Emi Nishida

Nagoya City University, Nagoya, Aichi, Japan

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Publications (17)44 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The activation of T cells is known to be accompanied by the temporary down-modulation of the T-cell receptor (TCR)/CD3 complex on the cell surface. Here we established a novel monoclonal antibody, Dow2, that temporarily induces down-modulation of the TCR/CD3 complex in mouse CD4+ T cells without activating T cells. Dow2 recognized the determinant on CD3ε; however, differences were observed in the binding mode between Dow2 and the agonistic anti-CD3ε Ab, 145–2C11. An injection of Dow2 in vivo resulted in T-cell anergy, and prolonged the survival of cardiac allografts without a marked increase in cytokine release. The phosphorylated forms of the signaling proteins PLC-γ1 and LAT in Dow2-induced anergic T cells were markedly decreased upon stimulation. However, the levels of phosphorylated LAT and PLCγ1 in Dow2-induced anergic T cells could be rescued in the presence of the proteasome inhibitor MG-132. These results suggest that proteasome-mediated degradation is involved in hypophosphorylated LAT and PLCγ1 in Dow2-induced anergic T cells. The novel CD3-specific Ab, Dow2, may provide us with a unique tool for inducing immunosuppression. This article is protected by copyright. All rights reserved
    European Journal of Immunology 03/2014; · 4.97 Impact Factor
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    ABSTRACT: Generalized pustular psoriasis (GPP) is a rare inflammatory skin disease that can be life-threatening. Recently, it has been reported that familial GPP (FGPP) is caused by homozygous or compound heterozygous mutations of IL36RN. However, the majority of GPP cases are sporadic and it is controversial whether IL36RN mutations are a causative/predisposing factor for sporadic GPP. We searched for IL36RN mutations in two groups of GPP patients in the Japanese population in this study: GPP without psoriasis vulgaris (PV), and GPP with PV. Eleven cases of GPP without PV (GPP alone) and 20 cases of GPP accompanied by PV (GPP with PV) were analyzed. Surprisingly, 9 out of 11 cases of GPP alone had homozygous or compound heterozygous mutations in IL36RN. In contrast, only 2 of 20 cases of GPP with PV had compound heterozygous mutations in IL36RN. The 2 cases of GPP with PV who had compound heterozygous mutations in IL36RN are siblings, and both cases had PV-susceptible HLA-A*0206. We determined that GPP alone is a distinct subtype of GPP and is etiologically distinguished from GPP with PV, and that the majority of GPP alone is caused by deficiency of the interleukin 36 receptor antagonist (DITRA) due to IL36RN mutations.Journal of Investigative Dermatology accepted article preview online, 22 May 2013; doi:10.1038/jid.2013.230.
    Journal of Investigative Dermatology 05/2013; · 6.19 Impact Factor
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    ABSTRACT: Findings from large epidemiologic studies indicate that there is a link between smoking and extrinsic skin ageing. We previously reported that matrix metalloproteinases (MMPs) mediate connective tissue damage in skin exposed to tobacco smoke extracts. Tobacco smoke contains more than 3800 constituents, including numerous water-insoluble polycyclic aromatic hydrocarbons (PAHs) that trigger aryl hydrocarbon receptor (AhR) signalling pathways. To analyse the molecular mechanisms involved in tobacco smoke-induced skin ageing, we exposed primary human fibroblasts and keratinocytes to tobacco smoke extracts. Hexane- and water-soluble tobacco smoke extracts significantly induced MMP-1 mRNA in both human cultured fibroblasts and keratinocytes in a dose-dependent manner. To clarify the involvement of the AhR pathway, we used a stable AhR-knockdown HaCaT cell line. AhR knockdown abolished the increased transcription of the AhR-dependent genes CYP1A1/CYP1B1 and MMP-1 induced by either of the tobacco smoke extracts. Furthermore, the tobacco smoke extracts induced 7-ethoxyresorufin-O-deethylase activity, which was almost completely abolished by AhR knockdown. Likewise, treating fibroblasts with AhR pathway inhibitors, that is, the flavonoids 3-methoxy-4-nitroflavone and α-naphthoflavone, blocked the expression of CYP1B1 and MMP-1. These findings suggest that the tobacco smoke extracts induce MMP-1 expression in human fibroblasts and keratinocytes via activation of the AhR pathway. Thus, the AhR pathway may be pathogenetically involved in extrinsic skin ageing.
    Experimental Dermatology 05/2013; 22(5):349-53. · 3.58 Impact Factor
  • Journal of Dermatological Science. 02/2013; 69(2):e10.
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    ABSTRACT: BACKGROUND: Mycosis fungoides (MF) is a malignant lymphoma characterized by expansion of CD4(+) memory T-cell clones. Infiltrating cells express CCR4, which is attracted to CC chemokine ligands 17 and 22 (thymus and activation-regulated chemokine [TARC]/CCL17 and TARC/CCL22). Bath-psoralen plus ultraviolet A (PUVA) is effective against MF. In patients with psoriasis, bath-PUVA induces circulating regulatory T cells (Tregs), which suppress effector T cells. To understand the mechanisms in MF, we analyzed lesion-infiltrating cells before and after bath-PUVA therapy. PATIENTS AND METHODS: Thirteen patients with MF (12 stage IB, 1 stage III; mean age 69.2 years, range 35-87 years; 6 men, 7 women) were recruited. RESULTS: Immunohistochemical analysis revealed that lesion CCR4-positive (CCR4(+)) cells and Tregs significantly decreased from 105.1 ± 164.8 cells/10(-2) mm(2) to 31.4 ± 39.0 cells/10(-2) mm(2) and from 78.1 ± 67.8 cells/10(-2) mm(2) to 24.7 ± 25.0 cells/10(-2) mm(2), respectively. Serum TARC levels significantly correlated with infiltrating CD3(+) (r = 0.997), CCR4(+) (r = 0.991), and forkhead box P3-positive (Foxp3(+)) cells (r = 0.843). Circulating Tregs before bath-PUVA therapy were not significantly different from those in healthy volunteers. Bath-PUVA did not significantly change the percentage of circulating Tregs. CONCLUSIONS: Bath-PUVA decreased CCR4(+) cells and Tregs in MF lesions but did not induce circulating Tregs, which might suppress effector T cells. Direct effects through skin lesions might eliminate both pathogenetically relevant cells and Tregs. Systemic immunosuppression was not induced.
    Clinical lymphoma, myeloma & leukemia 01/2013;
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    ABSTRACT: Photo(chemo)therapy is widely used to treat psoriasis, the pathogenesis of which might be caused by an imbalance of Th17 cells/regulatory T cells (Treg). In the present study, we evaluated the effects of photo(chemo)therapy on the Th17/Treg balance and Treg function. Peripheral blood was obtained from psoriasis patients treated with bath-psoralen ultraviolet A (UVA, n = 50) or narrowband ultraviolet B (UVB, n = 18), and age-matched healthy volunteers (n = 20). CD3(+)CD4(+)IL-17A(+) or CD4(+)CD25(+)Foxp3(+)cells were analyzed to estimate Th17 or Treg number by fluorescence-activated cell sorting. Moreover, CD4(+) CD25(-) T cells from patients treated with PUVA(n = 14) were incubated in CFSE and activated with or without CD4(+) CD25(+)T cells, and the suppressive function of CD4(+) CD25(+)T cells were analyzed. Photo(chemo)therapy significantly reduced Th17 levels from 5.66±3.15% to 2.96±2.89% in patients with increased Th17 (Th17/CD4>3.01% [mean+SD of controls]). In contrast, photo(chemo)therapy significantly increased Treg levels from 2.77±0.75 to 3.40±1.88% in patients with less than 4.07% Treg level, defined as the mean of controls. Furthermore, while Treg suppressed the CD4(+)CD25(-) T cell proliferation to a greater extent in controls (Treg Functional Ratio 94.4±4.28%) than in patients (70.3±25.1%), PUVA significantly increased Treg Functional Ratio to 88.1±6.47%. Th17 levels in severe patients (>30 PASI) were significantly higher as compared to controls. Th17 levels that were left after treatment in the patients not achieving PASI 50 (3.78±4.18%) were significantly higher than those in the patients achieving PASI 75 (1.83±1.87%). Treg levels in patients achieving PASI 90 (4.89±1.70%) were significantly higher than those in the patients not achieving PASI 90 (3.90±1.66%). Treg levels prior to treatment with Th17 high decreased group (5.16±2.20%) was significantly higher than that with Th17 high increased group (3.33±1.39%). These findings indicate that Treg is dysfunctional in psoriasis patients, and photochemotherapy restores those dysfunctional Treg. Photo(chemo)therapy resolved the Th17/Treg imbalance in patients with psoriasis.
    PLoS ONE 01/2013; 8(1):e54895. · 3.53 Impact Factor
  • Journal of dermatological science 10/2012; · 3.71 Impact Factor
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    ABSTRACT: Narrow-band ultraviolet B (NB-UVB) therapy is widely used for refractory skin diseases. Targeted phototherapy is now being used to reduce the number of sessions and to avoid exposing normal skin. We developed a targeted NB-UVB therapy using a flat-type lamp emitting a wavelength similar to that of the TL-01 fluorescent lamp. Six Japanese patients with psoriasis were recruited and treated with the flat-type NB-UVB device with an initial dose of 70% of the minimal erythema dose, with a 20% increase at each subsequent session. The plaque severity score was determined. All lesions of the tested patients were responsive to NB-UVB therapy using the flat-type lamp. The mean percent reduction of the lesion was 58.3 ± 17.7%. The mean cumulative dose was 20.8 ± 10.8 J/cm². No side effects were observed during treatment. The flat-type targeted NB-UVB device is compact and convenient, and highly effective for the treatment of limited psoriasis lesions.
    Photodermatology Photoimmunology and Photomedicine 10/2011; 27(5):248-50. · 1.52 Impact Factor
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    ABSTRACT: In this open-label study, we investigated the efficacy of excimer light (308 nm) with a filter to cut off wavelengths below 297 nm for the treatment of palmoplantar pustulosis (PPP). Twenty patients with PPP were recruited and treated once a week for a total of 30 sessions. Patient response was assessed every 10 sessions based on the Palmoplantar Pustulosis Area and Severity Index (PPPASI) score. Levels of Th17 cells and regulatory T cells (Treg) in the peripheral blood in patients with PPP were also evaluated. Mean PPPASI score was 19.5 at baseline, 13.2 at 10 treatments, 10.9 at 20 treatments and 9.5 at 30 treatments. Th17 levels after excimer therapy were not significantly different from those at baseline. In contrast, Treg levels after excimer therapy were significantly higher than those at baseline.
    Experimental Dermatology 06/2011; 20(9):768-70. · 3.58 Impact Factor
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    ABSTRACT: This study investigated phototherapy-induced changes in certain adipokine levels in patients with psoriasis. Patients with psoriasis (n=36) were recruited and body mass index (BMI) and disease severity (Psoriasis Area and Severity Index) were recorded. Serum resistin and leptin levels before and after bath-psoralen and ultraviolet (UV) A or narrow-band UVB therapy were examined by enzyme-linked immunosorbent assay. Serum leptin levels correlated positively with BMI. Phototherapy induced no remarkable change in the leptin levels, but significantly decreased serum resistin levels from 9.02±8.83 to 4.86±3.30ng/ml. Serum resistin levels might be involved in insulin resistance and inflammation, and correlate with disease severity in patients with psoriasis. The reduction in serum resistin induced by phototherapy might be related to the clinical efficacy of this treatment for psoriasis.
    Photodermatology Photoimmunology and Photomedicine 06/2011; 27(3):152-5. · 1.52 Impact Factor
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    ABSTRACT: We are trying to develop new Abs that can manipulate CD4 T cell responses and are usable as immunosuppressive agents. To this end, we performed functional screening, in which we examined the effect of an Ab on the proliferation of mouse CD4 T cells upon activation. The Ab, LP5, inhibited the activation of CD4 T cells stimulated with an anti-CD3 Ab or peptide antigen. The Ab alone had no stimulatory effect on CD4 T cells. Biochemical experiments demonstrated that LP5 recognized the Thy-1 (CD90) molecule. Interestingly, the treatment of CD4 T cells with LP5 in vitro induced a temporary down-regulation of CD3 expression at the cell surface. TCR molecules were also affected. Other anti-CD90 Abs not inhibitory to CD4 T cell activation failed to induce a reduction in CD3. Experiments in vitro revealed that the down-regulation caused by LP5 is due to an accelerated endocytosis of cell surface CD3. In addition, it was shown that CD3 down-regulation before or in the early stages of T cell activation is critical for the induction of hyporesponsiveness. Experiments in vivo showed that pre-treatment of CD4 T cells with LP5 inhibited the rejection of semi-allogeneic bone marrow transplants. Based on these observations, we propose that CD3 down-regulation without any stimulatory activity against T cells could be one approach to inhibiting T cell activation, and CD90 would be an appropriate target.
    Immunology letters 01/2011; 136(2):163-70. · 2.91 Impact Factor
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    ABSTRACT: Pustulosis palmaris et plantaris (PPP) is a chronic recurrent dermatitis characterized by intraepidermal pustules with erythematous scaling on the palms and soles. PPP shares many characteristics with psoriasis, but has a different genetic background. T helper 17 cells (Th17) have an important role in the pathogenesis of psoriasis. In psoriasis, regulatory T cells (Treg) are dysfunctional and circulating Th17 are increased. Whether Th17 are involved in PPP, however, is unclear. Therefore, we examined the Th17 population in peripheral blood mononuclear cells (PBMC) of patients with PPP. Foxp3(+) Treg was also analyzed. We examined circulating Th17 and Treg in the peripheral blood of PPP patients. PBMC were obtained from healthy volunteer controls (n = 26, mean ± SD age 33.11 ± 9.80 years) and PPP patients (n = 24, age 55.00 ± 12.26 years). The proportion of Th17 among the PBMC was 2.52 ± 0.811% (mean ± SD) in healthy controls and 3.23 ± 1.45% in PPP patients. The proportion of Th17 in the PPP patients was significantly higher than that in the healthy controls (p < 0.05, Student's t test). PPP patients had significantly fewer Treg (5.69 ± 1.86%) than healthy controls (7.10 ± 1.78%). Th17 was inversely correlated with Treg.
    Archives for Dermatological Research 01/2011; 303(6):441-4. · 2.71 Impact Factor
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    ABSTRACT: Narrow-band ultraviolet B (NB-UVB) for the treatment of refractory skin diseases, such as psoriasis and atopic dermatitis, requires an adequate irradiation protocol based on the minimal erythema dose (MED) to establish an optimal dosage schedule. Although MED can be measured using a systemic-type irradiation unit, there are difficulties associated with this device. There is no standardized device available to determine the MED for NB-UVB. Here, we compared a conventional device with a newly developed device for measuring MED. MED was measured in 16 psoriasis patients using both a conventional measuring device and the newly developed device, which comprised a hand-held NB-UVB (311-313 nm) flat-type fluorescent lamp with neutral density filters having different transmittances ranging from 10% to 90%. This device was designed to be stably maintained on the skin surface and to provide a highly accurate measurement with only one UV irradiation exposure while also preventing UV radiation from leaking to nonirradiated areas. The MED values obtained from each patient were the same using both devices. One-time irradiation using the new hand-held device with the NB-UVB flat-type fluorescent lamp is feasible and accurate for determining the MED to use in calculating the UV irradiation treatment dose.
    Photodermatology Photoimmunology and Photomedicine 03/2009; 25(1):41-4. · 1.52 Impact Factor
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    ABSTRACT: While the 1450 nm diode laser is highly effective for the treatment of acne, its use is associated with considerable pain. Low-energy, double-pass irradiation was attempted as an alternative to prevent the occurrence of pain as an adverse effect. This study aimed to evaluate the clinical efficacy of low-energy, double-pass, 1450 nm diode laser treatment in the treatment of acne in Asian patients. Thirty Japanese patients with inflammatory acne were treated with the low-energy, double-pass, 1450 nm diode laser at 2-4-week intervals. An open study was performed in patients that underwent at least five and up to 10 treatment sessions. The clinical effect was assessed using an acne grading scale. Of the 30 patients, 27 completed the study. The mean acne grades decreased from 3.9 to 1.4 (P<0.01) in the 27 patients. The pain was tolerated by 25 patients, and two patients required local anesthesia. No remarkable side effects occurred in any of the patients; all but a few patients had transient faint erythema. Low-energy, double-pass therapy is an alternative method that is beneficial for patients who complain of considerable pain. Furthermore, the method may have a lower risk of transient hyperpigmentation induced by cryogen spray, even in Asian patients who tend to develop inflammatory pigmentation.
    Photodermatology Photoimmunology and Photomedicine 02/2009; 25(1):3-7. · 1.52 Impact Factor
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    ABSTRACT: CD4(+)Foxp3(+) regulatory T cells (Treg cells) play an important role in maintaining self-tolerance as suppressive/regulatory CD4 T cells. In vitro analyses have revealed the characteristics of Treg cells, that is, hyporesponsiveness when stimulated via TCR in the presence of splenic APC. In this study, we report a new mAb, G3c, which can induce the expansion of Treg cells stimulated with anti-CD3 Ab along with splenic APC, the culture conditions in which Treg cells exhibit hyporesponsiveness. Surprisingly, G3c mAb recognized glucocorticoid-induced TNFR family-related proteins (GITR). G3c mAb had stronger co-stimulatory activity for both Treg cells and responder T cells than another anti-GITR Ab (DTA1) in vitro. The in vivo administration of G3c increased the number of Treg cells and had less effect in inducing anti-tumor immunity in normal mice, although G3c had some anti-tumor effect on non-Treg cells in the absence of Treg cells in vivo, in contrast to the anti-tumor therapeutic effect of DTA1 in normal mice. Therefore, we need to know that the manipulation of immune responses with the use of anti-GITR Abs results from a balance between co-stimulatory effects on Treg cells and on responder cells, and we must aim at a narrow window leading to the therapeutic effects.
    Immunology letters 11/2008; 121(2):97-104. · 2.91 Impact Factor
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    ABSTRACT: Aging leads to a decline in the reactivity of CD4 T cells, in humans and mice. However, we have reported that not all CD4 T cells in aged mice were hyporesponsive, that is, a particular subset maintained the ability to mount a normal response. In this study, we examined the possibility of recalling reactivity in the hyporesponsive CD4 T cell-subset in aged mice. In vivo experiments revealed the changes in CD4 T cell-subsets in aged mice to be antigen-independent and aging-dependent. Once the CD4 T cells became hyporesponsive, they persistently exhibited a weak response. Furthermore, immunization with a co-stimulatory antibody had no effect on T cell-responses in aged mice, although it had a significant effect in young mice. As this hyporesponsive subset accounts for the majority of CD4 T cells in aged mice, it is important to elucidate the cause of the hyporesponsiveness.
    Immunology Letters 09/2008; 121(1):27-32. · 2.34 Impact Factor
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    ABSTRACT: The effects of blue light phototherapy on inflammatory acne lesions were recently investigated. Many reports have used high-intensity, narrow-band 420 nm UV-free blue light delivery systems. The aim of this study was to evaluate a new blue light system (MultiClear) for targeted blue light phototherapy. Ten Japanese patients with acne on the face or back were treated with targeted blue light once or twice a week. Acne severity was graded according to the acne severity score suggested by Allen and Smith (1982). If the acne was prevalent on the back or chest, the acne severity score of Burton et al. (1971) was adopted. The new targeting blue light system is equipped with a flexible optical light guide as a delivery system and the treatment device is placed directly only on the affected area. Of the 10 patients, eight had a significantly reduced acne severity score without any side effects. Although two patients discontinued the study because of unsatisfactory results, none of the patients showed any harmful side effects from the targeted blue light phototherapy. Targeted blue light phototherapy with MultiClear is effective for the treatment of inflammatory acne lesions. This new irradiation device offers some advantages over previous blue light systems.
    Photodermatology Photoimmunology and Photomedicine 03/2007; 23(1):32-4. · 1.52 Impact Factor

Publication Stats

82 Citations
44.00 Total Impact Points


  • 2009–2013
    • Nagoya City University
      • Department of Geriatric and Environmental Dermatology
      Nagoya, Aichi, Japan
  • 2008–2011
    • Kyoto University
      • Graduate School of Medicine / Faculty of Medicine
      Kyoto, Kyoto-fu, Japan
    • National Center for Geriatrics and Gerontology
      • Department of Mechanism of Aging
      Ōbu, Aichi-ken, Japan