RESUMEN
CCR4 is a major trafficking receptor for T-helper (Th) 2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upregulated in the skin lesions of AD patients. Of note, thymic stromal lymphopoietin (TSLP), a master regulator of the Th2 immune response, promotes the expression of CCL17 and CCL22 in AD skin lesions. Here, we investigated the role of CCR4 in an AD mouse model induced by MC903, a TSLP inducer. Topical application of MC903 to ear skin increased the expression of not only TSLP but also CCL17, CCL22, the Th2 cytokine IL-4, and the Th17 cytokine IL-17A. Consistently, MC903 induced AD-like skin lesions as shown by increased epidermal thickness; increased infiltration of eosinophils, mast cells, type 2 innate lymphoid cells, Th2 cells, and Th17 cells; and elevated serum levels of total IgE. We also found increased expansion of Th2 cells and Th17 cells in the regional lymph nodes (LNs) of AD mice. Compound 22, a CCR4 inhibitor, ameliorated AD-like skin lesions with reduction of Th2 cells and Th17 cells in the skin lesions and regional LNs. We further confirmed that compound 22 diminished the expansion of Th2 cells and Th17 cells in the coculture of CD11c+ dendritic cells (DCs) and CD4+ T cells derived from the regional LNs of AD mice. Collectively, CCR4 antagonists may exhibit anti-allergic effects by inhibiting both the recruitment and expansion of Th2 cells and Th17 cells in AD.
Asunto(s)
Dermatitis Atópica , Ratones , Animales , Células Th2 , Células Th17 , Inmunidad Innata , Piel/patología , Citocinas/metabolismo , Linfopoyetina del Estroma Tímico , Inflamación/metabolismoRESUMEN
T helper 17 (Th17) cells express CC chemokine receptor 4 (CCR4) and secrete cytokines such as interleukin-17A (IL-17A) and granulocyte macrophage colony-stimulating factor (GM-CSF), while dendritic cells (DCs) produce CC chemokine ligand 22 (CCL22), a CCR4 ligand, upon stimulation with GM-CSF. Th17 cells are known to play a critical role in the pathogenesis of rheumatoid arthritis (RA). CCL22 has also been shown to be up-regulated in the synovial tissues of RA patients. Here, we investigated the role of CCR4 in collagen-induced arthritis (CIA), a mouse model of RA. DBA/1J mice efficiently developed CIA as shown by erythema, paw swelling, joint rigidity, and joint destruction. Th17 cells were increased in the arthritic joints and regional lymph nodes (LNs) of CIA mice. A fraction of Th17 cells were also shown to produce GM-CSF. On the other hand, we observed no significant increases of Th2 cells or Treg cells, the T cell subsets also known to express CCR4, in these tissues. We further observed clusters of CCR4-expressing memory Th17 cells and CCL22-producing DCs in the regional LNs of CIA mice, supporting the role of the CCR4-CCL22 axis in the expansion of Th17 cells in the regional LNs. Compound 22, a CCR4 inhibitor, ameliorated the disease severity with reduction of Th17 cells in the arthritic joints and regional LNs and Th17-DC clusters in the regional LNs. We further confirmed that CCR4-deficient mice in the C57BL/6J background were highly resistant to CIA induction compared with wild-type mice. Collectively, CCR4 contributes to the pathogenesis of CIA and may thus represent a new therapeutic target for RA.
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Artritis Experimental , Artritis Reumatoide , Ratones , Animales , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Receptores CCR4/fisiología , Células Th17/patología , Ligandos , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Artritis Reumatoide/patología , Modelos Animales de Enfermedad , Artritis Experimental/patología , QuimiocinasRESUMEN
BACKGROUND: The treatment of vitiligo can be challenging. Up-to-date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking. OBJECTIVES: To develop internationally agreed-upon expert-based recommendations for the treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in different online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence for different topics included in the algorithms. A survey was then given to a core group of eight experts to resolve the remaining issues. Subsequently, the recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The recommendations provided summarize the latest evidence regarding the use of topical therapies (steroids, calcineurin inhibitors and Jak-inhibitors) and systemic therapies, including steroids and other systemic immunomodulating or antioxidant agents. The different modalities of phototherapies (NB-UVB, photochemotherapy, excimer devices and home phototherapy), which are often combined with other therapies, are also summarized. Interventional approaches as well as depigmentation strategies are presented for specific indications. Finally, the status of innovative and targeted therapies under development is discussed. CONCLUSIONS: This international consensus statement culminated in expert-based clinical practice recommendations for the treatment of vitiligo. The development of new therapies is ongoing in vitiligo, and this will likely improve the future management of vitiligo, a disease that still has many unmet needs.
Asunto(s)
Fotoquimioterapia , Terapia Ultravioleta , Vitíligo , Humanos , Vitíligo/terapia , Vitíligo/tratamiento farmacológico , Fototerapia , Esteroides/uso terapéutico , Resultado del Tratamiento , Terapia CombinadaRESUMEN
BACKGROUND: The treatment of vitiligo can be challenging and depends on several factors such as the subtype, disease activity, vitiligo extent, and treatment goals. Vitiligo usually requires a long-term approach. To improve the management of vitiligo worldwide, a clear and up-to-date guide based on international consensus with uniform stepwise recommendations is needed. OBJECTIVES: To reach an international consensus on the nomenclature and to develop a management algorithm for the diagnosis, assessment, and treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence of topics included in the algorithms. A survey was utilized to resolve remaining issues among a core group of eight experts. Subsequently, the unanimous recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The algorithms highlight the importance of shared decision-making. Dermatologists are encouraged to provide patients with detailed explanations of the prognosis and expected therapeutic outcomes based on clinical examination. The treatment goal should be discussed and clearly emphasized to patients given the different approaches for disease stabilization and repigmentation. The evaluation of disease activity remains a cornerstone in the tailor-made approach to vitiligo patients. CONCLUSIONS: These new treatment algorithms are intended to guide clinical decision-making in clinical practice. Promising novel therapies for vitiligo are on the horizon, further highlighting the need for reliable outcome measurement instruments and greater emphasis on shared decision-making.
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Vitíligo , Humanos , Vitíligo/diagnóstico , Vitíligo/terapia , Consenso , Algoritmos , Toma de Decisiones Clínicas , Encuestas y CuestionariosRESUMEN
Atopic dermatitis (AD) is the most common inflammatory skin disease, which is characterized by excessive Th2 immune responses. In AD patients, the expression of the chemokines CCL17 and CCL22 is increased in skin lesions, leading to the infiltration of Th2 cells. In addition, typical pro-inflammatory cytokines, including TNF-α, IL-1ß and IL-6, have also been shown to be associated with the pathogenesis of AD. Recently, DDH-1, an ascorbic acid derivative, has been synthesized and demonstrated to have a more stabilized structure and better skin penetrability. Furthermore, DDH-1 has been shown to suppress pro-inflammatory cytokine expression in vitro and in vivo. Therefore, using an AD mouse model, we evaluated the effect of DDH-1 to reduce allergic skin inflammation. We found that cutaneous administration of DDH-1 significantly reduced the expression levels of TNF-α, IL-1ß and IL-6 in the skin lesions of AD-like mice. Additionally, DDH-1 administration also significantly reduced the expression levels of CCL17 and CCL22, resulting in decreased skin infiltration of Th2 cells. Consequently, DDH-1 reduced ear and epidermal thickness, the serum IgE levels and the number of infiltrating inflammatory cells and mast cells into the AD-like skin lesions. Combination treatment with DDH-1 and corticosteroid more efficiently improved the skin lesions compared with corticosteroid alone. Collectively, our results suggest that DDH-1 has an anti-allergic effect in an AD mouse model by reducing not only the pro-inflammatory cytokine expression but also the Th2-associated chemokine expression. Thus, DDH-1 may be beneficial for AD treatment and prevention as a monotherapy or in combination with corticosteroids.
Asunto(s)
Antialérgicos , Dermatitis Atópica , Animales , Antialérgicos/farmacología , Antialérgicos/uso terapéutico , Ácido Ascórbico/farmacología , Ácido Ascórbico/uso terapéutico , Citocinas/metabolismo , Modelos Animales de Enfermedad , Interleucina-6 , Ratones , Piel/patología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Extracellular ATP is known to promote Th17 cell differentiation in the intestinal lamina propria by stimulating CD70+CD11clow dendritic cells (DCs) via P2X receptors (P2XRs). Recent studies have also shown that Th17 cells enhance antitumor immunity by directly promoting proliferation of cytotoxic T lymphocytes (CTLs). These finding led us to test a P2XR agonist, αß-methylene ATP (αß-ATP), as a mucosal vaccine adjuvant to promote CTL responses through Th17 induction. We demonstrated that (i) CD70+CD11clow DCs were present in the nasal lamina propria and expressed P2X1R, P2X2R and P2X4R; (ii) CD70+CD11clow DCs isolated from the nasal lamina propria enhanced Th17 cell differentiation of cocultured splenic CD4+ T cells upon stimulation with αß-ATP; (iii) mice intranasally immunized with ovalbumin (OVA) and αß-ATP had increased OVA-specific Th17 cells and CTLs in the nasal lamina propria and regional lymph nodes; (iv) mice intranasally immunized with OVA and αß-ATP also had elevated resistance to E.G7-OVA tumor growth compared with those intranasally immunized with OVA alone; (v) suramin, a broad-range inhibitor of P2 receptors, suppressed the increases of OVA-specific Th17 cells and CTLs in mice intranasally immunized with OVA and αß-ATP; and (vi) suramin also abrogated the enhanced antitumor immunity of mice intranasally immunized with OVA and αß-ATP against E.G7-OVA. Collectively, αß-ATP may be a promising mucosal adjuvant that promotes antigen-specific CTL responses via CD70+CD11clow DC-mediated Th17 induction.
Asunto(s)
Adyuvantes de Vacunas/uso terapéutico , Células Dendríticas/inmunología , Melanoma Experimental/terapia , Ovalbúmina/administración & dosificación , Agonistas del Receptor Purinérgico P2X/farmacología , Linfocitos T Citotóxicos/inmunología , Adenosina Trifosfato/metabolismo , Animales , Ligando CD27/metabolismo , Diferenciación Celular/inmunología , Modelos Animales de Enfermedad , Inmunización , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Activación de Linfocitos/inmunología , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/inmunología , Antagonistas del Receptor Purinérgico P2X/farmacología , Receptores Purinérgicos P2X/inmunología , Suramina/farmacología , Células Th17/inmunologíaRESUMEN
Memory CD8+ cytotoxic T-lymphocytes (CTLs) play a key role in protective immunity against infection and cancer. However, the induction of memory CTLs with currently available vaccines remains difficult. The chemokine receptor XCR1 is predominantly expressed on CD103+ cross-presenting dendritic cells (DCs). Recently, we have demonstrated that a high activity form of murine lymphotactin/XCL1 (mXCL1-V21C/A59C), a ligand of XCR1, can induce antigen-specific memory CTLs by increasing the accumulation of CD103+ DCs in the vaccination site and the regional lymph nodes. Here, we combined a hydrophilic gel patch as a transcutaneous delivery device and mXCL1-V21C/A59C as an adjuvant to further enhance memory CTL responses. The transcutaneous delivery of ovalbumin (OVA) and mXCL1-V21C/A59C by the hydrophilic gel patch increased CD103+ DCs in the vaccination site and the regional lymph nodes for a prolonged period of time compared with the intradermal injection of OVA and mXCL1-V21C/A59C. Furthermore, the hydrophilic gel patch containing OVA and mXCL1-V21C/A59C strongly induced OVA-specific memory CTLs and efficiently inhibited the growth of OVA-expressing tumors more than the intradermal injection of OVA and mXCL1-V21C/A59C. Collectively, this type of hydrophilic gel patch and a high activity form of XCL1 may provide a useful tool for the induction of memory CTL responses.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/administración & dosificación , Quimiocinas C/administración & dosificación , Quimiocinas C/inmunología , Inmunización/métodos , Parche Transdérmico , Animales , Antígenos CD , Línea Celular , Células Dendríticas/inmunología , Geles , Interacciones Hidrofóbicas e Hidrofílicas , Cadenas alfa de Integrinas , Ratones Endogámicos C57BL , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Factores de TiempoRESUMEN
Psoriasis is a chronic inflammatory skin disease in which inflammatory cytokines play a major role in its pathogenesis. Because DDH-1, a novel amphipathic ascorbic acid derivative, has been recently shown to reduce inflammatory cytokine expression in human keratinocytes in vitro, we investigated its effect on imiquimod-induced psoriasis-like skin lesions in C57BL/6 mice. We first found that IL-1ß and TNF-α mRNA expression was significantly decreased in the skin lesions treated with DDH-1. Furthermore, cutaneous administration of DDH-1 ameliorated psoriasis-like skin lesions. These results suggest that DDH-1 may be effective in the prevention and supplemental treatment of psoriasis.
Asunto(s)
Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/uso terapéutico , Citocinas/inmunología , Psoriasis/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Ácido Ascórbico/farmacología , Citocinas/genética , Femenino , Imiquimod , Ratones Endogámicos C57BL , Psoriasis/inducido químicamente , Psoriasis/inmunología , Piel/efectos de los fármacos , Piel/inmunologíaRESUMEN
CCR4 is a major chemokine receptor expressed by Treg cells that downregulate immune responses. Here, we investigated the role of CCR4-mediated Treg cell recruitment in antigen-specific immune responses. CCR4-deficient mice immunized intramuscularly with ovalbumin (OVA) showed enhanced OVA-specific IgG responses. Furthermore, intramuscular administration of OVA induced the expression of MDC/CCL22, a ligand for CCR4, in macrophages of the muscle tissues, and enhanced the recruitment of CCR4+ Treg cells in wild-type mice, whereas this recruitment of Treg cells was severely impaired in CCR4-deficient mice. Furthermore, OVA-loaded dendritic cells (DCs) derived from the muscle injection site of CCR4-deficient mice had an upregulated expression of the DC activation marker CD40 and 86, and the lymphoid organ homing receptor CCR7 resulting in an increased number of migratory DCs in the regional lymph node. Compound 22, a CCR4 antagonist, also inhibited the recruitment of Treg cells to the muscle tissue, and further enhanced DC activation and homing to the regional lymph node. Consequently, Compound 22 enhanced OVA-specific IgG responses, and the expression levels of IL-4 and IFN-γ in CD4+ T cells and the levels of IFN-γ in CD8+ T cells. Finally, intramuscular administration of OVA and Compound 22 significantly inhibited the growth of OVA-expressing tumors. Collectively, CCR4 plays a pivotal role in Treg cell recruitment to the muscle tissue, and intramuscular administration of CCR4 antagonists may be a promising approach for enhancing vaccine efficacy.
Asunto(s)
Ganglios Linfáticos/inmunología , Piperazinas/farmacología , Piperidinas/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Receptores CCR4/antagonistas & inhibidores , Receptores CCR4/fisiología , Linfocitos T Reguladores/efectos de los fármacos , Vacunas , Adyuvantes Inmunológicos , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Línea Celular , Células Dendríticas/inmunología , Epítopos/inmunología , Expresión Génica/efectos de los fármacos , Inmunoglobulina G , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Músculos/inmunología , Ovalbúmina/inmunología , Receptores CCR4/deficiencia , Linfocitos T Reguladores/inmunologíaRESUMEN
BACKGROUND: In Japan, allergic contact dermatitis caused by hair colouring agents is a considerable problem for those occupationally exposed and also for consumers. Over the last 20 years, p-phenylenediamine (PPD) has been a common allergen, with â¼7% positive patch test reactions. OBJECTIVES: To investigate which ingredients caused allergic contact dermatitis related to hair dye and perming solutions in Japan, to assess whether PPD is suitable for screening for hair dye allergy, and to propose allergens for a Japanese hairdresser series. METHODS: We selected 19 hair cosmetic allergens, including PPD, Bandrowski's base, cysteamine HCl, and ammonium thioglycolate. Altogether 203 patients (26 males and 177 females) with suspected contact allergy to hair colouring or perming solutions at 14 hospitals in Japan were included. RESULTS: The highest prevalence of positive reactions (35.1%) was for PPD. p-Methylaminophenol and o-aminophenol were often positive, both in the PPD-positive and in the PPD-negative patients. Moreover, cysteamine HCl often yielded positive test reactions. CONCLUSIONS: PPD is insufficient to diagnose contact allergy caused by to hair dyes. We recommend 13 allergens to be included in a Japanese hairdresser series.
Asunto(s)
Dermatitis Alérgica por Contacto/diagnóstico , Dermatitis Profesional/diagnóstico , Tinturas para el Cabello/efectos adversos , Preparaciones para el Cabello/efectos adversos , Pruebas del Parche/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alérgenos , Dermatitis Alérgica por Contacto/etiología , Dermatitis Profesional/etiología , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Adulto JovenAsunto(s)
Dermatitis Alérgica por Contacto/etiología , Aparatos de Compresión Neumática Intermitente/efectos adversos , Etiquetado de Productos , Adolescente , Dermatitis Alérgica por Contacto/tratamiento farmacológico , Fluprednisolona/análogos & derivados , Fluprednisolona/uso terapéutico , Glucocorticoides/uso terapéutico , Humanos , Pierna , Masculino , Pruebas del ParcheRESUMEN
BACKGROUND: The precise pathogenesis of alopecia areata remains unknown, although this disease seems to be triggered by helper T cell infiltration in hair follicles. Recent studies of psoriasis and vitiligo have demonstrated the involvement of Th17 cells. Psoriasis and vitiligo occasionally develop concomitantly or inversely in patients with alopecia areata. OBJECTIVE: The aim of this study was to determine whether Th17 cells are present in the affected lesions of alopecia areata. METHODS: We performed immunofluorescent staining of representative immunocompetent cells that had infiltrated into the skin of the scalp in 4 individuals with alopecia areata (single patchy alopecia areata, multiple patchy alopecia areata, alopecia totalis and alopecia universalis). RESULTS: We found the infiltration of CD4(+)IL-17A(+) Th17 cells in the dermis, particularly around hair follicles, in all 4 cases. CONCLUSIONS: These findings suggest the possibility that alopecia areata is induced by a Th17 cell-associated autoimmune mechanism.
Asunto(s)
Alopecia Areata/inmunología , Alopecia Areata/patología , Dermis/patología , Folículo Piloso/patología , Células Th17/química , Adulto , Antígenos CD4/análisis , Linfocitos T CD8-positivos , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Interleucina-17/análisis , Masculino , Persona de Mediana Edad , Linfocitos T Reguladores , Adulto JovenRESUMEN
Patients with acquired haemophilia A usually show widespread subcutaneous bleeding. We describe an 86-year-old man with acquired haemophilia A associated with prostate carcinoma, showing initial localised giant haematoma and subsequent widespread subcutaneous bleeding. A localised giant haematoma may present as a first and important sign of acquired haemophilia A.
Asunto(s)
Carcinoma/diagnóstico , Hematoma/etiología , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Neoplasias de la Próstata/diagnóstico , Púrpura/etiología , Anciano de 80 o más Años , Carcinoma/complicaciones , Hematoma/tratamiento farmacológico , Hemofilia A/diagnóstico , Humanos , Masculino , Neoplasias de la Próstata/complicaciones , Púrpura/tratamiento farmacológicoRESUMEN
Hermansky-Pudlak syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules. In mice, at least 16 loci are associated with HPS, including sandy (sdy; ref. 7). Here we show that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells. We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1; refs. 9-11), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted and cappuccino, which are associated with HPS in mice. These findings show that BLOC-1 is important in producing the HPS phenotype in humans, indicate that dysbindin has a role in the biogenesis of lysosome-related organelles and identify unexpected interactions between components of DPC and BLOC-1.
Asunto(s)
Proteínas Portadoras/química , Proteínas Portadoras/genética , Proteínas Asociadas a la Distrofina , Síndrome de Hermanski-Pudlak/genética , Mutación , Animales , Células COS , Proteínas Portadoras/metabolismo , Proteínas del Citoesqueleto/metabolismo , Disbindina , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Lectinas , Sustancias Macromoleculares , Masculino , Melanosomas/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Transgénicos , Persona de Mediana Edad , Datos de Secuencia Molecular , Fosfoproteínas/metabolismo , Unión ProteicaRESUMEN
Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous disease involving abnormalities of melanosomes, platelet dense granules and lysosomes. Here we have used positional candidate and transgenic rescue approaches to identify the genes mutated in ruby-eye 2 and ruby-eye mice (ru2 and ru, respectively), two 'mimic' mouse models of HPS. We also show that these genes are orthologs of the genes mutated in individuals with HPS types 5 and 6, respectively, and that their protein products directly interact. Both genes are previously unknown and are found only in higher eukaryotes, and together represent a new class of genes that have evolved in higher organisms to govern the synthesis of highly specialized lysosome-related organelles.
Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular , Proteínas de Drosophila , Síndrome de Hermanski-Pudlak/genética , Proteínas de Insectos/genética , Proteínas de la Membrana/genética , Proteínas de Transporte de Membrana , Mutación/genética , Proteínas/genética , Complejo 3 de Proteína Adaptadora , Subunidades beta de Complejo de Proteína Adaptadora , Adulto , Secuencia de Aminoácidos , Animales , Células COS , Preescolar , Chlorocebus aethiops , Cromosomas Artificiales Bacterianos/genética , Cromosomas Artificiales de Bacteriófagos P1/genética , Modelos Animales de Enfermedad , Femenino , Síndrome de Hermanski-Pudlak/metabolismo , Síndrome de Hermanski-Pudlak/patología , Humanos , Masculino , Melanosomas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Datos de Secuencia Molecular , Oligopéptidos , Péptidos/inmunología , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Proteínas Proto-Oncogénicas c-myc/inmunología , Saccharomyces cerevisiae/metabolismo , Homología de Secuencia de Aminoácido , Transfección , Técnicas del Sistema de Dos HíbridosRESUMEN
Patients and Methods: A questionnaire survey was administered to 18, 14, and 3 patients introduced to home self-injection of dupilumab or mepolizumab using a pen-type device for atopic dermatitis, asthma alone, and asthma plus chronic rhinosinusitis with nasal polyps, respectively. Results: All but one participant wished to continue self-injection. Most participants affirmed the reduction in copayment (88.6%) and saving time and labor for hospital visits (88.6%). Six patients who received dupilumab complained of side effects, but all, except for one, continued the treatment. Of the 13 patients who had previously used a syringe-type device, 10 preferred the pen type because of its ease of use, while 3 (23%) preferred the syringe type because of the self-adjustable injection speed for pain control. Conclusion: Administration of biologics using pen-type devices is easier, and the introduction of home self-injection leads to a reduction in outpatient visits and copayment.
RESUMEN
Eotaxin-3/CCL26 is a functional ligand for CCR3 and abundantly produced by IL-4-/IL-13-stimulated vascular endothelial cells. CCL26 also functions as a natural antagonist for CCR1, CCR2, and CCR5. In this study, we report that CCL26 is yet a functional ligand for CX3CR1, the receptor for fractalkine/CX3CL1, which is expressed by CD16(+) NK cells, cytotoxic effector CD8(+) T cells, and CD14(low)CD16(high) monocytes. Albeit at relatively high concentrations, CCL26 induced calcium flux and chemotaxis in mouse L1.2 cells expressing human CX3CR1 but not mouse CX3CR1 and competed with CX3CL1 for binding to CX3CR1. In chemotaxis assays using human PBMCs, CCL26 attracted not only eosinophils but also CD16(+) NK cells, CD45RA(+)CD27(-)CD8(+) T cells, and CD14(low)CD16(high) monocytes. Intraperitoneal injection of CCL26 into mice rapidly recruited mouse eosinophils and intravenously transferred human CD16(+) NK cells into the peritoneal cavity. IL-4-stimulated HUVECs produced CCL26 and efficiently induced adhesion of cells expressing CX3CR1. Real-time PCR showed that skin lesions of psoriasis consistently contained CX3CL1 mRNA but not CCL26 mRNA, whereas those of atopic dermatitis contained CCL26 mRNA in all samples but CX3CL1 mRNA in only about half of the samples. Nevertheless, the skin lesions from both diseases consistently contained CX3CR1 mRNA at high levels. Thus, CCL26 may be partly responsible for the recruitment of cells expressing CX3CR1 in atopic dermatitis particularly when the expression of CX3CL1 is low. Collectively, CCL26 is another agonist for CX3CR1 and may play a dual role in allergic diseases by attracting eosinophils via CCR3 and killer lymphocytes and resident monocytes via CX3CR1.
Asunto(s)
Quimiocinas CC/metabolismo , Receptores de Quimiocina/metabolismo , Adulto , Animales , Receptor 1 de Quimiocinas CX3C , Señalización del Calcio/inmunología , Línea Celular , Células Cultivadas , Quimiocina CCL26 , Quimiocinas CC/agonistas , Quimiocinas CC/fisiología , Quimiotaxis de Leucocito/inmunología , Homeostasis/inmunología , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ligandos , Masculino , Ratones , Ratones Endogámicos BALB C , Monocitos/inmunología , Monocitos/metabolismo , Monocitos/patología , Receptores CCR3/metabolismo , Receptores CCR3/fisiología , Receptores de Quimiocina/genética , Receptores de Quimiocina/fisiología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismoRESUMEN
OBJECTIVE: Somatic mutations in the epidermal growth factor receptor gene are associated with a therapeutic response to epidermal growth factor receptor tyrosine kinase inhibitors such as gefitinib and erlotinib in patients with non-small cell lung cancer. Although the safety profile of these drugs is favorable, a small proportion of patients with EGFR mutation-positive non-small cell lung cancer must discontinue treatment because of adverse events such as interstitial lung disease and hepatotoxicity. Subsequent chemotherapy has not been optimized in such patients. METHODS: We performed a retrospective analysis of EGFR mutation-positive non-small cell lung cancer patients who received both gefitinib and erlotinib at our institution. Patients received the second epidermal growth factor receptor-tyrosine kinase inhibitor after experiencing an adverse event or progressive disease on the first epidermal growth factor receptor-tyrosine kinase inhibitor. RESULTS: We identified 14 patients who received both gefitinib and erlotinib in the course of their treatment. Three patients initially treated with gefitinib and two with erlotinib discontinued epidermal growth factor receptor-tyrosine kinase inhibitor therapy because of severe non-hematologic toxicity (one because of gefitinib-induced interstitial lung disease, one because of erlotinib-induced lupus erythematosus-like eruption and three because of hepatotoxicity). All five of these patients were able successfully to continue therapy with the second epidermal growth factor receptor-tyrosine kinase inhibitor with no evidence of a recurrent adverse event. Progression-free survival was significantly longer in these five patients than in the nine patients who discontinued treatment with the first epidermal growth factor receptor-tyrosine kinase inhibitor because of disease progression. CONCLUSIONS: EGFR mutation-positive non-small cell lung cancer patients who discontinue treatment with a first epidermal growth factor receptor-tyrosine kinase inhibitor because of an adverse event benefit substantially from switching to a second epidermal growth factor receptor-tyrosine kinase inhibitor before the development of drug resistance.