissues Recent data in humans and mice suggest that Th17 cells play an important role in the pathogenesis of a diverse group of immune-mediated diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma Initial reports also propose a role for Th17 cells in tumorigenesis and transplant rejection Important differences, as well as many similarities, are emerging when the biology of Th17 cells in the mouse is compared with corresponding phenomena in humans As our understanding of human Th17 biology grows, the mechanisms underlying many diseases are becoming more apparent, resulting in a new appreciation for both previously known and more recently discovered cytokines, chemokines, and feedback mechanisms Given the strong association between excessive Th17 activity and human disease, new therapeutic approaches targeting Th17 cells are highly promising, but the potential safety of such treatments may be limited by the role of these cells in normal host defenses against infection

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Th17 cells in human disease

Interleukin-17A (IL-17A) is elaborated by the T helper 17 (T(H)17) subset of T(H) cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A-producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.

Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

https://stm.sciencemag.org/content/suppl/2010/10/04/2.52.52ra72.DC1/2-52ra72_SM.pdf

Supplementary Materials for Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

Autoimmune and inflammatory uveitis are a group of potentially blinding intraocular inflammatory diseases that arise without a known infectious trigger and are often associated with immunological responses to unique retinal proteins. In the United States, about 10% of the cases of severe visual handicap are attributed to this group of disorders. As I discuss here, experimental models of ocular autoimmunity targeting retinal proteins have brought about a better understanding of the basic immunological mechanisms involved in the pathogenesis of uveitis and are serving as templates for the development of novel therapies.

/pdf/a-look-at-autoimmunity-and-inflammation-in-the-eye-rfbe54h39d.pdf

A look at autoimmunity and inflammation in the eye

Autoreactive effector CD4+ T cells have been associated with the pathogenesis of autoimmune disorders. Early studies implicated the interferon (IFN)-γ-producing T helper (Th)1 subset of CD4+ cells as the causal agents in the pathogenesis of autoimmunity. However, further studies have suggested a more complex story. In models thought to be driven by Th1 cells, mice lacking the hallmark Th1 cytokine IFN-γ were not protected but tended to have enhanced susceptibility to disease. Identification of the IL-17-producing CD4+ effector cell lineage (Th17) has helped shed light on this issue. Th17 effector cells are induced in parallel to Th1, and, like Th1, polarized Th17 cells have the capacity to cause inflammation and autoimmune disease. This, together with the finding that deficiency of the Th17-related cytokine IL-23 but not the Th1-related cytokine IL-12 causes resistance, led to the notion that Th17 cells are the chief contributors to autoimmune tissue inflammation. Nevertheless, mice lacking IL-17 are not protected from disease and display elevated numbers of IFN-γ-producing CD4+ T cells, and, in some cases, lack of IFN-γ does confer resistance. Recent studies report overlapping as well as differential roles of these cells in tissue inflammation, which suggests the existence of a more complex relationship between these two effector T-cell subsets than has hitherto been suspected. This review will attempt to bring together current information regarding interaction, balance, and collaborative potential between the Th1 and Th17 effector lineages.

https://nyaspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1749-6632.2009.05133.x

Th1 and Th17 cells

PURPOSE. Behcet disease (BD) is a systemic inflammatory dis- ease presumably caused by an autoimmune response. The interleukin (IL)-23/IL-17 pathway has been demonstrated to be involved in the development and maintenance of certain in- flammatory diseases. This study was designed to investigate the role of IL-23 and IL-17 in BD. METHODS. IL-23p19 mRNA in peripheral blood mononuclear cells (PBMCs) was examined using RT-PCR. The levels of IL-23, IL-17, and IFN- in sera or PBMCs were detected by ELISA. Flow cytometry was used to evaluate the frequencies of IL-17- producing and IFN--producing T cells and the expression of CD45RO. RESULTS. Results showed that the expression of IL-23p19 mRNA, IL-23, IL-17, and IFN- was markedly elevated in BD patients with active uveitis. The frequencies of IL-17-produc- ing and IFN--producing T cells from PBMCs were significantly upregulated in BD patients with active uveitis. The increased IL-17 (3.10% 0.53%) in BD patients with active uveitis was primarily produced by CD45RO memory T cells. Recombi- nant (r) IL-23 could upregulate IL-17 production by poly- clonally stimulated PBMCs, whereas interferon (IFN)- down- regulated IL-17 production. CONCLUSIONS. These findings reveal that the levels of IL-23, IL-17, and IFN- are elevated in BD patients with active uveitis, and they suggest that the IL-23/IL-17 pathway together with IFN- is associated with the active intraocular inflammation in BD patients. (Invest Ophthalmol Vis Sci. 2008;49:3058 -3064)

Upregulated IL-23 and IL-17 in Behçet patients with active uveitis.

Background Vogt-Koyanagi-Harada (VKH) disease is a systemic refractory autoimmune disease. IL-23 has been thought to play a critical role in autoimmune disease through inducing the development of IL-17–producing CD4 + T cells. Objective To investigate the expression of IL-23 and IL-17 and the influence of IL-23 on IL-17 production in patients with VKH disease. Methods Blood samples were taken from 25 patients with VKH disease and 16 healthy controls. Peripheral blood mononuclear cells (PBMCs) were subjected to analysis of IL-23p19 mRNA and IL-23 protein expression using RT-PCR and ELISA, respectively. The IL-17 levels in the supernatants of PBMCs and CD4 + T cells cultured in the absence or presence of recombinant (r)IL-23, rIL-12, or anti–IFN-γ were determined by ELISA. Results The patients with VKH disease with active uveitis showed an elevated level of IL-23p19 mRNA in PBMCs, higher IL-23 in the serum and supernatants of PBMCs, and increased production of IL-17 by polyclonally stimulated PBMCs and CD4 + T cells. Recombinant IL-23 significantly enhanced IL-17 production, whereas rIL-12 and IFN-γ inhibited IL-17 production. More importantly, IL-17 production was significantly increased in patients with active uveitis in the presence of rIL-23. Both rIL-23 and rIL-12 enhanced IFN-γ production. Conclusion The results suggest that IL-23–stimulated production of IL-17 by CD4 + T cells may be responsible for the development of uveitis seen in patients with VKH disease. Clinical implications This study provides a new insight into the mechanism involved in the development of VKH disease.

IL-23 promotes CD4+ T cells to produce IL-17 in Vogt-Koyanagi-Harada disease

Purpose Behcet's disease (BD) is a systemic inflammatory disease presumably caused by an autoimmune response. Interleukin (IL)-17 has been demonstrated to be involved in the development and maintenance of certain inflammatory diseases, including BD. This study was designed to investigate the influence of cyclosporine A (CsA) on IL-17 production by peripheral blood mononuclear cells (PBMCs) from BD patients in vitro and in vivo. Methods Fifteen BD patients with active uveitis were involved in this study. Blood samples were taken from these patients for analysis of IL-17 and interferon (IFN)-gamma. Six patients were re-evaluated at 1 and 3 months after treatment with CsA. The levels of IL-17 and IFN-gamma in the supernatants of PBMCs from patients before treatment cultured without or with CsA at different concentrations were detected by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to evaluate the frequencies of IL-17-producing and IFN-gamma-producing T cells and the expression of CD69 on CD4(+) or CD8(+) T cells before, 1, and 3 months after CsA treatment. Results The results showed that significantly higher levels of IL-17 and IFN-gamma were observed in active BD patients as compared with controls. Treatment with CsA could inhibit the production of both cytokines in association with an amelioration of intraocular inflammation. In vitro, CsA significantly inhibited the production of IL-17 and IFN-gamma by PBMCs activated with anti-CD3 and anti-CD28 antibodies or phorbol 12-myristate,13-acetate and ionomycin in BD patients with active uveitis. However, CSA did not influence the CD69 expression in CD4(+) and CD8(+) T cells induced by phorbol 12-myristate,13-acetate (PMA) ionomycin. Conclusions Our findings showed that CsA can significantly inhibit the intraocular inflammation of BD patients and the expression of IL-17 and IFN-gamma in vivo and in vitro. The results suggested that the inhibitory effect of CsA on uveitis in BD patients may be partially mediated through inhibiting the production of IL-17 and IFN-gamma.

/pdf/production-of-interleukin-17-in-behcet-s-disease-is-1axx1aejvd.pdf

Production of interleukin-17 in Behcet's disease is inhibited by cyclosporin A.

Regulatory CD4+CD25+ T cells have been proven to be essential for maintenance of peripheral tolerance and autoimmune diseases. ACAID is a model of immune privilege in the eye. Relatively little is known about the role and phenotype of these regulatory CD4+CD25+ T cells in ACAID. Injection of OVA into the anterior chamber of BALB/C mice was performed to induce ACAID. The frequencies of splenic CD4+CD25+ Tregs and the expression of CTLA-4 and LAG-3 on these cells were determined by flow cytometry. Magnetic cell sorting was used to isolate CD4+CD25+ and CD4+CD25−T cells. The function of CD4+CD25+ T cells was detected by in vitro immunosuppression assays and in vivo adoptive transfer. ACAID was successfully induced following an i.c. injection of OVA. Frequencies of CD4+CD25+ and Tregs were significantly increased in ACAID mice as compared to those in controls. The CD4+CD25+ T cells stimulated with OVA in ACAID mice showed a stronger suppressive ability in vitro than those seen in non-ACAID mice. CD4+CD25+ T cells from ACAID mice, but not from non-ACAID mice, were able to suppress DTH responses in an antigen-specific manner following adoptive transfer. The frequencies of CTLA-4 or LAG-3 on Tregs in ACAID mice were higher as compared with those in naive mice. Splenic CD4+CD25+Foxp3+T cells expressing CTLA4 and LAG3 play an important role in the induction of ACAID.

CD4 + CD25 + Tregs express an increased LAG-3 and CTLA-4 in anterior chamber-associated immune deviation

Purpose: To assess the expression of T-cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) in the spleens of BALB/c mice undergoing anterior chamber-associated immune deviation (ACAID). Methods: ACAID was generated after intracameral (i.c.) injection of ovalbumin (OVA) into BALB/c mice and evaluated by assessing the delayed-type hypersensitivity (DTH) response following a subsequent subcutaneous (s.c.) injection of OVA emulsified in complete Freund's adjuvant (CFA) on Days 0, 3, 7, 14, 21 and 28. Tim-3 mRNA levels were detected using real-time RT-PCR, and the frequency of CD4+Tim-3+ T cells in splenocytes as well as the coexpression of Tim-3 with CD25 on CD4+ T cells were assessed by flow cytometry. Results: A significantly suppressed DTH response was observed on Days 7, 14, 21, and 28, but not on Days 0 and 3 during the development of ACAID. The levels of Tim-3 mRNA and the frequency of CD4+CD25+Tim-3+ T cells in the splenocytes reached a peak on Day 3, declined on Day 7, and returned to ...

Xuefei Zhu

Papers

Upregulated IL-23 and IL-17 in Behçet patients with active uveitis.

IL-23 promotes CD4+ T cells to produce IL-17 in Vogt-Koyanagi-Harada disease

Production of interleukin-17 in Behcet's disease is inhibited by cyclosporin A.

CD4 + CD25 + Tregs express an increased LAG-3 and CTLA-4 in anterior chamber-associated immune deviation

Expression of Tim-3 is transiently increased before development of anterior chamber-associated immune deviation.