RESUMEN
Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (nNationMS = 946, nBIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-ß-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
Asunto(s)
Monocitos/efectos de la radiación , Esclerosis Múltiple/sangre , Esclerosis Múltiple/inmunología , Receptor de Melanocortina Tipo 1/genética , Transcriptoma/efectos de la radiación , Vitamina D/sangre , Linfocitos B/efectos de la radiación , Estudios de Cohortes , Femenino , Variación Genética , Genotipo , Humanos , Interferón beta/farmacología , Interferón beta/uso terapéutico , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Esclerosis Múltiple/patología , Esclerosis Múltiple/radioterapia , Fenotipo , Fototerapia , Recurrencia , Índice de Severidad de la Enfermedad , Luz Solar , Linfocitos T/metabolismo , Linfocitos T/efectos de la radiación , Transcriptoma/genéticaRESUMEN
Psoriasis is a chronic inflammatory disease appearing as scaly erythematous cutaneous lesions, which are characterized by parakeratosis and acanthosis as well as the infiltration of immune cells, such as T helper-1 and T helper-17 cells. Here, we demonstrated that KdPT, a tripeptide structurally related to the C-terminal amino acids of alpha-melanocyte-stimulating hormone, which was previously shown to exhibit anti-inflammatory effects in intestinal inflammation, ameliorated ongoing disease in the mouse model of imiquimod-induced psoriasis-like skin inflammation and in the small xenotransplant mouse model of psoriasis. We could show that systemic KdPT treatment significantly reduced hyperkeratosis and acanthosis in murine as well as human skin. Moreover, KdPT upregulated Foxp3 in CD4+ T cells from mice and from peripheral blood of individuals with psoriasis and decreased the expression of type 1 inflammatory cytokines, indicating that the beneficial effect of KdPT was, at least in part, mediated by the induction of functional regulatory T cells that suppressed the activation of pathogenic CD4+ IFN-γ+ and CD4+ IL-17+ T cells. Thus, these data might suggest KdPT as a potential novel therapeutic alternative for the treatment of psoriasis.
Asunto(s)
Antiinflamatorios/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Oligopéptidos/uso terapéutico , Psoriasis/tratamiento farmacológico , Animales , Antiinflamatorios/farmacología , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/patología , Células Cultivadas , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/metabolismo , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Queratosis/tratamiento farmacológico , Células de Langerhans/efectos de los fármacos , Células de Langerhans/inmunología , Ratones , Ratones Endogámicos BALB C , Oligopéptidos/farmacología , Psoriasis/inmunología , Psoriasis/metabolismo , Psoriasis/patología , Células TH1/efectos de los fármacos , Células TH1/patología , Células Th17/efectos de los fármacos , Células Th17/patología , Trasplante HeterólogoRESUMEN
κ-Opioid receptors (KORs) play a predominant role in pain alleviation, itching skin diseases, depression and neurodegenerative disorders such as multiple sclerosis. Therefore, imaging of KOR by a fluorinated PET tracer was envisaged. Two strategies were followed to introduce a F atom into the very potent class of cis,trans-configured perhydroquinoxalines. Whereas the synthesis of fluoroethyltriazole 2 has already been reported, fluoropyrrolidines 14 (1-[2-(3,4-dichlorophenyl)acetyl]-8-[(R)-3-fluoropyrrolidin-1-yl]-perhydroquinoxalines) were prepared by SN2 substitution of a cyclic sulfuric acid derivative with hydroxypyrrolidine and subsequent transformation of the OH moiety into a F substituent. Fluoropyrrolidines 14 showed similar low-nanomolar KOR affinity and selectivity to the corresponding pyrrolidines, but the corresponding alcohols were slightly less active. In the cAMP and ß-arrestin assay, 14b (proton at the 4-position) exhibited similar KOR agonistic activity as U-50,488. The fluoro derivatives 14b and 14c (CO2CH3 at the 4-position) revealed KOR-mediated anti-inflammatory activity as CD11c and the IFN-γ production were reduced significantly in mouse and human dendritic cells. Compounds 14b and 14-c also displayed anti-inflammatory and immunomodulatory activity in mouse and human T cells. The PET tracer [18F]-2 was prepared by 1,3-dipolar cycloaddition. In vivo, [18F]-2 did not label KOR due to very fast elimination kinetics. Nucleophilic substitution of a mesylate precursor provided [18F]-14c. Unfortunately, defluorination of [18F]-14c occurred inâ vivo, which was analyzed in detail by inâ vitro studies.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Quinoxalinas/farmacología , Radiofármacos/farmacología , Receptores Opioides kappa/agonistas , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Encéfalo/metabolismo , Células Cultivadas , Citocinas/análisis , Radioisótopos de Flúor , Cobayas , Halogenación , Humanos , Ratones , Ratones Endogámicos C57BL , Tomografía de Emisión de Positrones , Quinoxalinas/síntesis química , Quinoxalinas/química , Radiofármacos/síntesis química , Radiofármacos/química , Receptores Opioides kappa/metabolismoRESUMEN
Multiple sclerosis (MS) is a disease of presumed auto-immune origin. Long-standing observations such as the correlation between MS incidence and geographical latitude or the levels of Vitamin D (Vit D) in the serum have implicated the environmental factors UVB radiation and diet in the etiology of the disease. Clinical trials have been conducted and are currently underway to elucidate whether a Vit D enriched diet or treatment with UVB can influence MS incidence, -severity, and -progression, as well as the ideal time point for treatment. This review summarizes the current scientific knowledge to the environmental factors UVB-light and Vit D concerning the clinical aspects of MS in epidemiological studies and clinical trials.
Asunto(s)
Esclerosis Múltiple/sangre , Luz Solar , Deficiencia de Vitamina D/sangre , Vitamina D/sangre , Ensayos Clínicos como Asunto/métodos , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/epidemiología , Rayos Ultravioleta , Vitamina D/administración & dosificación , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/epidemiologíaRESUMEN
Neuroinflammatory disorders, such as multiple sclerosis or experimental autoimmune encephalomyelitis (EAE), an established mouse model mimicking part of the human pathology, are characterized by inflammatory infiltrates containing T helper 1 (TH1) and TH17 cells, which cause demyelination and neurodegeneration. Disease onset and perpetuation are mediated by peripherally generated autoreactive T cells infiltrating into the central nervous system, where they are restimulated by antigen-presenting cells. Here, we show that newly designed peripherally active, potent, and selective κ-opioid receptor (KOR) agonists comprising the ethylenediamine KOR pharmacophore in a perhydroquinoxaline scaffold exhibit potent anti-inflammatory capacities in primary antigen presenting cells as well as T cells. In the EAE model, the secondary amine 12 and the triazole 14 were able to ameliorate disease severity and to delay disease onset by blocking effector T cell activation. Importantly, the beneficial effects were mediated via signaling through KOR because off-target effects were excluded by using KOR-deficient mouse mutants.
Asunto(s)
Antineoplásicos/química , Quinoxalinas/química , Receptores Opioides kappa/agonistas , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sitios de Unión , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Células HEK293 , Humanos , Interferón gamma/metabolismo , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Quinoxalinas/farmacología , Quinoxalinas/uso terapéutico , Receptores Opioides kappa/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Células TH1/citología , Células TH1/efectos de los fármacos , Células TH1/metabolismoRESUMEN
In inflammation-associated progressive neuroinflammatory disorders, such as multiple sclerosis (MS), inflammatory infiltrates containing T helper 1 (TH1) and TH17 cells cause demyelination and neuronal degeneration. Regulatory T cells (Treg) control the activation and infiltration of autoreactive T cells into the central nervous system (CNS). In MS and experimental autoimmune encephalomyelitis (EAE) in mice, Treg function is impaired. We show that a recently approved drug, Nle4-d-Phe7-α-melanocyte-stimulating hormone (NDP-MSH), induced functional Treg, resulting in amelioration of EAE progression in mice. NDP-MSH also prevented immune cell infiltration into the CNS by restoring the integrity of the blood-brain barrier. NDP-MSH exerted long-lasting neuroprotective effects in mice with EAE and prevented excitotoxic death and reestablished action potential firing in mouse and human neurons in vitro. Neuroprotection by NDP-MSH was mediated via signaling through the melanocortin-1 and orphan nuclear 4 receptors in mouse and human neurons. NDP-MSH may be of benefit in treating neuroinflammatory diseases such as relapsing-remitting MS and related disorders.