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1.
J Neuroinflammation ; 17(1): 334, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33158438

RESUMO

OBJECTIVE: Air pollution has been recently identified as a risk factor for multiple sclerosis. Aim of this study was to investigate the immunological mechanism underlying the clinical association between air pollution, namely exposure to particulate matter 10 (PM10), and inflammatory activity of multiple sclerosis (MS) METHODS: Daily recording of PM10 was obtained by monitors depending on the residence of subjects. Expression of molecules involved in activation, adhesion, and migration of T lymphocytes were tested by flow cytometry in 57 MS patients and 19 healthy controls. We next assessed in vitro the effect of PM10 on expression of C-C chemokine receptors 6 (CCR6) by peripheral blood mononuclear cells (PBMCs), on cytokine production by monocyte-derived dendritic cells (mdDC), and on T cell polarization in PBMC/mdDC mixed cultures. RESULTS: We identified a significant correlation between mean PM10 levels and expression of CCR6 CD4+ T circulating cells in MS patients. This was paralleled by the observation in vitro of a higher level of CCR6 expression on PBMC following treatment with increased doses of particulate matter. Moreover, in mdDC cultures, particulate matter induced the secretion by mdDC of Th17 polarizing IL1 beta, IL6, and IL23 and, in mdDC/PBMC mixed cultures, enhanced generation of IL17-producing T cells. CONCLUSIONS: Ex vivo and in vitro studies support the pro-inflammatory role of PM in MS, by upregulating expression of CCR6 on circulating CD4+ T cells and inducing in innate immune cells the production of Th17 polarizing cytokines. Therefore, we speculate that in MS respiratory exposure to PM10 may induce the production in the lung of autoreactive Th17 lymphocytes and boost their migratory properties through the blood-brain barrier.


Assuntos
Poluição do Ar/efeitos adversos , Mediadores da Inflamação/sangue , Esclerose Múltipla/sangue , Esclerose Múltipla/induzido quimicamente , Material Particulado/efeitos adversos , Adulto , Células Cultivadas , Feminino , Humanos , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/diagnóstico , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico
2.
Front Neurosci ; 13: 344, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037054

RESUMO

The lack of biomarkers in Amyotrophic Lateral Sclerosis (ALS) makes it difficult to determine the stage of the disease in patients and, therefore, it delays therapeutic trials. Microvesicles (MVs) are possible biomarkers implicated in physiological and pathological functions, however, their role in ALS remains unclear. We investigated whether plasma derived microvesicles could be overrepresented in a group of 40 patients affected by ALS compared to 28 Alzheimer's Disease (AD) patients and 36 healthy volunteers. Leukocyte derived MVs (LMVs) compared to endothelial, platelet, erythrocyte derived MVs, were mostly present in ALS patients compared to AD patients and healthy donors. Correlation analysis corrected for the presence of confounding variables (riluzole, age at onset, site of onset, gender) was tested between PRL (Progression Rate at the Last visit) and LMVs, and a statistically significant value was found (Pearson partial correlation r = 0.407, p = 0.006). We also investigated SOD1, TDP-43 intravesicular protein level in LMVs. Misfolded SOD1 was selectively transported by LMVs and its protein level was associated with the percentage of LMVs in slow progressing patients (r = 0.545, p = 0.033). Our preliminary findings suggest that LMVs are upregulated in ALS patients and they can be considered possible markers of disease progression.

3.
AIDS ; 19(11): 1173-81, 2005 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-15990570

RESUMO

BACKGROUND: The hydroxyurea-didanosine combination has been shown to limit immune activation (a major pathogenic component of HIV/AIDS) and suppress viral load by both antiviral and cytostatic ('virostatic') activities. Virostatics action represent a novel approach to attack HIV/AIDS from multiple directions; however, the use of these drugs is limited by the lack of understanding of their dose-dependent mechanism of action and by fear of pancreatic toxicity, even though a large review of ACTG studies has shown that hydroxyurea does not increase the incidence of pancreatitis. METHODS: In vitro cytostatic and cytotoxic activity, inhibition of viral replication and immune activation by pharmacologically attainable plasma concentrations of hydroxyurea (10-100 micromol/l) and didanosine (1-5 micromol/l) were analyzed by cell proliferation, viability, apoptosis and infection assays using peripheral blood mononuclear cells. In vivo, 600, 900 and 1200 mg daily doses of hydroxyurea in combination with standard doses of didanosine and stavudine were studied in 115 randomized chronically infected patients. RESULTS: A cytostatic low (10 micromol/l) concentration of hydroxyurea inhibited cell proliferation and HIV replication in vitro. A gradual switch from cytostatic to cytotoxic effects was observed by increasing hydroxyurea concentration to 50-100 micromol/l, predicting that lower doses of hydroxyurea would be less toxic and more potent in vivo. The clinical results confirmed that 600 mg hydroxyurea was better tolerated, had fewer side effects and was more potent in suppressing HIV replication than the higher doses. CONCLUSIONS: A bimodal, dose-dependent, cytostatic-cytotoxic switch is an immune-based mechanism explaining the apparent paradox that lowering the dose of hydroxyurea to 600 mg daily induces maximal antiviral suppression in HIV-infected patients.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Didanosina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Hidroxiureia/administração & dosagem , Inibidores da Síntese de Ácido Nucleico/administração & dosagem , Replicação Viral/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Humanos , Hidroxiureia/efeitos adversos , Dose Máxima Tolerável , Inibidores da Síntese de Ácido Nucleico/efeitos adversos , Pancreatopatias/induzido quimicamente , Carga Viral
4.
AIDS ; 19(2): 137-44, 2005 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-15668538

RESUMO

OBJECTIVE: To demonstrate that, despite a dose-dependent cytostatic effect, hydroxyurea (HU) does not have immunosuppressive effects. METHODS: The effects of HU on T lymphocyte proliferation parameters, activation phenotype and cytokine production were examined in vitro after exposure to clinically relevant concentrations of HU (10, 50, and 100 micromol/l). The effects of HU in vivo on CD4 T cell counts, viral load, activation phenotype and virus-specific response were examined in 17 Rhesus macaques infected with SIV(mac251) and randomized into three groups: untreated controls; treated with (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) and didanosine (ddI) only; and treated with PMPA, didanosine, and HU. RESULTS: The in vitro inhibition of T lymphocyte proliferation confirmed the cytostatic effect of HU, with a linear dose-dependent effect; however, no relevant differences were found in the expression of activation markers between treated and untreated controls. Both T helper type 1 and type 2 cytokine production were enhanced by HU. Consistent with the in vitro results, a blunted increase of peripheral CD4 T cells was observed in vivo in the HU group, without relevant effects on the expression of activation markers, and SIV-specific T cell responses were not affected by HU. CONCLUSIONS: Hyper-proliferation of T-lymphocytes is a major factor contributing to HIV pathogenesis. HU exerts a cytostatic effect on T lymphocytes, without altering their activation and apparently without having an immunosuppressive effect. The increase in cytokine production at the single cell level might compensate for the decrease in the percentage of activated CD4 T lymphocytes, without overall impairment of HIV-specific immune responses.


Assuntos
Antineoplásicos/farmacologia , Hidroxiureia/farmacologia , Imunossupressores/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Antígenos CD/imunologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Relação Dose-Resposta a Droga , Humanos , Interferon gama/imunologia , Ativação Linfocitária/efeitos dos fármacos , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia
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