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1.
Int J Mol Sci ; 23(20)2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36293352

RESUMO

Rift Valley fever (RVF) is a zoonotic and emerging disease, caused by the RVF virus (RVFV). In ruminants, it leads to "abortion storms" and enhanced mortality rates in young animals, whereas in humans it can cause symptoms like severe hemorrhagic fever or encephalitis. The role of the innate and adaptive immune response in disease initiation and progression is still poorly defined. The present study used the attenuated RVFV strain clone 13 to investigate viral spread, tissue tropism, and histopathological lesions after intranasal infection in C57BL/6 wild type (WT) and type I interferon (IFN-I) receptor I knockout (IFNAR-/-) mice. In WT mice, 104 PFU RVFV (high dose) resulted in a fatal encephalitis, but no hepatitis 7-11 days post infection (dpi), whereas 103 PFU RVFV (low dose) did not cause clinical disease or significant histopathological lesions in liver and the central nervous system (CNS). In contrast, IFNAR-/- mice infected with 103 PFU RVFV developed hepatocellular necrosis resulting in death at 2-5 dpi and lacked encephalitis. These results show that IFNAR signaling prevents systemic spread of the attenuated RVFV strain clone 13, but not the dissemination to the CNS and subsequent fatal disease. Consequently, neurotropic viruses may be able to evade antiviral IFN-I signaling pathways by using the transneuronal instead of the hematogenous route.


Assuntos
Carcinoma Hepatocelular , Encefalite , Interferon Tipo I , Neoplasias Hepáticas , Vírus da Febre do Vale do Rift , Humanos , Animais , Camundongos , Vírus da Febre do Vale do Rift/genética , Receptor de Interferon alfa e beta/genética , Camundongos Endogâmicos C57BL , Antivirais , Necrose
2.
J Neurosci Res ; 99(10): 2478-2492, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34296786

RESUMO

Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, is typically transmitted upon tick bite and can cause meningitis and encephalitis in humans. In TBEV-infected mice, mitochondrial antiviral-signaling protein (MAVS), the downstream adaptor of retinoic acid-inducible gene-I (RIG-I)-like receptor (RLR) signaling, is needed to induce early type I interferon (IFN) responses and to confer protection. To characterize the brain-resident cell subset that produces protective IFN-ß in TBEV-infected mice, we isolated neurons, astrocytes, and microglia from mice and exposed these cell types to TBEV in vitro. Under such conditions, neurons showed the highest percentage of infected cells, whereas astrocytes and microglia were infected to a lesser extent. In the supernatant (SN) of infected neurons, IFN-ß was not detectable, while infected astrocytes showed high and microglia low IFN-ß expression. Transcriptome analyses of astrocytes implied that MAVS signaling was needed early after TBEV infection. Accordingly, MAVS-deficient astrocytes showed enhanced TBEV infection and significantly reduced early IFN-ß responses. Nevertheless, at later time points, moderate amounts of IFN-ß were detected in the SN of infected MAVS-deficient astrocytes. Transcriptome analyses indicated that MAVS deficiency negatively affected the induction of early anti-viral responses, which resulted in significantly increased TBEV replication. Treatment with MyD88 and TRIF inhibiting peptides reduced only late IFN-ß responses of TBEV-infected WT astrocytes and blocked entirely IFN-ß responses of infected MAVS-deficient astrocytes. Thus, upon TBEV exposure of brain-resident cells, astrocytes are important IFN-ß producers showing biphasic IFN-ß induction that initially depends on MAVS and later on MyD88/TRIF signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Astrócitos/metabolismo , Vírus da Encefalite Transmitidos por Carrapatos/metabolismo , Encefalite Transmitida por Carrapatos/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Animais , Astrócitos/virologia , Encefalite Transmitida por Carrapatos/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais/fisiologia
3.
J Neuroinflammation ; 13(1): 250, 2016 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-27658519

RESUMO

BACKGROUND: Teriflunomide, an inhibitor of dihydroorotate dehydrogenase, is thought to ameliorate multiple sclerosis by reducing activation-induced proliferation of lymphocytes, which is highly dependent on de novo pyrimidine synthesis. Nevertheless, its immunomodulatory effects on resident glial cells in the central nervous system are only poorly understood. METHODS: In this study, we employed physiologically relevant concentrations of teriflunomide and investigated its effects on survival, proliferation, activation, and function of primary rat microglia in vitro. RESULTS: We demonstrate that teriflunomide had no cytotoxic effect on microglia and had only a minor impact on microglial activation. In a concentration- and time-dependent manner, teriflunomide significantly downregulated surface expression of the co-stimulatory molecule CD86. Furthermore, in the highest concentration applied (5 µM), it slightly increased the expression of interleukin-10 in microglia in response to lipopolysaccharide. Treatment with low concentrations of teriflunomide (0.25-1 µM) did not have any impact on the activation or proliferation of microglia. At 5 µM concentration of teriflunomide, we observed a reduction of approximately 30 % in proliferation of microglia in mixed glial cell cultures. CONCLUSIONS: Taken together, our in vitro findings suggest that at higher concentrations, teriflunomide potentially exerts its effects by reducing microglial proliferation and not by modulating the M1-/M2-like cell differentiation of primary rat microglia. Thus, teriflunomide has no major impact on the plasticity of microglia; however, the anti-proliferative and minimal anti-inflammatory effects might be clinically relevant for immune modulation in the treatment of neuroinflammatory CNS diseases such as multiple sclerosis.

4.
Vaccines (Basel) ; 12(1)2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-38276677

RESUMO

Tick-borne encephalitis (TBE) is a serious neurological disease caused by TBE virus (TBEV). Because antiviral treatment options are not available, vaccination is the key prophylactic measure against TBEV infections. Despite the availability of effective vaccines, cases of vaccination breakthrough infections have been reported. The multienzymatic non-structural protein 3 (NS3) of orthoflaviviruses plays an important role in polyprotein processing and virus replication. In the present study, we evaluated NS3 of TBEV as a potential vaccine target for the induction of protective immunity. To this end, a recombinant modified vaccinia virus Ankara that drives the expression of the TBEV NS3 gene (MVA-NS3) was constructed. MVA-NS3 was used to immunize C57BL/6 mice. It induced NS3-specific immune responses, in particular T cell responses, especially against the helicase domain of NS3. However, MVA-NS3-immunized mice were not protected from subsequent challenge infection with a lethal dose of the TBEV strain Neudoerfl, indicating that in contrast to immunity to prME and NS1, NS3-specific immunity is not an independent correlate of protection against TBEV in this mouse model.

5.
Lancet Infect Dis ; 24(11): 1245-1253, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39068957

RESUMO

BACKGROUND: Rift Valley fever virus, a pathogen to ruminants, camelids, and humans, is an emerging mosquito-borne bunyavirus currently endemic to Africa and the Arabian Peninsula. Although animals are primarily infected via mosquito bites, humans mainly become infected following contact with infected tissues or fluids of infected animals. There is an urgent need for adequate countermeasures, especially for humans, because effective therapeutics or vaccines are not yet available. Here we assessed the safety, tolerability, and immunogenicity of a next-generation, four-segmented, live-attenuated vaccine candidate, referred to as hRVFV-4s, in humans. METHODS: A first-in-human, single-centre, randomised, double-blind, placebo-controlled trial was done in Belgium in which a single dose of hRVFV-4s was administered to healthy volunteers aged 18-45 years. Participants were randomly assigned using an interactive web response system. The study population encompassed 75 participants naive to Rift Valley fever virus infection, divided over three dosage groups (cohorts) of 25 participants each. All participants were followed up until 6 months. Using a staggered dose escalating approach, 20 individuals of each cohort were injected in the deltoid muscle of the non-dominant arm with either 104 (low dose), 105 (medium dose), or 106 (high dose) of 50% tissue culture infectious dose of hRVFV-4s as based on animal data, and five individuals per cohort received formulation buffer as a placebo. Primary outcome measures in the intention-to-treat population were adverse events and tolerability. Secondary outcome measures were vaccine-induced viraemia, vaccine virus shedding, Rift Valley fever virus nucleocapsid antibody responses (with ELISA), and neutralising antibody titres. Furthermore, exploratory objectives included the assessment of cellular immune responses by ELISpot. The trial was registered with the EU Clinical Trials Register, 2022-501460-17-00. FINDINGS: Between August and December, 2022, all 75 participants were vaccinated. No serious adverse events or vaccine-related severe adverse events were reported. Pain at the injection site (51 [85%] of 60 participants) was most frequently reported as solicited local adverse event, and headache (28 [47%] of 60) and fatigue (28 [47%] of 60) as solicited systemic adverse events in the active group. No vaccine virus RNA was detected in any of the blood, saliva, urine, or semen samples. Rift Valley fever virus nucleocapsid antibody responses were detected in most participants who were vaccinated with hRVFV-4s (43 [72%] of 60 on day 14) irrespective of the administered dose. In contrast, a clear dose-response relationship was observed for neutralising antibodies on day 28 with four (20%) of 20 participants responding in the low-dose group, 13 (65%) of 20 responding in the medium-dose group, and all participants (20 [100%] of 20) responding in the high-dose group. Consistent with the antibody responses, cellular immune responses against the nucleocapsid protein were detected in all dose groups, whereas a more dose-dependent response was observed for the Gn and Gc surface glycoproteins. Neutralising antibody titres declined over time, whereas nucleocapsid antibody responses remained relatively stable for at least 6 months. INTERPRETATION: The hRVFV-4s vaccine showed a high safety profile and excellent tolerability across all tested dose regimens, eliciting robust immune responses, particularly with the high-dose administration. The findings strongly support further clinical development of this candidate vaccine for human use. FUNDING: The Coalition for Epidemic Preparedness Innovations with support from the EU Horizon 2020 programme.


Assuntos
Anticorpos Antivirais , Febre do Vale de Rift , Vírus da Febre do Vale do Rift , Vacinas Atenuadas , Vacinas Virais , Humanos , Febre do Vale de Rift/prevenção & controle , Febre do Vale de Rift/imunologia , Adulto , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/administração & dosagem , Vírus da Febre do Vale do Rift/imunologia , Masculino , Método Duplo-Cego , Feminino , Adulto Jovem , Anticorpos Antivirais/sangue , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversos , Pessoa de Meia-Idade , Voluntários Saudáveis , Adolescente , Bélgica , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia
6.
Viruses ; 15(4)2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-37112795

RESUMO

Dengue virus serotypes 1 to 4 (DENV1-4) place nearly half the global population at risk of infection and the licenced tetravalent dengue vaccine fails to protect individuals who have not previously been exposed to DENV. The development of intervention strategies had long been hampered by the lack of a suitable small animal model. DENV does not replicate in wild-type mice due to its inability to antagonise the mouse type I interferon (IFN) response. Mice deficient in type I IFN signalling (Ifnar1-/- mice) are highly susceptible to DENV infection, but their immunocompromised status makes it difficult to interpret immune responses elicited by experimental vaccines. To develop an alternative mouse model for vaccine testing, we treated adult wild-type mice with MAR1-5A3-an IFNAR1-blocking, non-cell-depleting antibody-prior to infection with the DENV2 strain D2Y98P. This approach would allow for vaccination of immunocompetent mice and subsequent inhibition of type I IFN signalling prior to challenge infection. While Ifnar1-/- mice quickly succumbed to infection, MAR1-5A3-treated mice did not show any signs of illness but eventually seroconverted. Infectious virus was recovered from the sera and visceral organs of Ifnar1-/- mice, but not from those of mice treated with MAR1-5A3. However, high levels of viral RNA were detected in the samples of MAR1-5A3-treated mice, indicating productive viral replication and dissemination. This transiently immunocompromised mouse model of DENV2 infection will aid the pre-clinical assessment of next-generation vaccines as well as novel antiviral treatments.


Assuntos
Vacinas contra Dengue , Vírus da Dengue , Dengue , Interferon Tipo I , Animais , Camundongos , Vírus da Dengue/genética , Transdução de Sinais , Vacinação , Anticorpos Bloqueadores , Anticorpos Antivirais
7.
Vaccines (Basel) ; 11(4)2023 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-37112626

RESUMO

The four serotypes of dengue virus (DENV1-4) continue to pose a major public health threat. The first licenced dengue vaccine, which expresses the surface proteins of DENV1-4, has performed poorly in immunologically naïve individuals, sensitising them to antibody-enhanced dengue disease. DENV non-structural protein 1 (NS1) can directly induce vascular leakage, the hallmark of severe dengue disease, which is blocked by NS1-specific antibodies, making it an attractive target for vaccine development. However, the intrinsic ability of NS1 to trigger vascular leakage is a potential drawback of its use as a vaccine antigen. Here, we modified DENV2 NS1 by mutating an N-linked glycosylation site associated with NS1-induced endothelial hyperpermeability and used modified vaccinia virus Ankara (MVA) as a vector for its delivery. The resulting construct, rMVA-D2-NS1-N207Q, displayed high genetic stability and drove efficient secretion of NS1-N207Q from infected cells. Secreted NS1-N207Q was composed of dimers and lacked N-linked glycosylation at position 207. Prime-boost immunisation of C57BL/6J mice induced high levels of NS1-specific antibodies binding various conformations of NS1 and elicited NS1-specific CD4+ T-cell responses. Our findings support rMVA-D2-NS1-N207Q as a promising and potentially safer alternative to existing NS1-based vaccine candidates, warranting further pre-clinical testing in a relevant mouse model of DENV infection.

8.
Pathogens ; 12(9)2023 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-37764982

RESUMO

Rift Valley Fever Virus is a mosquito-borne phlebovirus causing febrile or haemorrhagic illness in ruminants and humans. The virus can prevent the induction of the antiviral interferon response through its NSs proteins. Mutations in the NSs gene may allow the induction of innate proinflammatory immune responses and lead to attenuation of the virus. Upon infection, virus-specific antibodies and T cells are induced that may afford protection against subsequent infections. Thus, all arms of the adaptive immune system contribute to prevention of disease progression. These findings will aid the design of vaccines using the currently available platforms. Vaccine candidates have shown promise in safety and efficacy trials in susceptible animal species and these may contribute to the control of RVFV infections and prevention of disease progression in humans and ruminants.

9.
Front Immunol ; 14: 1134371, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36926332

RESUMO

Introduction: Naturally attenuated Langat virus (LGTV) and highly pathogenic tick-borne encephalitis virus (TBEV) share antigenically similar viral proteins and are grouped together in the same flavivirus serocomplex. In the early 1970s, this has encouraged the usage of LGTV as a potential live attenuated vaccine against tick-borne encephalitis (TBE) until cases of encephalitis were reported among vaccinees. Previously, we have shown in a mouse model that immunity induced against LGTV protects mice against lethal TBEV challenge infection. However, the immune correlates of this protection have not been studied. Methods: We used the strategy of adoptive transfer of either serum or T cells from LGTV infected mice into naïve recipient mice and challenged them with lethal dose of TBEV. Results: We show that mouse infection with LGTV induced both cross-reactive antibodies and T cells against TBEV. To identify correlates of protection, Monitoring the disease progression in these mice for 16 days post infection, showed that serum from LGTV infected mice efficiently protected from developing severe disease. On the other hand, adoptive transfer of T cells from LGTV infected mice failed to provide protection. Histopathological investigation of infected brains suggested a possible role of microglia and T cells in inflammatory processes within the brain. Discussion: Our data provide key information regarding the immune correlates of protection induced by LGTV infection of mice which may help design better vaccines against TBEV.


Assuntos
Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Infecções por Flavivirus , Camundongos , Animais , Anticorpos , Encéfalo , Vacinas Atenuadas
10.
J Virol Methods ; 317: 114733, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37068591

RESUMO

ß-Propiolactone (BPL) is an organic compound widely used as an inactivating agent in vaccine development and production, for example for SARS-CoV, SARS-CoV-2 and Influenza viruses. Inactivation of pathogens by BPL is based on an irreversible alkylation of nucleic acids but also on acetylation and cross-linking between proteins, DNA or RNA. However, the protocols for BPL inactivation of viruses vary widely. Handling of infectious, enriched SARS-CoV-2 specimens and diagnostic samples from COVID-19 patients is recommended in biosafety level (BSL)- 3 or BSL-2 laboratories, respectively. We validated BPL inactivation of SARS-CoV-2 in saliva samples with the objective to use saliva from COVID-19 patients for training of scent dogs for the detection of SARS-CoV-2 positive individuals. Therefore, saliva samples and cell culture medium buffered with NaHCO3 (pH 8.3) were comparatively spiked with SARS-CoV-2 and inactivated with 0.1 % BPL for 1 h (h) or 71 h ( ± 1 h) at 2-8 °C, followed by hydrolysis of BPL at 37 °C for 1 or 2 h, converting BPL into non-toxic beta-hydroxy-propionic acid. SARS-CoV-2 inactivation was demonstrated by a titre reduction of up to 10^4 TCID50/ml in the spiked samples for both inactivation periods using virus titration and virus isolation, respectively. The validated method was confirmed by successful inactivation of pathogens in saliva samples from COVID-19 patients. Furthermore, we reviewed the currently available literature on SARS-CoV-2 inactivation by BPL. Accordingly, BPL-inactivated, hydrolysed samples can be handled in a non-laboratory setting. Furthermore, our BPL inactivation protocols can be adapted to validation experiments with other pathogens.


Assuntos
COVID-19 , Vírus , Cães , Animais , Propiolactona , Saliva , Odorantes , COVID-19/diagnóstico , Inativação de Vírus , SARS-CoV-2
11.
Front Immunol ; 14: 1177324, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37483628

RESUMO

Introduction: Tick-borne encephalitis virus (TBEV) is one of the most relevant tick-transmitted neurotropic arboviruses in Europe and Asia and the causative agent of tick-borne encephalitis (TBE). Annually more than 10,000 TBE cases are reported despite having vaccines available. In Europe, the vaccines FSME-IMMUN® and Encepur® based on formaldehyde-inactivated whole viruses are licensed. However, demanding vaccination schedules contribute to sub-optimal vaccination uptake and breakthrough infections have been reported repeatedly. Due to its immunogenic properties as well as its role in viral replication and disease pathogenesis, the non-structural protein 1 (NS1) of flaviviruses has become of interest for non-virion based flavivirus vaccine candidates in recent years. Methods: Therefore, immunogenicity and protective efficacy of TBEV NS1 expressed by neuraminidase (NA)-deficient Influenza A virus (IAV) or Modified Vaccinia virus Ankara (MVA) vectors were investigated in this study. Results: With these recombinant viral vectors TBEV NS1-specific antibody and T cell responses were induced. Upon heterologous prime/boost regimens partial protection against lethal TBEV challenge infection was afforded in mice. Discussion: This supports the inclusion of NS1 as a vaccine component in next generation TBEV vaccines.


Assuntos
Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Vacinas contra Influenza , Influenza Humana , Orthomyxoviridae , Animais , Camundongos , Humanos , Vaccinia virus , Anticorpos Antivirais , Influenza Humana/prevenção & controle , Imunidade Celular
12.
Front Immunol ; 14: 1182963, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37153588

RESUMO

Introduction: Tick-borne encephalitis virus (TBEV) is an important human pathogen that can cause a serious disease involving the central nervous system (tick-borne encephalitis, TBE). Although approved inactivated vaccines are available, the number of TBE cases is rising, and breakthrough infections in fully vaccinated subjects have been reported in recent years. Methods: In the present study, we generated and characterized a recombinant Modified Vaccinia virus Ankara (MVA) for the delivery of the pre-membrane (prM) and envelope (E) proteins of TBEV (MVA-prME). Results: MVA-prME was tested in mice in comparison with a licensed vaccine FSME-IMMUN® and proved to be highly immunogenic and afforded full protection against challenge infection with TBEV. Discussion: Our data indicate that MVA-prME holds promise as an improved next-generation vaccine for the prevention of TBE.


Assuntos
Vírus da Encefalite Transmitidos por Carrapatos , Vacinas Virais , Humanos , Animais , Camundongos , Vírus da Encefalite Transmitidos por Carrapatos/genética , Anticorpos Neutralizantes , Anticorpos Antivirais , Vaccinia virus/genética
13.
Vaccines (Basel) ; 9(3)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652698

RESUMO

Tick-borne encephalitis virus (TBEV) is a leading cause of vector-borne viral encephalitis with expanding endemic regions across Europe. In this study we tested in mice the efficacy of preinfection with a closely related low-virulent flavivirus, Langat virus (LGTV strain TP21), or a naturally avirulent TBEV strain (TBEV-280) in providing protection against lethal infection with the highly virulent TBEV strain (referred to as TBEV-Hypr). We show that prior infection with TP21 or TBEV-280 is efficient in protecting mice from lethal TBEV-Hypr challenge. Histopathological analysis of brains from nonimmunized mice revealed neuronal TBEV infection and necrosis. Neuroinflammation, gliosis, and neuronal necrosis was however also observed in some of the TP21 and TBEV-280 preinfected mice although at reduced frequency as compared to the nonimmunized TBEV-Hypr infected mice. qPCR detected the presence of viral RNA in the CNS of both TP21 and TBEV-280 immunized mice after TBEV-Hypr challenge, but significantly reduced compared to mock-immunized mice. Our results indicate that although TBEV-Hypr infection is effectively controlled in the periphery upon immunization with low-virulent LGTV or naturally avirulent TBEV 280, it may still enter the CNS of these animals. These findings contribute to our understanding of causes for vaccine failure in individuals vaccinated with TBE vaccines.

14.
Mol Med Rep ; 12(4): 6171-7, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26239526

RESUMO

FTY720 is a new oral immunomodulatory therapy for the treatment of multiple sclerosis (MS). There is strong evidence that FTY720 has direct effects on brain resident cells such as astrocytes acting via sphingosine­1­phosphate (S1P) receptors. In the present study, the mRNA expression of S1P receptors as well as selected cytokines, chemokines and growth factors were investigated in primary murine astrocytes under inflammatory conditions in the presence or absence of the phosphorylated form of FTY720 (FTY720­P). Following stimulation with either the pro­inflammatory cytokine tumor necrosis factor­α (TNF­α) or with bacterial lipopolysaccharide, there was an increased expression of the receptors S1P1 and S1P3, the cytokines and chemokines interleukin (IL)­1ß, chemokine (C­C­motif) ligand 2 (CCL­2), CCL­20 and chemokine (C­X­C­motif) ligand 12 as well as the growth factors insulin­like growth factor­1, ciliary neurotrophic factor and glial cell line­derived neurotrophic factor (GDNF). FTY720­P led to an increased expression of IL­1ß and GDNF at distinct time points following co­stimulation with TNF­α compared with TNF­α treatment alone. However, the presence of FTY720­P did not have any further significant effects on the expression of S1P receptors, cytokines or growth factors, suggesting that the regulation of these target genes in astrocytes is not likely to be a major mechanism underlying the effect of FTY720­P in diseases such as MS.


Assuntos
Astrócitos/efeitos dos fármacos , Inflamação/metabolismo , Organofosfatos/farmacologia , Esfingosina/análogos & derivados , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CCL20/genética , Quimiocina CCL20/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Inflamação/patologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
15.
PLoS One ; 8(7): e69795, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23922802

RESUMO

For the treatment of patients with multiple sclerosis there are no regenerative approaches to enhance remyelination. Mesenchymal stem cells (MSC) have been proposed to exert such regenerative functions. Intravenous administration of human MSC reduced the clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model mimicking some aspects of multiple sclerosis. However, it is not clear if this effect was achieved by systemic immunomodulation or if there is an active neuroregeneration in the central nervous system (CNS). In order to investigate remyelination and regeneration in the CNS we analysed the effects of intravenously and intranasally applied murine and human bone marrow-derived MSC on cuprizone induced demyelination, a toxic animal model which allows analysis of remyelination without the influence of the peripheral immune system. In contrast to EAE no effects of MSC on de- and remyelination and glial cell reactions were found. In addition, neither murine nor human MSC entered the lesions in the CNS in this toxic model. In conclusion, MSC are not directed into CNS lesions in the cuprizone model where the blood-brain-barrier is intact and thus cannot provide support for regenerative processes.


Assuntos
Células da Medula Óssea/citologia , Doenças Desmielinizantes/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Animais , Contagem de Células , Rastreamento de Células , Quimiocinas/genética , Quimiocinas/metabolismo , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Cuprizona , Citoproteção , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/patologia , Comportamento Alimentar , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Imuno-Histoquímica , Integrina alfa4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Compostos Orgânicos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
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