Antigen-Specific T Cells Transduced with IL-10 Ameliorate Experimentally Induced Arthritis Without Impairing the Systemic Immune Response to the Antigen

Setoguchi, Keigo; Misaki, Yoshikata; Araki, Yoshitaka; Fujio, Keishi; Kawahata, K.; Kitamura, Toshio; Yamamoto, Kazuhiko

doi:10.4049/jimmunol.165.10.5980

Cited by 42 publications

(27 citation statements)

References 38 publications

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“…ZuanyAmorim et al (34) reported that the instillation of recombinant murine IL-10 with Ag to the lung reduces Ag inhalation-induced eosinophilic inflammation, whereas IL-10 alone does not show a suppressive effect. In another system, IL-10 delivered into the ankle attenuated arthritis that was initiated by direct injection of OVA-Ag into the ankle in presensitized mice without affecting the immune response in the spleen (52). These studies support our findings.…”

Section: Discussionsupporting

confidence: 81%

In Vivo IL-10 Gene Delivery Suppresses Airway Eosinophilia and Hyperreactivity by Down-Regulating APC Functions and Migration without Impairing the Antigen-Specific Systemic Immune Response in a Mouse Model of Allergic Airway Inflammation

Nakagome

Dohi

Okunishi

et al. 2005

The Journal of Immunology

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IL-10 is an immunosuppressive cytokine. Although previous studies have reported that exogenous delivery of IL-10 reduced airway inflammation in experimental allergic airway inflammation, the mechanism of action has not been fully clarified. In this report, we elucidated a mechanism of action of IL-10 in vivo. BALB/c mice were immunized and aerosol challenged with OVA-Ag. We delivered the IL-10 gene to the mice before systemic sensitization or during aerosol Ag challenge by administering an IL-10-producing plasmid vector. Not only presensitization delivery of IL-10, as reported, but also delivery during inflammation strongly suppressed the development of airway eosinophilia and hyperreactivity. Presensitization delivery suppressed the Ag-specific Th2-type immune response in both the lung and spleen. In contrast, delivery in the effector phase suppressed the Th2 response only in the lung, whereas that in the spleen was not affected. IL-10 gene delivery did not induce the development of a regulatory phenotype of T cells or dendritic cells; rather, it suppressed the overall functions of CD11c+ APCs of the lung such as Ag-presenting capacity, cytokine production, and transportation of OVA-Ag to lymph nodes, thus attenuating Th2-mediated allergic airway inflammation. Further, IL-10 revealed a distinct immunosuppressive effect in the presence of Ag and APCs. These results suggest that suppression of APC function in the lung, the site of immune response, played a critical role in the IL-10-mediated suppression of Ag-induced airway inflammation and hyperreactivity. Therefore, if delivered selectively, IL-10 could site specifically suppress the Ag-specific immune response without affecting systemic immune responses.

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Section: Discussionsupporting

confidence: 81%

In Vivo IL-10 Gene Delivery Suppresses Airway Eosinophilia and Hyperreactivity by Down-Regulating APC Functions and Migration without Impairing the Antigen-Specific Systemic Immune Response in a Mouse Model of Allergic Airway Inflammation

Nakagome

Dohi

Okunishi

et al. 2005

The Journal of Immunology

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“…Administration of recombinant murine IL-10 or of T cells engineered to secrete rat IL-10 constitutively was shown to down-regulate autoimmune arthritis (33,34). In addition, IL-10 can render activated T cells susceptible to the action of TGF␤1 (35).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Adjuvant Arthritis by a DNA Vaccine Encoding Human Heat Shock Protein 60

Quintana

Carmi

Mor

et al. 2002

The Journal of Immunology

128

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Adjuvant arthritis (AA) is an autoimmune disease inducible in rats involving T cell reactivity to the mycobacterial 65-kDa heat shock protein (HSP65). HSP65-specific T cells cross-reactive with the mammalian 60-kDa heat shock protein (HSP60) are thought to participate in the modulation of AA. In this work we studied the effects on AA of DNA vaccination using constructs coding for HSP65 (pHSP65) or human HSP60 (pHSP60). We found that both constructs could inhibit AA, but that pHSP60 was more effective than pHSP65. The immune effects associated with specific DNA-induced suppression of AA were complex and included enhanced T cell proliferation to a variety of disease-associated Ags. Effective vaccination with HSP60 or HSP65 DNA led paradoxically to up-regulation of IFN-γ secretion to HSP60 and, concomitantly, to down-regulation of IFN-γ secretion to the P180-188 epitope of HSP65. There were also variable changes in the profiles of IL-10 secretion to different Ags. However, vaccination with pHSP60 or pHSP65 enhanced the production of TGFβ1 to both HSP60 and HSP65 epitopes. Our results support a regulatory role for HSP60 autoreactivity in AA and demonstrate that this control mechanism can be activated by DNA vaccination with both HSP60 or HSP65.

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“…Recently, local delivery of Th2 cytokines, using hybridomas (8) or dendritic cells (10,11) transfected with either IL-4 or IL-10, was found to be effective in the prevention of arthritis in animal models. In light of the fact that NKT cells are known to rapidly invade and accumulate in inflammatory lesions in a manner similar to inflammatory cells (34), stimulation of NKT cells to selectively induce Th2 cytokines might be a powerful strategy to deliver these cytokines to inflammatory lesions.…”

Section: Discussionmentioning

confidence: 99%

Suppression of collagen‐induced arthritis by natural killer T cell activation with OCH, a sphingosine‐truncated analog of α‐galactosylceramide

Chiba¹,

Oki²,

Miyamoto³

et al. 2004

Arthritis & Rheumatism

160

141

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Objective. OCH, a synthetic analog of ␣-galactosylceramide with a truncated sphingosine chain, stimulates natural killer T (NKT) cells to produce predominantly Th2 cytokines. Thus, OCH may be a potential agent for the treatment of Th1-mediated autoimmune diseases. This study was designed to evaluate the protective effects of OCH on collagen-induced arthritis (CIA) in mice.Methods. Mice were immunized with type II collagen (CII) and injected intraperitoneally twice per week with OCH, before or after the onset of CIA. They were monitored to assess the effect of OCH treatment on the severity of disease. Anti-CII antibodies and cytokine production were measured by enzyme-linked immunosorbent assay. Expression of cytokine genes was determined by quantitative reverse transcriptasepolymerase chain reaction.Results. OCH inhibited CIA in wild-type C57BL/6 (B6) mice but not in NKT-deficient mice. OCH suppressed CIA in SJL mice, which are prone to autoimmune diseases and have a deficiency in the number and function of NKT cells which is similar to that in patients with autoimmune diseases, even after disease has already developed. Disease protection conferred by OCH correlated with its ability to selectively induce Th2 cytokine production mediated by NKT cells and to promote collagen-specific Th2 responses. Neutralization of interleukin-4 (IL-4) or IL-10 with monoclonal antibodies abolished disease protection by OCH, indicating a critical role for these cytokines. Conclusion. Taken together, our findings suggest that OCH holds possibilities as a therapeutic agent for autoimmune diseases such as rheumatoid arthritis.Rheumatoid arthritis (RA) is a common autoimmune disease characterized by persistent inflammation of joints resulting in progressive destruction of cartilage and bone. Although its precise etiology is not clearly understood, cumulative evidence suggests that Th1 cells secreting interferon-␥ (IFN␥) and tumor necrosis factor ␣ (TNF␣) exacerbate disease, whereas Th2 cells producing interleukin-4 (IL-4) and IL-10 suppress arthritis (1). Studies with animal models have demonstrated that systemic or locally administered IL-4 and IL-10 can effectively protect against arthritis in mice (2-11).Natural killer T (NKT) cells are a unique subset of T cells that coexpress T cell receptor ␣/␤ (TCR␣/␤) and receptors from the NK lineage. NKT cells express an invariant TCR␣ chain (encoded by a V ␣ 14-J ␣ 281 rearrangement in mice and a homologous V ␣ 24-J ␣ Q rearrangement in humans). Unlike conventional T cells that recognize peptides in association with major histocompatibility complex (MHC), NKT cells recognize glycolipid antigens bound to the nonpolymorphic class I MHC-like protein, CD1d. NKT cells have been implicated in a variety of immune responses such as infection and tumor immunity. One striking feature of NKT cells is their capacity to secrete a large amount of cytokines,

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Antigen-Specific T Cells Transduced with IL-10 Ameliorate Experimentally Induced Arthritis Without Impairing the Systemic Immune Response to the Antigen

Cited by 42 publications

References 38 publications

In Vivo IL-10 Gene Delivery Suppresses Airway Eosinophilia and Hyperreactivity by Down-Regulating APC Functions and Migration without Impairing the Antigen-Specific Systemic Immune Response in a Mouse Model of Allergic Airway Inflammation

In Vivo IL-10 Gene Delivery Suppresses Airway Eosinophilia and Hyperreactivity by Down-Regulating APC Functions and Migration without Impairing the Antigen-Specific Systemic Immune Response in a Mouse Model of Allergic Airway Inflammation

Inhibition of Adjuvant Arthritis by a DNA Vaccine Encoding Human Heat Shock Protein 60

Suppression of collagen‐induced arthritis by natural killer T cell activation with OCH, a sphingosine‐truncated analog of α‐galactosylceramide

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