Publications by authors named "Tomomitsu Miyagaki"

134 Publications

Multiple pigmented nevi induced by the combination of encorafenib and cetuximab in a colon cancer patient.

J Dermatol 2022 Apr 10. Epub 2022 Apr 10.

Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Japan.

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http://dx.doi.org/10.1111/1346-8138.16393DOI Listing
April 2022

Roles of OX40 and OX40 Ligand in Mycosis Fungoides and Sézary Syndrome.

Int J Mol Sci 2021 Nov 22;22(22). Epub 2021 Nov 22.

Department of Dermatology, Graduate School of Medicine, the University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Mycosis fungoides (MF) and Sézary syndrome (SS), the most common types of cutaneous T-cell lymphoma (CTCL), are characterized by proliferation of mature CD4+ T-helper cells. Patients with advanced-stage MF and SS have poor prognosis, with 5-year survival rates of 52%. Although a variety of systemic therapies are currently available, there are no curative options for such patients except for stem cell transplantation, and thus the treatment of advanced MF and SS still remains challenging. Therefore, elucidation of the pathophysiology of MF/SS and development of medical treatments are desired. In this study, we focused on a molecule called OX40. We examined OX40 and OX40L expression and function using clinical samples of MF and SS and CTCL cell lines. OX40 and OX40L were co-expressed on tumor cells of MF and SS. OX40 and OX40L expression was increased and correlated with disease severity markers in MF/SS patients. Anti-OX40 antibody and anti-OX40L antibody suppressed the proliferation of CTCL cell lines both in vitro and in vivo. These results suggest that OX40-OX40L interactions could contribute to the proliferation of MF/SS tumor cells and that the disruption of OX40-OX40L interactions could become a new therapeutic strategy for the treatment of MF/SS.
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http://dx.doi.org/10.3390/ijms222212576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617822PMC
November 2021

Lymphatic Dysfunction Exacerbates Cutaneous Tumorigenesis and Psoriasis-Like Skin Inflammation through Accumulation of Inflammatory Cytokines.

J Invest Dermatol 2021 Nov 13. Epub 2021 Nov 13.

Department of Dermatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Lymphatic transport plays an important role in coordinating local immune responses. However, the biologic effects of impaired lymphatic flow in vivo are not fully understood. In this study, we investigated the roles of the lymphatic system in skin carcinogenesis and psoriasis-like inflammation using k-cyclin transgenic (kCYC) mice, which demonstrate severe lymphatic dysfunction. kCYC mice showed augmented tumor growth in the two-stage skin carcinogenesis model and severe clinical scores in imiquimod-induced psoriasis-like skin inflammation compared with wild-type mice. Although mRNA levels of inflammatory cytokines in skin after topical application of 12-O-tetradecanoylphorbol-13-acetate or imiquimod were comparable between kCYC and wild-type mice, protein levels of inflammatory cytokines, such as IL-17A, IL-22, and IL-23, were significantly upregulated in kCYC mice in both models. Consistently, signal transducer and activator of transcription 3 pathway and NF-κB signaling were augmented in epidermal keratinocytes in kCYC mice. These results suggest that lymphatic dysfunction in kCYC mice caused accumulation of inflammatory cytokines, leading to the exacerbation of two-stage skin carcinogenesis and imiquimod-induced psoriasis-like skin inflammation. These findings add insight into the clinical problems of secondary malignancies and inflammatory dermatoses that may occur with extremity lymphedema.
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http://dx.doi.org/10.1016/j.jid.2021.05.039DOI Listing
November 2021

Safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma: Real-world experience from post-marketing surveillance.

J Dermatol 2022 Feb 18;49(2):253-262. Epub 2021 Oct 18.

Department of Dermatology, International University of Health and Welfare, Chiba, Japan.

To establish real-world evidence about the safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma, we conducted a nationwide cohort study using data from post-marketing surveillance for bexarotene treatment. In total, 294 patients with cutaneous T-cell lymphoma were identified between June 2016 and June 2018. Of these, 267 patients were included as the safety analysis set. Of the 267 patients, 175 were included in the efficacy analysis set. Of these, 139 patients had mycosis fungoides, including 46 with early stage disease and 93 with advanced stage disease. Among the 139 patients with mycosis fungoides, the objective response rate was 46.8%. A significant difference in objective response rate was detected between patients who started with bexarotene at 300 mg/m (61.6%) and patients who started with bexarotene at less than 300 mg/m (22.6%, p < 0.001). Of the 139 patients with mycosis fungoides, 92 were treated with a combination of bexarotene plus photo(chemo)therapy. A significant difference in objective response rate was seen between bexarotene with a combination of photo(chemo)therapy (57.6%) and bexarotene without a combination of photo(chemo)therapy (25.5%, p < 0.001). Starting bexarotene at 300 mg/m and combination with photo(chemo)therapy were detected as independent factors influencing response. Common treatment-related adverse events included hypothyroidism (85.8%), hypertriglyceridemia (68.5%), hypercholesterolemia (43.8%), and neutropenia (21.3%). Hypertriglyceridemia, hypercholesterolemia, and neutropenia occurred more frequently in patients who started with bexarotene at 300 mg/m than patients who started with bexarotene at less than 300 mg/m (hypertriglyceridemia, 76.4% vs. 57.0%, p = 0.001; hypercholesterolemia, 49.0% vs. 36.4%, p = 0.045; neutropenia, 28.0% vs. 12.1%, p = 0.002; respectively). The present study indicates that starting bexarotene at 300 mg/m and combination of photo(chemo)therapy offer a promising efficacy for the treatment of patients with mycosis fungoides. Efficacy of low-dose bexarotene plus photo(chemo)therapy should be evaluated in future.
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http://dx.doi.org/10.1111/1346-8138.16201DOI Listing
February 2022

Diagnosis of Early Mycosis Fungoides.

Diagnostics (Basel) 2021 Sep 19;11(9). Epub 2021 Sep 19.

Department of Dermatology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki 216-8511, Kanagawa, Japan.

Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphomas, generally has a favorable clinical course. Early MF typically presents erythematous patches and/or plaques and lasts for many years without affecting the life expectancy. Only limited cases progress to develop skin tumors, with subsequent lymph nodes and rarely visceral organ involvement. One of the clinical problems in early MF is the difficulty in differentiating the disease from benign inflammatory disorders (BIDs), such as atopic dermatitis, chronic eczema, and psoriasis. In some MF cases, clinical and pathological findings are similar to those of BIDs. However, the accurate diagnosis of early MF is quite important, as inappropriate treatment including immunosuppressants can cause unfavorable or even fatal outcomes. This article focuses on general methods and novel tools for diagnosis of early MF.
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http://dx.doi.org/10.3390/diagnostics11091721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465146PMC
September 2021

CD147-Cyclophilin a Interactions Promote Proliferation and Survival of Cutaneous T-Cell Lymphoma.

Int J Mol Sci 2021 Jul 23;22(15). Epub 2021 Jul 23.

Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.

CD147, a transmembrane glycoprotein that belongs to the immunoglobulin superfamily, and cyclophilin A (CypA), one of the binding partners of CD147, are overexpressed in tumor cells and associated with the progression of several malignancies, including both solid and hematological malignancies. However, CD147 and CypA involvement in cutaneous T-cell lymphoma (CTCL) has not been reported. In this study, we examined CD147 and CypA expression and function using clinical samples of mycosis fungoides (MF) and Sézary syndrome (SS) and CTCL cell lines. CD147 and CypA were overexpressed by tumor cells of MF/SS, and CypA was also expressed by epidermal keratinocytes in MF/SS lesional skin. Serum CypA levels were increased and correlated with disease severity markers in MF/SS patients. Anti-CD147 antibody and/or anti-CypA antibody suppressed the proliferation of CTCL cell lines, both in vitro and in vivo, via downregulation of phosphorylated extracellular-regulated kinase 1/2 and Akt. These results suggest that CD147-CypA interactions can contribute to the proliferation of MF/SS tumor cells in both a autocrine and paracrine manner, and that the disruption of CD147-CypA interactions could be a new therapeutic strategy for the treatment of MF/SS.
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http://dx.doi.org/10.3390/ijms22157889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346093PMC
July 2021

Diagnosis and prognostic stratification of cutaneous lymphoma.

J Dermatol 2022 Feb 4;49(2):210-222. Epub 2021 Aug 4.

Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan.

Primary cutaneous lymphomas are a heterogenous group of non-Hodgkin's lymphoma of both T/natural killer-cell and B-cell origin and defined to primarily present in the skin without extracutaneous involvement at diagnosis. In contrast to nodal non-Hodgkin's lymphoma, cutaneous T-cell lymphomas (CTCL) are more generally seen than cutaneous B-cell lymphomas (CBCL). CTCL and CBCL have various subtypes and each subtype has specifically characteristic clinical, pathological, and prognostic features. The diagnostic methods and staging evaluation of cutaneous lymphomas is mostly common in various guidelines created by professional societies. The diagnosis is made comprehensively based on clinical, pathological, laboratory, radiological, and genetic findings. On the other hand, definite prognostic stratification has not been completely established yet in most cutaneous lymphomas. This article focuses on the general and novel diagnostic methods and the current findings about prognostic factors and stratification in cutaneous lymphomas.
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http://dx.doi.org/10.1111/1346-8138.16099DOI Listing
February 2022

Sitagliptin-associated bullous pemphigoid with autoantibodies against BP230 and laminin-332.

Int J Dermatol 2022 05 1;61(5):e184-e186. Epub 2021 Jul 1.

Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

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http://dx.doi.org/10.1111/ijd.15762DOI Listing
May 2022

Stewart-Treves syndrome associated with disuse edema in amyotrophic lateral sclerosis.

J Dermatol 2021 Sep 31;48(9):e443-e444. Epub 2021 May 31.

Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Japan.

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http://dx.doi.org/10.1111/1346-8138.16004DOI Listing
September 2021

Complete pruritus relief by oren-gedoku-to in eruptive pruritic papular porokeratosis.

J Dermatol 2021 Aug 13;48(8):e378-e379. Epub 2021 May 13.

Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

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http://dx.doi.org/10.1111/1346-8138.15947DOI Listing
August 2021

Phase II study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma.

Cancer Sci 2021 Jun 3;112(6):2426-2435. Epub 2021 May 3.

Department of Hematology, National Cancer Center Hospital, National Cancer Center Hospital, Tokyo, Japan.

E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin-2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single-arm phase II study of E7777 in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T-cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression-free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.
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http://dx.doi.org/10.1111/cas.14906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177793PMC
June 2021

Arthritis and enthesitis during dupilumab therapy completely remitted by celecoxib.

J Dermatol 2021 Jun 28;48(6):e279-e280. Epub 2021 Mar 28.

Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan.

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http://dx.doi.org/10.1111/1346-8138.15872DOI Listing
June 2021

Increased Regulatory T Cells and Decreased Myeloid-Derived Suppressor Cells Induced by High CCL17 Levels May Account for Normal Incidence of Cancers among Patients with Atopic Dermatitis.

Int J Mol Sci 2021 Feb 18;22(4). Epub 2021 Feb 18.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.

The incidence of cancers in atopic dermatitis (AD) is not increased, although the Th2-dominant environment is known to downregulate tumor immunity. To gain mechanistic insights regarding tumor immunity in AD, we utilized CCL17 transgenic (TG) mice overexpressing CCL17, which is a key chemokine in AD. Tumor formation and lung metastasis were accelerated in CCL17 TG mice when melanoma cells were injected subcutaneously or intravenously. Flow cytometric analysis showed increases in regulatory T cells (Tregs) in lymph nodes in CCL17 TG mice with high mRNA levels of and in tumors, suggesting that Tregs attenuated tumor immunity. The frequency of myeloid-derived suppressor cells (MDSCs), however, was significantly decreased in tumors of CCL17 TG mice, suggesting that decreased MDSCs might promote tumor immunity. Expression of , a chemoattractant of MDSCs, was decreased in tumors of CCL17 TG mice. Depletion of Tregs by the anti-CD25 antibody markedly reduced tumor volumes in CCL17 TG mice, suggesting that tumor immunity was accelerated by the decrease in MDSCs in the absence of Tregs. Thus, CCL17 attenuates tumor immunity by increasing Tregs and Th2 cells, while it decreases MDSCs through reductions in CXCL17, which may work as a "safety-net" to reduce the risk of malignant tumors in the Th2-dominant environment.
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http://dx.doi.org/10.3390/ijms22042025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922104PMC
February 2021

A case of facial redness in atopic dermatitis occurring during dupilumab treatment successfully treated with topical delgocitinib ointment.

Dermatol Ther 2021 03 25;34(2):e14888. Epub 2021 Feb 25.

Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

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http://dx.doi.org/10.1111/dth.14888DOI Listing
March 2021

Mycosis fungoides and Sézary syndrome tumor cells express epidermal fatty acid-binding protein, whose expression decreases with loss of epidermotropism.

J Dermatol 2021 May 9;48(5):685-689. Epub 2021 Feb 9.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Fatty acid binding protein (FABP) is a family of transport proteins for fatty acid (FA). Epidermal FABP (E-FABP) is highly expressed by resident memory T cells (T ) in the skin. It supports the uptake of exogenous FA for long-term survival of skin T . Mycosis fungoides (MF) is regarded as malignancy of skin T . In this study, we investigated E-FABP expression in psoriasis vulgaris (PV), atopic dermatitis (AD), MF, and Sézary syndrome (SS). E-FABP mRNA levels in PV were much higher than those in healthy controls. E-FABP mRNA levels in AD and MF/SS lesional skin were also significantly higher than those of normal skin. By immunohistochemical staining, E-FABP was positive in MF/SS lesional skin. Interestingly, E-FABP was stained positive in epidermotropic lymphoid cells in patch, plaque, and erythrodermic lesions of MF/SS, suggesting that a part of tumor cells expressed E-FABP. In tumorous lesions, however, most dermal tumor cells were negative for E-FABP. Immunohistochemical staining using patch/plaque lesions and tumorous lesions from the same patients also revealed that E-FABP expression decreased in tumorous lesions. Our study has suggested that MF/SS tumor cells express E-FABP, whose expression decreases with loss of epidermotropism.
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http://dx.doi.org/10.1111/1346-8138.15775DOI Listing
May 2021

Intravascular large B-cell lymphoma mimicking erythema nodosum: A case report and review of published works.

J Dermatol 2021 Apr 7;48(4):e184-e185. Epub 2021 Feb 7.

Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan.

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http://dx.doi.org/10.1111/1346-8138.15792DOI Listing
April 2021

A case of mycosis fungoides successfully treated with combination of bexarotene and mogamulizumab.

Dermatol Ther 2021 03 27;34(2):e14805. Epub 2021 Jan 27.

Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/dth.14805DOI Listing
March 2021

HMGB1-mediated chromatin remodeling attenuates gene expression for the protection from allergic contact dermatitis.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Dermatology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan;

Dysregulation of inflammatory cytokines in keratinocytes promote the pathogenesis of the skin inflammation, such as allergic contact dermatitis (ACD). High-mobility group box 1 protein (HMGB1) has been implicated in the promotion of skin inflammation upon its extracellular release as a damage-associated molecular pattern molecule. However, whether and how HMGB1 in keratinocytes contributes to ACD and other skin disorders remain elusive. In this study, we generated conditional knockout mice in which the gene is specifically deleted in keratinocytes, and examined its role in ACD models. Interestingly, the mutant mice showed exacerbated skin inflammation, accompanied by increased ear thickening in 2,4-dinitrofluorobenezene-induced ACDs. The mRNA expression of interleukin-24 (IL-24), a cytokine known to critically contribute to ACD pathogenesis, was elevated in skin lesions of the mutant mice. As with constitutively expressed, IL-4-induced mRNA, expression was also augmented in the -deficient keratinocytes, which would account for the exacerbation of ACD in the mutant mice. Mechanistically, we observed an increased binding of trimethyl histone H3 (lys4) (H3K4me3), a hallmark of transcriptionally active genes, to the promoter region of the gene in the -deficient cells. Thus, the nuclear HMGB1 is a critical "gate keeper" in that the dermal homeostasis is contingent to its function in chromatin remodeling. Our study revealed a facet of nuclear HMGB1, namely its antiinflammatory function in keratinocytes for the skin homeostasis.
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http://dx.doi.org/10.1073/pnas.2022343118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817117PMC
January 2021

Mycosis Fungoides and Sézary Syndrome: Updates and Review of Current Therapy.

Curr Treat Options Oncol 2021 01 7;22(2):10. Epub 2021 Jan 7.

Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

Opinion Statement: While most patients with early-stage mycosis fungoides (MF) follow an indolent course, patients with advanced-stage MF/Sézary syndrome (SS) have a poor prognosis with a median survival of less than 5 years. Although there are a number of treatments currently available, achieving and maintaining a durable response remain challenging, especially in advanced-stage MF/SS. The choice of frontline therapy is dependent on the stage of disease. For early-stage MF, the treatment concept is to control skin lesions mainly by skin-directed therapies, such as topical therapies, phototherapies, and radiotherapies. For advanced-stage MF/SS, systemic treatments by biological or targeted therapies including bexarotene and interferon either alone or in combination are tried first, with more immunosuppressive chemotherapies being reserved for refractory or rapidly progressive disease. Recent improvements in biological or targeted therapies include brentuximab vedotin and mogamulizumab. When biopsy samples have 10% or more CD30-positive malignant cells, brentuximab vedotin, an anti-CD30 antibody conjugated to monomethyl auristin E, can be a desirable treatment option. For cases with blood involvement, mogamulizumab, an antibody binding to C-C chemokine receptor 4, is effective with high response rates. In the refractory setting, alemtuzumab, histone deacetylase inhibitors, pralatrexate, gemcitabine, and doxorubicin are considered as the treatment option. Because only allogeneic hematopoietic stem cell transplantation can offer a chance of cure with durable complete remission, advanced-stage patients with a markedly short life expectancy should be evaluated for eligibility. Given that there are few randomized controlled studies in the literature, it is necessary to investigate which therapy is preferable for each patient with MF/SS by comparative prospective trials.
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http://dx.doi.org/10.1007/s11864-020-00809-wDOI Listing
January 2021

Outlines of the Japanese guidelines for the management of primary cutaneous lymphomas 2020.

J Dermatol 2021 Feb 27;48(2):e49-e71. Epub 2020 Nov 27.

Department of Dermatology, International University of Health and Welfare, Narita, Japan.

Since the publication of the Japanese "Guidelines for the management of cutaneous lymphomas" in 2011, the World Health Organization (WHO) classification of hematolymphoid neoplasms and the WHO-European Organisation for Research and Treatment of Cancer classification for primary cutaneous lymphomas were updated and a number of novel systemic drugs for cutaneous T-cell lymphoma had been approved in Japan. In 2020, we revised the Japanese guidelines for the management of cutaneous lymphomas with consideration of the recent advances in the understanding of the pathophysiology and classification of cutaneous lymphomas together with the update of treatment strategies reflecting the advent of novel drugs. In addition to a brief explanation of epidemiology, diagnosis, staging system, prognosis and management of each subtype of cutaneous lymphomas, the recommendations for nine clinical questions regarding treatment options that can vary even among experts are also described. A systematic review process and determination of recommendations in answer to each clinical question have been performed in accordance with the Grading of Recommendations, Assessment, Development and Evaluation scheme by a multidisciplinary expert panel consisting of dermatologists, a hematologist and a radiation oncologist. In this article, we present the outlines of the revised Japanese "Guidelines for the management of cutaneous lymphomas".
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http://dx.doi.org/10.1111/1346-8138.15707DOI Listing
February 2021

TLR2 Deficiency Exacerbates Imiquimod-Induced Psoriasis-Like Skin Inflammation through Decrease in Regulatory T Cells and Impaired IL-10 Production.

Int J Mol Sci 2020 Nov 13;21(22). Epub 2020 Nov 13.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.

Emerging evidence has demonstrated that Toll-like receptors (TLRs) are associated with autoimmune diseases. In this study, we investigated the role of TLR2 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although TLR2 signaling is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, TLR2 deficiency unexpectedly exacerbated psoriasiform skin inflammation. Importantly, messenger RNA (mRNA) levels of Foxp-3 and IL-10 in the lesional skin were significantly decreased in TLR2 KO mice compared with wild-type mice. Furthermore, flow cytometric analysis of the lymph nodes revealed that the frequency of regulatory T cells (Tregs) among CD4-positive cells was decreased. Notably, stimulation with Pam3CSK4 (TLR2/1 ligand) or Pam2CSK4 (TLR2/6 ligand) increased IL-10 production from Tregs and DCs and the proliferation of Tregs. Finally, adoptive transfer of Tregs from wild-type mice reduced imiquimod-induced skin inflammation in TLR2 KO mice. Taken together, our results suggest that TLR2 signaling directly enhances Treg proliferation and IL-10 production by Tregs and DCs, suppressing imiquimod-induced psoriasis-like skin inflammation. Enhancement of TLR2 signaling may be a new therapeutic strategy for psoriasis.
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http://dx.doi.org/10.3390/ijms21228560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696365PMC
November 2020

CX3CR1 Deficiency Attenuates DNFB-Induced Contact Hypersensitivity Through Skewed Polarization Towards M2 Phenotype in Macrophages.

Int J Mol Sci 2020 Oct 7;21(19). Epub 2020 Oct 7.

Department of Dermatology, the University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.

CX3CL1 can function as both an adhesion molecule and a chemokine for CX3CR1 cells, such as T cells, monocytes, and NK cells. Recent studies have demonstrated that CX3CL1-CX3CR1 interaction is associated with the development of various inflammatory skin diseases. In this study, we examined CX3CR1 involvement in 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity using CX3CR1 mice. Ear swelling and dermal edema were attenuated after DNFB challenge in CX3CR1 mice. Expression of TNF-α, IL-6, and M1 macrophage markers was decreased in the ears of CX3CR1 mice, whereas expression of M2 macrophage markers including arginase-1 was increased. Decreased TNF-α and IL-6 expression and increased arginase-1 expression were found in peritoneal macrophages from CX3CR1 mice. Furthermore, ear swelling was attenuated by depleting dermal macrophages in wild-type mice to a similar level to CX3CR1 mice. These results suggest that CX3CR1 deficiency could induce skewed polarization towards M2 phenotype in macrophages, resulting in attenuation of contact hypersensitivity response.
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http://dx.doi.org/10.3390/ijms21197401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582565PMC
October 2020

Exploration of biomarkers to predict clinical improvement of atopic dermatitis in patients treated with dupilumab: A study protocol.

Medicine (Baltimore) 2020 Sep;99(38):e22043

Department of Dermatology, Osaka Habikino Medical Center, Habikino City, Osaka.

Background: Atopic dermatitis (AD) is a common eczematous skin disorder that profoundly reduces the quality of life due to intractable pruritus. Excellent therapeutic success of the anti-interleukin 4 receptor-α antibody dupilumab in clinical trials and a real-world clinical context indicates the crucial roles of interleukin (IL)-4 and IL-13 in the pathogenesis of AD. Along with the clinical improvement in skin scores and pruritus, dupilumab significantly and progressively reduces and normalizes the upregulated expression of T helper type 2 signatures such as Chemokine (C-C motif) ligand (CCL)17, CCL18, CCL22, and CCL26 in the lesional skin of AD. However, no blood/serum biomarkers are known to predict good or poor outcome in patients with AD treated with dupilumab.

Methods: Patients are at least 18 years of age and have moderate-to-severe AD with Eczema Area and Severity Index (EASI) ≥16, Investigator's Global Assessment ≥3, and body surface area ≥10%. We are going to enroll more than 130 subjects from 18 medical facilities. Clinical objective findings will be evaluated by EASI. Subjective symptoms will be assessed by Patient-Oriented Eczema Measure, Numerical Rating Scale for Pruritus (Pruritus-NRS), Skin Comfort-NRS, and Treatment Satisfaction-NRS. We will measure 18 blood/serum biomarkers including % eosinophils in blood cell count, lactate dehydrogenase, total IgE, soluble interleukin 2 receptor, CCL17, CCL18, CCL22, CCL26, CCL27, IL-13, IL-22, IL-24, IL-25, IL-31, IL-33, thymic stromal lymphopoietin, periostin, and squamous cell carcinoma antigen-2. The clinical evaluation and biomarker sampling will be performed at 0, 2, 4, 8, and 16 weeks of dupilumab treatment. We will also perform proteomic analysis (of roughly 300 proteins) of the patients' sera obtained at 0 and 2 weeks of treatment. The primary endpoint is the association between "baseline levels of 18 biomarkers" and "% change from baseline of EASI at 16 weeks of dupilumab treatment."

Discussion: This is the first clinical trial to explore the biomarkers, including potential proteomic markers, most strongly associated with improvement in EASI in patients with moderate-to-severe AD treated with dupilumab for 16 weeks (B-PAD study). A limitation is that we will only enroll Japanese patients.
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http://dx.doi.org/10.1097/MD.0000000000022043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505282PMC
September 2020

Atrophic erythema in a patient with immunoglobulin G4-related sclerosing sialadenitis.

J Dermatol 2020 Oct 19;47(10):e360-e362. Epub 2020 Jul 19.

Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan.

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http://dx.doi.org/10.1111/1346-8138.15518DOI Listing
October 2020

Regulatory B10 Cells Increase after Rituximab Therapy but Not after Conventional Immunosuppression in Patients with Pemphigus.

J Invest Dermatol 2021 02 3;141(2):443-446. Epub 2020 Jul 3.

Department of Dermatology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.06.018DOI Listing
February 2021

Increase of lymphocytes and eosinophils, and decrease of neutrophils at an early stage of anti-PD-1 antibody treatment is a favorable sign for advanced malignant melanoma.

Drug Discov Ther 2020 Jul 27;14(3):117-121. Epub 2020 Jun 27.

Department of Dermatology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.

The advent of immune checkpoint inhibitors such as anti-PD-1 antibodies had a striking impact on the treatment for advanced malignant melanoma. However, less than half of the patients benefited from those antibodies, and biomarkers that could sensitively differentiate responders from non-responders are urgently needed. Herein, we explored such biomarkers by retrospectively analyzing clinical data from patients with advanced malignant melanoma treated with nivolumab and pembrolizumab. We found that anti-PD-1 antibody was especially effective for those with metastasis only to soft tissues. Although no significant difference was found in the baseline value of relative neutrophil count (RNC), relative lymphocyte count (RLC), neutrophil to lymphocyte ratio (NLR), and relative eosinophil count (REC) between responders and non-responders, responders after anti-PD-1 therapy revealed the increase of lymphocytes and eosinophils and the decrease of neutrophils within the first 6 weeks of the treatment. We also calculated the change of RNC and RLC 3 weeks and 6 weeks after the initiation of the therapy and designated as NΔ3-LΔ3 and NΔ6-LΔ6 respectively. NΔ3-LΔ3 was significantly decreased in responders, which suggest that the neutrophil decrease and lymphocyte increase after as early as 3 weeks of anti-PD-1 therapy might be a useful clinical indicator. In addition, the difference of NΔ6-LΔ6 between responders and non-responders was even more robust. These data suggest that change of RNC, RLC, and REC together with the combination of NΔ3-LΔ3 and NΔ6-LΔ6 might be a useful tool for early and sensitive biomarkers for anti-PD-1 therapy.
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http://dx.doi.org/10.5582/ddt.2020.03043DOI Listing
July 2020

Exacerbated Imiquimod-Induced Psoriasis-Like Skin Inflammation in IRF5-Deficient Mice.

Int J Mol Sci 2020 May 23;21(10). Epub 2020 May 23.

Department of Dermatology, the University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.

Interferon regulatory factors (IRFs) play diverse roles in the regulation of the innate and adaptive immune responses in various diseases. In psoriasis, IRF2 is known to be involved in pathogenesis, while studies on other IRFs are limited. In this study, we investigated the role of IRF5 in psoriasis using imiquimod-induced psoriasis-like dermatitis. Although IRF5 is known to play a critical role in the induction of proinflammatory cytokines by immune cells, such as dendritic cells (DCs), macrophages, and monocytes, IRF5 deficiency unexpectedly exacerbated psoriasiform skin inflammation. The interferon-α and tumor necrosis factor-α mRNA expression levels were decreased, while levels of Th17 cytokines including IL-17, IL-22, and IL-23 were increased in IRF5-deficient mice. Furthermore, IL-23 expression in DCs from IRF5-deficient mice was upregulated both in steady state and after toll-like receptor 7/8 agonist stimulation. Importantly, the expression of IRF4, which is also important for the IL-23 production in DCs, was augmented in DCs from IRF5-deficient mice. Taken together, our results suggest that IRF5 deficiency induces the upregulation of IRF4 in DCs followed by augmented IL-23 production, resulting in the amplification of Th17 responses and the exacerbation of imiquimod-induced psoriasis-like skin inflammation. The regulation of IRF4 or IRF5 expression may be a novel therapeutic approach to psoriasis.
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http://dx.doi.org/10.3390/ijms21103681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279463PMC
May 2020

A case of folliculotropic mycosis fungoides successfully treated with topical steroid treatment.

J Cancer Res Ther 2020 Jan-Mar;16(1):196-198

Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.4103/jcrt.JCRT_75_17DOI Listing
May 2020

Increased Expression of Delta-like Ligand 4 in Mycosis Fungoides.

Acta Derm Venereol 2020 02 25;100(4):adv00059. Epub 2020 Feb 25.

Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

In many malignancies, dysregulation of the Notch pathways, composed of 4 Notch receptors (Notch1-4) and 5 Notch ligands (Jagged1-2, Delta-like ligand-1, 3-4), is associated with their development. In mycosis fungoides, interaction between Notch1 and Jagged1 is known to activate the Notch pathways and promote the proliferation of tumour cells. However, the involvement of other Notch ligands has not been reported. This study investigated the roles of Delta-like ligand 4 in mycosis fungoides. Delta-like ligand 4 mRNA levels in lesional skin of patients with mycosis fungoides were significantly elevated compared with those of normal controls, and correlated with disease-specific mortality. Immunohistochemical staining demonstrated prominent expression of Delta-like ligand 4 on vascular endothelial cells and tumour cells in mycosis fungoides lesional skin. In addition, Delta-like ligand 4 augmented the proliferation of cutaneous T-cell lym-phoma cell lines. These results suggest that enhanced Delta-like ligand 4 expression may contribute directly to the progression of mycosis fungoides through proliferating tumour cells.
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http://dx.doi.org/10.2340/00015555-3402DOI Listing
February 2020

Primary cutaneous γδ T-cell lymphoma with unusual immunophenotype: A case report and review of published work.

J Dermatol 2020 Mar 7;47(3):300-305. Epub 2020 Jan 7.

Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Primary cutaneous γδ T-cell lymphoma (CGD-TCL) is a rare form of primary cutaneous lymphoma. The histopathological features of CGD-TCL are still unclear because of its rarity. Here, we report a case of a 77-year-old Japanese man who presented with a 9-month history of erythematous plaques on his left forearm. Skin biopsy specimens revealed the infiltration of atypical medium/large-sized lymphocytes from the epidermis to the deep dermis. Atypical lymphocytes were positive for CD3, CD5, CD8 and Vδ1, and negative for CD4, CD7, CD56, EBER-ISH, intracellular antigen-1, granzyme B and perforin. CD30 was partially expressed. We also reviewed 246 cases of CGD-TCL from the published work. CD4 CD8 double-negative cases were 113 of 196 cases (57.6%), followed by CD4 CD8 cases (52/196, 26.5%). CD5 was expressed in 25.8% of the cases (34/132). At least one cytotoxic molecule marker was expressed in 150 of 160 cases (93.8%). Some cases showed an indolent clinical course, especially in mycosis fungoides-like CGD-TCL cases. CD5 positivity and lack of cytotoxic molecule expression could be associated with a better prognosis. In addition, CD30 expression was found in approximately half of CGD-TCL cases (51/112 cases), suggesting that brentuximab vedotin could be a good treatment option for such patients. Further studies with more cases with detailed clinical and pathological information are necessary to elucidate the etiology and prognostic markers of this entity.
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http://dx.doi.org/10.1111/1346-8138.15215DOI Listing
March 2020
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