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1.
J Eur Acad Dermatol Venereol ; 32(11): 1930-1939, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29633373

RESUMO

BACKGROUND: To date, biological treatments have been assessed in subjects with a long-term history of psoriasis and previous failures to systemic and topical therapies. In rheumatoid arthritis and other immune-mediated inflammatory diseases, early intensive systemic treatment prolongs treatment-free remission. We hypothesize that, by treating patients with psoriasis early with an effective systemic therapy, we may be able to alter the clinical outcome and the natural course of the disease. The STEPIn study (NCT03020199) investigates early intervention with secukinumab versus narrow-band ultraviolet B (nb-UVB) phototherapy in subjects with new-onset psoriasis. OBJECTIVE: To determine whether early intervention with either nb-UVB treatment or secukinumab in subjects with new-onset plaque psoriasis might modify the natural course of the disease. METHODS: One hundred and sixty subjects aged 18-50 years with new-onset (≤12 months) moderate-to-severe plaque psoriasis and naïve to systemic treatment and phototherapy will be randomized to secukinumab 300 mg or nb-UVB. The Main Study has two treatment arms: Arm A1, subcutaneous secukinumab 300 mg at baseline, Weeks 1, 2, 3 and 4, and every 4 weeks thereafter until and including Week 52; Arm B1, one/two cycles of nb-UVB for 12 weeks each (maximum 28-week break between cycles). After treatment discontinuation, patients will be followed up and monitored for disease activity up to Week 208. A Mechanistic Sub-study will assess immunological changes and pathogenic tissue-resident memory T cells in skin biopsies. CONCLUSIONS: STEPIn is the first study to investigate whether early intensive treatment in new-onset psoriasis can modify the long-term natural course of the disease and thus become a novel treatment strategy for patients with psoriasis.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Psoríase/tratamento farmacológico , Psoríase/radioterapia , Terapia Ultravioleta/métodos , Adolescente , Adulto , Anticorpos Monoclonais Humanizados , Relação Dose-Resposta a Droga , Esquema de Medicação , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Psoríase/diagnóstico , Medição de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
2.
Clin Exp Allergy ; 44(8): 1033-43, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24912880

RESUMO

Innate lymphoid cells (ILC) is the collective term for a group of related innate lymphocytes, including NK cells and the more recently appreciated non-NK ILC (ILC1, ILC2 and ILC3). ILC all depend on the common γ-chain of the IL-2 receptor and the transcription factor Id2. Furthermore, ILC lack rearranged antigen-receptors such as those expressed by T and B cells. Recent data indicate that non-NK ILC contribute to a wide range of homeostatic and pathophysiological processes primarily by virtue of cytokine production. A lot of effort has been put into understanding the role for the non-NK ILC in mucosal homeostasis, including in the gut and lungs. Recent reports also point towards a role for ILC in skin inflammation. In the lung, ILC may propagate stromal-derived danger signals, with subsequent induction of mainly type 2 cytokine production. This might represent an early trigger of type 2-mediated pathology, which subsequently also engages the adaptive immune system. Similarly, in the skin, ILC are well placed to sense keratinocyte-derived danger signals in an antigen-independent manner. Recent findings link ILC2 to atopic dermatitis and ILC3 to psoriasis. In this review, we provide an updated perspective on the role for non-NK ILC in atopic and non-atopic inflammation in the airways as well as in the skin.


Assuntos
Dermatite/imunologia , Hipersensibilidade Imediata/imunologia , Imunidade Inata , Inflamação/imunologia , Linfócitos/imunologia , Doenças Respiratórias/imunologia , Animais , Dermatite/genética , Dermatite/metabolismo , Humanos , Hipersensibilidade Imediata/genética , Hipersensibilidade Imediata/metabolismo , Inflamação/genética , Inflamação/metabolismo , Pulmão/imunologia , Pulmão/patologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos/metabolismo , Doenças Respiratórias/genética , Doenças Respiratórias/metabolismo
3.
Parasite Immunol ; 34(12): 551-61, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23009296

RESUMO

Cutaneous leishmaniasis (CL) is caused by parasitic infection of dermal macrophages resulting in intense immune-mediated tissue inflammation and skin ulceration. The severity of the disease is dependent on parasite species as well as the immune responses evoked by the host. Most cases of CL heal spontaneously. In rare cases, the ulcer/s become chronic, and some Leishmania species may induce mucosal leishmaniasis (MCL) leading to severe tissue damage. Due to difficulties in obtaining skin tissue, most human studies of CL have been limited to the analysis of peripheral blood. While systemic responses may be good correlates of immunity, tissue damage and local immune responses at the site of infection is seldom reflected in alterations in the peripheral blood. In this review, we discuss the different forms of CL focusing on the in situ responses in established disease and the mechanisms involved in pathology and healing of Leishmania infection. Great effort has been put into animal models dissecting the immune events behind the evolution of disease, tissue pathology and parasite control. These models of genetically engineered, immune deficient mice or mice given therapy prior to onset of overt disease poorly reflect the clinical situation, where patients seek treatment once infection is well established. Models of established disease are needed to address the clinical challenge of identifying new therapeutic targets in treatment CL. Through understanding immune deviations during CL potential benefits and risks of emerging biological drugs in leishmaniasis can be addressed.


Assuntos
Leishmania/imunologia , Leishmania/patogenicidade , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Pele/imunologia , Pele/patologia , Animais , Modelos Animais de Doenças , Humanos , Leishmaniose Cutânea/parasitologia , Camundongos , Pele/parasitologia
4.
Clin Exp Immunol ; 153(2): 221-30, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18713141

RESUMO

Natural killer (NK) cells contribute to immunity as the first line of defence in numerous infections by early cytokine secretion and cytotoxicity. In Leishmania infection, NK cells contribute with interferon-gamma and may assist in directing the immune response towards T helper type 1, which is essential for successful control of the parasites. Thus, NK cells may play an important role in both resistance and control of the infection. However, during Leishmania infection NK cells show signs of suppression. To explore the reason for this suppression, we exposed naive and interleukin (IL)-2 activated NK cells directly to promastigotes of Leishmania major in vitro. As a rapid consequence of contact between naive NK cells and promastigotes, expression of NK cell receptors show significant changes. We identify one of the major surface molecules of promastigotes, glycoprotein (gp) 63, as an important agent for these suppressive effects by using promastigotes of a gp63ko strain of L. major. Furthermore, proliferation of IL-2-activated purified NK cells is suppressed after exposure to the wild-type but not to gp63ko promastigotes. However, gp63ko L. major induced no NK cell proliferation when NK cells were co-cultured with peripheral blood mononuclear cells populations such as CD14(+) monocytes or T cells.


Assuntos
Antígenos de Protozoários/imunologia , Células Matadoras Naturais/imunologia , Leishmania major , Leishmaniose Cutânea/imunologia , Metaloendopeptidases/imunologia , Adulto , Animais , Estudos de Casos e Controles , Proliferação de Células , Testes Imunológicos de Citotoxicidade , Citometria de Fluxo , Humanos , Interferon gama/análise , Interleucina-2/imunologia , Ativação Linfocitária , Masculino , Ligação Proteica
5.
J Steroid Biochem Mol Biol ; 52(2): 181-6, 1995 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-7873452

RESUMO

Steroid 21-hydroxylase activity was assayed in low-speed supernatants prepared from whole cell homogenates of mouse and rat tissues. Kidney supernatants had an activity which was approximately 2-5% that of adrenal preparations while heart muscle was found to be without 21-hydroxylase activity. When the enzyme kinetics were characterized, both adrenal and kidney low-speed supernatants demonstrated saturation kinetics, but with very different Vmax and Km values. Using polymerase chain reaction amplification after reverse transcriptase synthesis of cDNA from isolated RNA (RT-PCR), we found low levels of mRNA for steroid 21-hydroxylase in mouse kidney, but none in heart muscle. Thus, extra-adrenal steroid 21-hydroxylase activity in the kidney may be mediated by the same enzyme as found in adrenals.


Assuntos
Rim/enzimologia , RNA Mensageiro/metabolismo , Esteroide 21-Hidroxilase/metabolismo , Glândulas Suprarrenais/enzimologia , Animais , Sequência de Bases , Hidroxilação , Cinética , Camundongos , Dados de Sequência Molecular , Especificidade de Órgãos , Ratos , Ratos Sprague-Dawley , Esteroide 21-Hidroxilase/biossíntese , Esteroide 21-Hidroxilase/genética
6.
Clin Exp Immunol ; 117(3): 529-34, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10469058

RESUMO

We have previously shown that natural killer (NK) cells play a role in protection against leishmaniasis. Furthermore, we have shown that NK cells in mononuclear cells derived from unexposed donors are induced to proliferate in vitro in response to leishmanial antigens. Since interleukin (IL)-12, a strong inducer of NK cells, acts on the early events in NK cells and T-cells, and is considered as an adjuvant for use in a potential antileishmaniasis antigen, we wished to investigate how this cytokine influences the in vitro Leishmania induced proliferative and cytokine response in healthy donors. We demonstrate that in an innate response to Leishmania antigen involving NK cells, a critical level of IL-12 is required to induce interferon (IFN)-gamma secretion below which, IL-10 is released in amounts which apparently inhibit IFN-gamma secretion and cellular proliferation. However, at higher IL-12 levels, there is simultaneous secretion of IFN-gamma and IL-10 as well as proliferation of cells. In a similar vein, exogenous IL-10 in turn inhibited IFN-gamma secretion as well as proliferation when used at low/medium concentrations, but at high concentrations this effect was abolished and replaced by the simultaneous detection of IFN-gamma, IL-10 and proliferation. The contribution of NK cells in cross regulation of these two very important immuneregulatory cytokines and the effect of exogenous IL-12 in a Leishmania driven response are discussed.


Assuntos
Interleucina-10/imunologia , Interleucina-12/imunologia , Células Matadoras Naturais/imunologia , Leishmania/imunologia , Animais , Antígenos de Protozoários/imunologia , Doadores de Sangue , Divisão Celular , Células Cultivadas , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Interleucina-12/farmacologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia
7.
Clin Exp Immunol ; 130(2): 307-13, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12390320

RESUMO

Several studies in murine systems have suggested a role of apoptosis in the pathogenesis of leishmaniasis. However, the role of apoptosis in visceral leishmaniasis in man has not been explored. In this study, we show that patients with visceral leishmaniasis demonstrate significant dysregulation of Fas and Fas ligand. Levels of soluble Fas (sFas) and soluble Fas ligand (sFasL) were elevated in plasma of patients with active visceral leishmaniasis (VL) and individuals co-infected with VL-HIV-1 compared to healthy controls. The levels of sFas and sFasL were normalized 6 months after successful treatment. In VL patients, the expression of membrane bound Fas, and to a lower extent FasL, were up-regulated on Leishmania donovani-infected spleen cells, the site of parasite multiplication. Expression of Fas and FasL on peripheral blood mononuclear cells was within normal range, probably reflecting that the blood is not a normal site of L. donovani infection. Furthermore, this is suggested by the finding that in vitro infection of macrophages with L. donovani up-regulated Fas expression on the surface of infected cells and enhanced the levels of sFasL in supernatants from infected cultures. How this dysregulation may affect the pathogenesis of human visceral leishmaniasis is discussed.


Assuntos
Leishmaniose Visceral/imunologia , Glicoproteínas de Membrana/metabolismo , Receptor fas/metabolismo , Animais , Apoptose , Células Cultivadas , Proteína Ligante Fas , Infecções por HIV/complicações , Humanos , Leishmania donovani/patogenicidade , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/patologia , Leucócitos Mononucleares/imunologia , Macrófagos/imunologia , Macrófagos/parasitologia , Glicoproteínas de Membrana/sangue , Baço/imunologia , Receptor fas/sangue
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