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1.
BMJ Open ; 9(10): e032695, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666276

RESUMO

INTRODUCTION: Haemophagocytic lymphohistiocytosis (HLH) in adults is characterised by toxic immune activation and a sepsis-like syndrome, leading to high numbers of undiagnosed cases and mortality rates of up to 68%. Early diagnosis and specific immune suppressive treatment are mandatory to avoid fatal outcome, but the diagnostic criteria (HLH-2004) are adopted from paediatric HLH and have not been validated in adults. Experimental studies suggest biomarkers to sufficiently diagnose HLH. However, biomarkers for the diagnosis of adult HLH have not yet been investigated. METHODS AND ANALYSIS: The HEMICU (Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients) study aims to estimate the incidence rate of adult HLH among suspected adult patients in intensive care units (ICUs). Screening for HLH will be performed in 16 ICUs of Charité - Universitätsmedizin Berlin. The inclusion criteria are bicytopaenia, hyperferritinaemia (≥500 µg/L), fever or when HLH is suspected by the clinician. Over a period of 2 years, we expect inclusion of about 100 patients with suspected HLH. HLH will be diagnosed if at least five of the HLH-2004 criteria are fulfilled, together with an expert review; all other included patients will serve as controls. Second, a panel of potential biomarker candidates will be explored. DNA, plasma and serum will be stored in a biobank. The primary endpoint of the study is the incidence rate of adult HLH among suspected adult patients during ICU stay. Out of a variety of measured biomarkers, this study furthermore aims to find highly potential biomarkers for the diagnosis of adult HLH in ICU. The results of this study will contribute to improved recognition and patient outcome of adult HLH in clinical routine. ETHICS AND DISSEMINATION: The institutional ethics committee approved this study on 1 August 2018 (Ethics Committee of Charité - Universitätsmedizin Berlin, EA4/006/18). The results of the study will be disseminated in an international peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT03510650.

2.
Nat Med ; 25(2): 242-248, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30374197

RESUMO

The discovery of the highly efficient site-specific nuclease system CRISPR-Cas9 from Streptococcus pyogenes has galvanized the field of gene therapy1,2. The immunogenicity of Cas9 nuclease has been demonstrated in mice3,4. Preexisting immunity against therapeutic gene vectors or their cargo can decrease the efficacy of a potentially curative treatment and may pose significant safety issues3-6. S. pyogenes is a common cause for infectious diseases in humans, but it remains unclear whether it induces a T cell memory against the Cas9 nuclease7,8. Here, we show the presence of a preexisting ubiquitous effector T cell response directed toward the most widely used Cas9 homolog from S. pyogenes (SpCas9) within healthy humans. We characterize SpCas9-reactive T cells within the CD4/CD8 compartments for multi-effector potency, cytotoxicity, and lineage determination. In-depth analysis of SpCas9-reactive T cells reveals a high frequency of SpCas9-reactive regulatory T cells that can mitigate SpCas9-reactive effector T cell proliferation and function in vitro. Our results shed light on T cell-mediated immunity toward CRISPR-associated nucleases and offer a possible solution to overcome the problem of preexisting immunity.


Assuntos
Proteína 9 Associada à CRISPR/metabolismo , Streptococcus pyogenes/metabolismo , Linfócitos T/imunologia , Adolescente , Adulto , Feminino , Humanos , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
J Neuroinflammation ; 15(1): 162, 2018 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-29803225

RESUMO

BACKGROUND: Parkinson's disease (PD) is characterized by dopaminergic cell loss and inflammation in the substantia nigra (SN) leading to motor deficits but also to hippocampus-associated non-motor symptoms such as spatial learning and memory deficits. The cognitive decline is correlated with impaired adult hippocampal neurogenesis resulting from dopamine deficit and inflammation, represented in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) mouse model of PD. In the inflammatory tissue, cyclooxygenase (COX) is upregulated leading to an ongoing inflammatory process such as prostaglandin-mediated increased cytokine levels. Therefore, inhibition of COX by indomethacin may prevent the inflammatory response and the impairment of adult hippocampal neurogenesis. METHODS: Wildtype C57Bl/6 and transgenic Nestin-GFP mice were treated with MPTP followed by short-term or long-term indomethacin treatment. Then, aspects of inflammation and neurogenesis were evaluated by cell counts using immunofluorescence and immunohistochemical stainings in the SN and dentate gyrus (DG). Furthermore, hippocampal mRNA expression of neurogenesis-related genes of the Notch, Wnt, and sonic hedgehog signaling pathways and neurogenic factors were assessed, and protein levels of serum cytokines were measured. RESULTS: Indomethacin restored the reduction of the survival rate of new mature neurons and reduced the amount of amoeboid CD68+ cells in the DG after MPTP treatment. Indomethacin downregulated genes of the Wnt and Notch signaling pathways and increased neuroD6 expression. In the SN, indomethacin reduced the pro-inflammatory cellular response without reversing dopaminergic cell loss. CONCLUSION: Indomethacin has a pro-neurogenic and thereby restorative effect and an anti-inflammatory effect on the cellular level in the DG following MPTP treatment. Therefore, COX inhibitors such as indomethacin may represent a therapeutic option to restore adult neurogenesis in PD.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Neurônios Dopaminérgicos/patologia , Hipocampo/efeitos dos fármacos , Indometacina/uso terapêutico , Intoxicação por MPTP/patologia , Neurogênese/efeitos dos fármacos , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Bromodesoxiuridina/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nestina/genética , Nestina/metabolismo , Neurogênese/fisiologia , Neuropeptídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Tempo
4.
Stroke ; 46(11): 3232-40, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26451017

RESUMO

BACKGROUND AND PURPOSE: Temporary immunosuppression has been identified as a major risk factor for the development of pneumonia after acute central nervous system injury. Although overactivation of the sympathetic nervous system was previously shown to mediate suppression of systemic cellular immune responses after stroke, the role of the parasympathetic cholinergic anti-inflammatory pathway in the antibacterial defense in lung remains largely elusive. METHODS: The middle cerebral artery occlusion model in mice was used to examine the influence of the parasympathetic nervous system on poststroke immunosuppression. We used heart rate variability measurement by telemetry, vagotomy, α7 nicotinic acetylcholine receptor-deficient mice, and parasympathomimetics (nicotine, PNU282987) to measure and modulate parasympathetic activity. RESULTS: Here, we demonstrate a rapidly increased parasympathetic activity in mice after experimental stroke. Inhibition of cholinergic signaling by either vagotomy or by using α7 nicotinic acetylcholine receptor-deficient mice reversed pulmonary immune hyporesponsiveness and prevented pneumonia after stroke. In vivo and ex vivo studies on the role of α7 nicotinic acetylcholine receptor on different lung cells using bone marrow chimeric mice and isolated primary cells indicated that not only macrophages but also alveolar epithelial cells are a major cellular target of cholinergic anti-inflammatory signaling in the lung. CONCLUSIONS: Thus, cholinergic pathways play a pivotal role in the development of pulmonary infections after acute central nervous system injury.


Assuntos
Imunidade Inata/imunologia , Infarto da Artéria Cerebral Média/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Pneumonia/imunologia , Animais , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Líquido da Lavagem Broncoalveolar/microbiologia , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/imunologia , Imunidade Inata/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Macrófagos Alveolares/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Sistema Nervoso Parassimpático/efeitos dos fármacos , Sistema Nervoso Parassimpático/imunologia , Parassimpatomiméticos/farmacologia , Pneumonia/microbiologia , Receptores Nicotínicos/genética , Receptores Nicotínicos/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia , Transdução de Sinais , Acidente Vascular Cerebral/imunologia , Vagotomia
5.
Regen Med ; 10(4): 431-46, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26022763

RESUMO

BACKGROUND: Mesenchymal stem cells (MSC) are easily harvested, and possess anti-inflammatory and trophic properties. Furthermore, MSC promote neuroprotection and neurogenesis, which could greatly benefit neurodegenerative disorders, such as Parkinson's disease. METHODS: MSC were transplanted one week after 6-hydroxydopamine lesioning and effects were evaluated after 6 months. RESULTS: MSC localized around the substantia nigra and the arachnoid mater, expressing pericyte and endothelial markers. MSC protected dopamine levels and upregulated peripheral anti-inflammatory cytokines. Furthermore, adipose-derived MSC increased neurogenesis in hippocampal and subventricular regions, and boosted memory functioning. CONCLUSION: Considering that hyposmia and loss of memory function are two major nonmotor symptoms in Parkinson's disease, transplants with modulatory effects on the hippocampus and subventricular zone could provide a disease-modifying therapy.


Assuntos
Tecido Adiposo/citologia , Anti-Inflamatórios/metabolismo , Cognição , Células-Tronco Mesenquimais/citologia , Atividade Motora , Neurogênese , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Anfetamina , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Hipocampo/patologia , Humanos , Masculino , Aprendizagem em Labirinto , Memória de Curto Prazo , Transplante de Células-Tronco Mesenquimais , Degeneração Neural/patologia , Doença de Parkinson/patologia , Ratos Wistar , Rotação , Substância Negra/patologia , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/metabolismo , Adulto Jovem
6.
Am J Respir Cell Mol Biol ; 51(6): 730-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24960575

RESUMO

Lung diseases, including pneumonia and asthma, are among the most prevalent human disorders, and murine models have been established to investigate their pathobiology and develop novel treatment approaches. Whereas bronchoscopy is valuable for diagnostic and therapeutic procedures in patients, no equivalent for small rodents has been established. Here, we introduce a miniaturized video-bronchoscopy system offering new opportunities in experimental lung research. With an outer diameter of 0.75 mm, it is possible to advance the optics into the main bronchi of mice. An irrigation channel allows bronchoalveolar lavage and unilateral application of substances to one lung. Even a unilateral infection is possible, enabling researchers to use the contralateral lung as internal control.


Assuntos
Broncoscópios , Pulmão/patologia , Animais , Broncoscopia/métodos , Modelos Animais de Doenças , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Fatores Ativadores de Macrófagos/farmacologia , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Infecções por Orthomyxoviridae/diagnóstico , Infecções por Orthomyxoviridae/imunologia , Pneumonia Pneumocócica/diagnóstico , Pneumonia Pneumocócica/imunologia , Streptococcus pneumoniae/imunologia
7.
Sci Transl Med ; 5(177): 177ra36, 2013 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-23515078

RESUMO

There is growing evidence that adaptive immunity contributes to endogenous regeneration processes: For example, endogenous bone fracture repair is modulated by T cells even in the absence of infection. Because delayed or incomplete fracture healing is associated with poor long-term outcomes and high socioeconomic costs, we investigated the relationship between an individual's immune reactivity and healing outcome. Our study revealed that delayed fracture healing significantly correlated with enhanced levels of terminally differentiated CD8(+) effector memory T (TEMRA) cells (CD3(+)CD8(+)CD11a(++)CD28(-)CD57(+) T cells) in peripheral blood. This difference was long lasting, reflecting rather the individual's immune profile in response to lifelong antigen exposure than a post-fracture reaction. Moreover, CD8(+) TEMRA cells were enriched in fracture hematoma; these cells were the major producers of interferon-γ/tumor necrosis factor-α, which inhibit osteogenic differentiation and survival of human mesenchymal stromal cells. Accordingly, depletion of CD8(+) T cells in a mouse osteotomy model resulted in enhanced endogenous fracture regeneration, whereas a transfer of CD8(+) T cells impaired the healing process. Our data demonstrate the high impact of the individual adaptive immune profile on endogenous bone regeneration. Quantification of CD8(+) TEMRA cells represents a potential marker for the prognosis of the healing outcome and opens new opportunities for early and targeted intervention strategies.


Assuntos
Regeneração Óssea/imunologia , Regeneração Óssea/fisiologia , Linfócitos T CD8-Positivos/metabolismo , Adulto , Diferenciação Celular/fisiologia , Feminino , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
8.
PLoS One ; 8(1): e55199, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23383108

RESUMO

The transmembrane envelope protein gp41 of the human immunodeficiency virus HIV-1 plays an important role during infection allowing fusion of the viral and cellular membrane. In addition, there is increasing evidence that gp41 may contribute to the immunodeficiency induced by HIV-1. Recombinant gp41 and a synthetic peptide corresponding to a highly conserved domain in gp41, the immunosuppressive (isu) domain, have been shown to inhibit mitogen-induced activation of human peripheral blood mononuclear cells (PBMCs) and to increase release of IL-6 and IL-10 from these cells. We recently reported that a single mutation in the isu domain of gp41 abrogated the immunosuppressive properties and that HIV-1 sequences containing such abrogating mutations had never been isolated from infected individuals. Here, we studied the influence of the isu peptide on the release of 66 cytokines and the expression of 27,000 genes in PBMCs. Incubation of PBMCs with isu peptide homopolymers increased the expression of 16 cytokines among them IL-6 and IL-10, and decreased that of IL-2 and CXCL9. Interestingly, the extend of cytokine modulation was donor-dependent. Among the genes up-regulated were IL-6, IL-8, IL-10 but also MMP-1, TREM-1 and IL-1beta. Most importantly, genes involved in innate immunity such as FCN1 and SEPP1 were found down-regulated. Many changes in cytokine expression demonstrated in our experiments were also found in HIV-1 infected individuals. These data indicate that the isu domain of gp41 has a broad impact on gene expression and cytokine release and therefore may be involved in HIV-1 induced immunopathogenesis.


Assuntos
Citocinas/metabolismo , Regulação da Expressão Gênica/imunologia , Proteína gp41 do Envelope de HIV/imunologia , Proteína gp41 do Envelope de HIV/metabolismo , HIV-1/genética , Leucócitos Mononucleares/metabolismo , Sequência de Aminoácidos , Ensaio de Imunoadsorção Enzimática , HIV-1/imunologia , Humanos , Análise em Microsséries , Dados de Sequência Molecular , Peptídeos/genética , Polimorfismo de Nucleotídeo Único/genética , Estrutura Terciária de Proteína/genética , Reação em Cadeia da Polimerase em Tempo Real
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