RESUMO
Interferon-beta (IFN-beta) is an effective treatment for a subgroup of patients with multiple sclerosis (MS). The mechanism of action as well as the pathophysiological basis of responsiveness to IFN-beta is not well understood. To improve treatment considerations in MS patients predictive markers for response to IFN-beta therapy at early timepoints are needed. Here we correlated changes in serum cytokine levels (IL-13, IL-10, IL-5, IL-4, IFN-gamma) with the clinical response to IFN-beta treatment. Serum cytokine levels of 77 untreated and 43 IFN-beta treated relapsing-remitting MS patients (RRMS) were measured by ELISA, including longitudinal measurements in 17 patients. We found a significant upregulation of IL-10 and IL-5 serum cytokine levels during IFN-beta therapy. However, clinical response was only associated with IL-10 serum levels (p=0.038; positive predictive value 0.95, negative predictive value 0.43) but not with IL-5. The predictive power was increased by a combined testing of IL-10 with expression of co-signaling molecules on monocytes, that were previously shown to change during IFN-beta therapy. In a subgroup of 17 patients testing of 4 markers had a positive and negative predictive value of 1.0 for at least 2 of these markers being positive in treatment responders. The results suggest that serum IL-10 is useful to predict treatment response to IFN-beta particularly in combination with a panel of other IFN-beta dependent parameters.
Assuntos
Citocinas/sangue , Interferon beta/uso terapêutico , Interleucina-10/sangue , Monócitos/imunologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Adulto , Antígenos CD/sangue , Antígeno B7-2/sangue , Antígenos CD40/sangue , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Interferon beta/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1 , Regulação para CimaRESUMO
Interferon-beta (IFN-beta) reduces disease activity in a subgroup of patients with relapsing remitting multiple sclerosis (MS). The mechanism of action as well as the pathophysiological basis of responsiveness to IFN-beta is not well understood. Since T-cell activation plays an important part in the pathophysiology of MS, we here investigated the effect of IFN-beta on the expression of co-signaling pathways (CD28-CD80/CD86, CD154-CD40, ICOS-ICOSL, PD-1-PD-L1/2) in MS patients and correlated the results with the clinical response to IFN-beta in individual patients. Expression of co-signaling molecules was measured by flow cytometry in vitro on peripheral blood mononuclear cells after incubation with IFN-beta, and in vivo in whole blood samples of 32 untreated and 24 IFN-beta treated MS patients, including 13 patients longitudinal. IFN-beta treatment induced upregulation of CD40, CD80, CD86, PD-L1 and PD-L2 on monocytes as well as PD-L1 on CD4+-T-cells in vitro and in vivo. IFN-beta treated MS patients were grouped into responders and non-responders on the basis of Kurtzkés EDSS (expanded disability status scale) progression and relapse rate. Upregulation of CD40, CD86 and PD-L2 on monocytes was associated with treatment response to IFN-beta (P < 0.001, P = 0.028 and P = 0.028, respectively). Our results show that IFN-beta upregulates co-stimulatory as well as co-inhibitory molecules in vitro and in vivo implicating that modulation of the balance between positive and negative co-stimulatory signals might be an important part of the mechanism of action of IFN-beta in MS. Upregulation of the expression of CD40, CD86 and PD-L2 may be useful as a predictive marker for clinical response to IFN-beta treatment at early timepoints during IFN-beta therapy.
Assuntos
Antígenos CD/metabolismo , Antígeno B7-2/metabolismo , Antígenos CD40/metabolismo , Fatores Imunológicos/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interferon beta/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Anticorpos/sangue , Antígeno B7-H1 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Feminino , Citometria de Fluxo , Humanos , Fatores Imunológicos/imunologia , Interferon beta/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1 , Fator de Transcrição STAT1/efeitos dos fármacos , Fator de Transcrição STAT1/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
BACKGROUND: Spontaneous intracranial hypotension (SIH) is increasingly recognized as a clinically variable and likely underdiagnosed syndrome caused by non-traumatic CSF leaks. The aim of this study was to correlate the findings of imaging studies - magnetic resonance imaging (MRI), radionuclide cisternography - with clinical features and CSF pressure in SIH in order to improve the diagnostic yield and management in patients with SIH. METHODS: Clinical case study of 10 consecutive cases of SIH, MRI, radio-isotope cisternography. RESULTS: 5 out of 10 patients had unusual clinical symptoms of SIH(2 subdural haematomas, 1 gait ataxia, 1 tinnitus, 1 haemodialysis-associated headache). In 7 patients pachymeningeal gadolinium enhancement was detected in MRI accompanied by a reduced CSF opening pressure. In contrast, the 3 patients with normal MRI also had a normal CSF pressure. Radio-isotope cisternography was abnormal in all patients tested. There was no correlation between the severity of clinical symptoms and MRI or radionuclide cisternography findings. CONCLUSIONS: The spectrum of clinical symptoms and imaging findings in SIH is highly variable. There- fore the diagnosis of SIH is often delayed. Radio-isotope cisternography is an important additional diagnostic method to detect CSF leaks or pathological kinetics of radio-isotope movement particularly in cases with normal MRI findings.
Assuntos
Encéfalo/patologia , Hipertensão Intracraniana/diagnóstico por imagem , Hipertensão Intracraniana/patologia , Hipertensão Intracraniana/fisiopatologia , Adulto , Idoso , Pressão do Líquido Cefalorraquidiano , Feminino , Gadolínio , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Intensificação de Imagem Radiográfica , Cintilografia , Tomografia Computadorizada por Raios XRESUMO
Dendritic cells (DCs) are key regulators of immune responses and have been associated with autoimmunity in animal models and human disease. The effects of interferon beta (IFN-beta), an immunomodulatory cytokine used in multiple sclerosis (MS) therapy, on DCs are not well understood. Monocyte-derived DCs at different stages of maturation were stimulated with IFN-beta and DC-phenotype and stimulatory function were measured. IFN-beta inhibited the development of DCs at early stages but enhanced DC maturation. Moreover, IFN-beta enhanced the capacity of DCs to stimulate autologous T-cells to secrete IL-13, IL-10 and IL-5. Thus, IFN-beta has both immunostimulatory and immunosuppressive effects on DCs depending on the stage of maturation.