Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 55
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Neuroinflammation ; 16(1): 167, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31416452

RESUMO

BACKGROUND: Although effective in reducing relapse rate and delaying progression, current therapies for multiple sclerosis (MS) do not completely halt disease progression. T cell autoimmunity to myelin antigens is considered one of the main mechanisms driving MS. It is characterized by autoreactivity to disease-initiating myelin antigen epitope(s), followed by a cascade of epitope spreading, which are both strongly patient-dependent. Targeting a variety of MS-associated antigens by myelin antigen-presenting tolerogenic dendritic cells (tolDC) is a promising treatment strategy to re-establish tolerance in MS. Electroporation with mRNA encoding myelin proteins is an innovative technique to load tolDC with the full spectrum of naturally processed myelin-derived epitopes. METHODS: In this study, we generated murine tolDC presenting myelin oligodendrocyte glycoprotein (MOG) using mRNA electroporation and we assessed the efficacy of MOG mRNA-electroporated tolDC to dampen pathogenic T cell responses in experimental autoimmune encephalomyelitis (EAE). For this, MOG35-55-immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α,25-dihydroxyvitamin D3-treated tolDC electroporated with MOG-encoding mRNA. Mice were scored daily for signs of paralysis. At day 25, myelin reactivity was evaluated following restimulation of splenocytes with myelin-derived epitopes. Ex vivo magnetic resonance imaging (MRI) was performed to assess spinal cord inflammatory lesion load. RESULTS: Treatment of MOG35-55-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG35-55-pulsed tolDC led to a stabilization of the EAE clinical score from the first administration onwards, whereas it worsened in mice treated with non-antigen-loaded tolDC or with vehicle only. In addition, MOG35-55-specific pro-inflammatory pathogenic T cell responses and myelin antigen epitope spreading were inhibited in the peripheral immune system of tolDC-treated mice. Finally, magnetic resonance imaging analysis of hyperintense spots along the spinal cord was in line with the clinical score. CONCLUSIONS: Electroporation with mRNA is an efficient and versatile tool to generate myelin-presenting tolDC that are capable to stabilize the clinical score in EAE. These results pave the way for further research into mRNA-electroporated tolDC treatment as a patient-tailored therapy for MS.


Assuntos
Células Dendríticas/metabolismo , Eletroporação/métodos , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/terapia , Glicoproteína Mielina-Oligodendrócito/metabolismo , RNA Mensageiro/metabolismo , Animais , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Tolerância Imunológica/fisiologia , Células K562 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , RNA Mensageiro/administração & dosagem , RNA Mensageiro/imunologia
2.
J Vis Exp ; (145)2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30985749

RESUMO

The neurovascular unit (NVU) is composed of microvascular endothelial cells forming the blood-brain barrier (BBB), an endothelial basement membrane with embedded pericytes, and the glia limitans composed by the parenchymal basement membrane and astrocytic end-feed embracing the abluminal aspect of central nervous system (CNS) microvessels. In addition to maintaining CNS homeostasis the NVU controls immune cell trafficking into the CNS. During immunosurveillance of the CNS low numbers of activated lymphocytes can cross the endothelial barrier without causing BBB dysfunction or clinical disease. In contrast, during neuroinflammation such as in multiple sclerosis or its animal model experimental autoimmune encephalomyelitis (EAE) a large number of immune cells can cross the BBB and subsequently the glia limitans eventually reaching the CNS parenchyma leading to clinical disease. Immune cell migration into the CNS parenchyma is thus a two-step process that involves a sequential migration across the endothelial and glial barrier of the NVU employing distinct molecular mechanisms. If following their passage across the endothelial barrier, T cells encounter their cognate antigen on perivascular antigen-presenting cells their local reactivation will initiate subsequent mechanisms leading to the focal activation of gelatinases, which will enable the T cells to cross the glial barrier and enter the CNS parenchyma. Thus, assessing both, BBB permeability and MMP activity in spatial correlation to immune cell accumulation in the CNS during EAE allows to specify loss of integrity of the endothelial and glial barriers of the NVU. We here show how to induce EAE in C57BL/6 mice by active immunization and how to subsequently analyze BBB permeability in vivo using a combination of exogenous fluorescent tracers. We further show, how to visualize and localize gelatinase activity in EAE brains by in situ zymogaphy coupled to immunofluorescent stainings of BBB basement membranes and CD45+ invading immune cells.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Permeabilidade da Membrana Celular , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/patologia , Células Endoteliais/patologia , Neuroglia/patologia , Animais , Transporte Biológico , Movimento Celular/fisiologia , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/metabolismo , Células Endoteliais/metabolismo , Feminino , Adjuvante de Freund , Imunização , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Neuroglia/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Gravação em Vídeo
3.
Nat Immunol ; 20(2): 195-205, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643267

RESUMO

The developmental programs that generate a broad repertoire of regulatory T cells (Treg cells) able to respond to both self antigens and non-self antigens remain unclear. Here we found that mature Treg cells were generated through two distinct developmental programs involving CD25+ Treg cell progenitors (CD25+ TregP cells) and Foxp3lo Treg cell progenitors (Foxp3lo TregP cells). CD25+ TregP cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3lo TregP cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3lo TregP cells. The development of both CD25+ TregP cells and Foxp3lo TregP cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25+ TregP cells and Foxp3lo TregP cells arose by coopting negative-selection programs and positive-selection programs, respectively. Treg cells derived from CD25+ TregP cells, but not those derived from Foxp3lo TregP cells, prevented experimental autoimmune encephalitis. Our findings indicate that Treg cells arise through two distinct developmental programs that are both required for a comprehensive Treg cell repertoire capable of establishing immunotolerance.


Assuntos
Diferenciação Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , Células Progenitoras Linfoides/fisiologia , Linfócitos T Reguladores/fisiologia , Timo/crescimento & desenvolvimento , Animais , Autoantígenos/imunologia , Colite/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Tolerância Imunológica/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Células Progenitoras Linfoides/transplante , Camundongos , Camundongos Transgênicos , Mycobacterium tuberculosis/imunologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Transdução de Sinais , Organismos Livres de Patógenos Específicos , Timo/citologia , Timo/imunologia
4.
Nat Commun ; 10(1): 229, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651548

RESUMO

There are no conventional lymphatic vessels within the CNS parenchyma, although it has been hypothesized that lymphatics near the cribriform plate or dura maintain fluid homeostasis and immune surveillance during steady-state conditions. However, the role of these lymphatic vessels during neuroinflammation is not well understood. We report that lymphatic vessels near the cribriform plate undergo lymphangiogenesis in a VEGFC - VEGFR3 dependent manner during experimental autoimmune encephalomyelitis (EAE) and drain both CSF and cells that were once in the CNS parenchyma. Lymphangiogenesis also contributes to the drainage of CNS derived antigens that leads to antigen specific T cell proliferation in the draining lymph nodes during EAE. In contrast, meningeal lymphatics do not undergo lymphangiogenesis during EAE, suggesting heterogeneity in CNS lymphatics. We conclude that increased lymphangiogenesis near the cribriform plate can contribute to the management of neuroinflammation-induced fluid accumulation and immune surveillance.


Assuntos
Encéfalo/imunologia , Encefalomielite Autoimune Experimental/imunologia , Linfangiogênese/imunologia , Vasos Linfáticos/imunologia , Linfócitos T/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos/imunologia , Antígenos/metabolismo , Encéfalo/diagnóstico por imagem , Proliferação de Células , Líquido Cefalorraquidiano/imunologia , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Osso Etmoide , Azul Evans/administração & dosagem , Feminino , Humanos , Vigilância Imunológica/imunologia , Vasos Linfáticos/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Toxina Pertussis/administração & dosagem , Toxina Pertussis/imunologia , Fator C de Crescimento do Endotélio Vascular/imunologia , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/imunologia , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
Cell Death Dis ; 9(11): 1130, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30425241

RESUMO

The aryl hydrocarbon receptor (AHR) is a transcription factor activated by ligand highly expressed on TH17 cells, and AHR-deficient CD4+ T cells have impaired production of IL-17A and IL-22. Although AHR activation can exacerbate in vivo TH17 cell-mediated autoimmunity, accumulating data indicate that AHR is a nonpathogenic TH17 marker. Thus it remains unclear how AHR activation is regulated and impacts on the generation of TH17 subsets. Here we demonstrated that AHR pathway is activated during in vitro pathogenic TH17 polarization, but it is quickly downregulated. Under these conditions, additional AHR activation promoted IL-22 but not IL-17A. Interestingly, AHR high sustained expression and IL-17A promotion were only achieved when TGFß1 was present in the culture. In addition to the effect on AHR regulation, TGFß1 presented a dual role by simultaneously suppressing the TH17 pathogenic phenotype acquisition. This latter effect was independent of AHR stimulation, since its activation did not confer a TH17 anti-inflammatory profile and Ahr-/- cells did not upregulate any TH17 pathogenic marker. Through the use of EAE model, we demonstrated that AHR is still functional in encephalitogenic CD4+ T cells and the adoptive transfer of Ahr-/- TH17 cells to recipient mice resulted in milder EAE development when compared to their WT counterparts. Altogether, our data demonstrated that although AHR is highly expressed on in vitro-generated nonpathogenic TH17 cells, its ligation does not shift TH17 cells to an anti-inflammatory phenotype. Further studies investigating the role of AHR beyond TH17 differentiation may provide a useful understanding of the physiopathology of autoimmune diseases.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Transdução de Sinais/imunologia , Células Th17/imunologia , Fator de Crescimento Transformador beta1/farmacologia , Transferência Adotiva , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica , Humanos , Imunofenotipagem , Interleucina-17/genética , Interleucina-17/imunologia , Interleucinas/genética , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Fenótipo , Cultura Primária de Células , Receptores de Hidrocarboneto Arílico/deficiência , Receptores de Hidrocarboneto Arílico/genética , Células Th17/efeitos dos fármacos , Células Th17/patologia , Células Th17/transplante
6.
ACS Nano ; 12(11): 11579-11590, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30265798

RESUMO

While there has been extensive development of soluble epitope-specific peptides to induce immune tolerance for the treatment of autoimmune diseases, the clinical efficacy of soluble-peptides-based immunotherapy was still uncertain. Recent strategies to develop antigen carriers coupled with peptides have shown promising results in preclinical animal models. Here we developed functional amphiphilic hyperbranched (HB) polymers with different grafting degrees of hydrophobic chains as antigen myelin antigen oligodendrocyte glycoprotein (MOG) peptide carriers and evaluated their ability to induce immune tolerance. We show that these polymers could efficiently deliver antigen peptide, and the uptake amount by bone marrow dendritic cells (BMDCs) was correlated with the hydrophobicity of polymers. We observe that these polymers have a higher ability to activate BMDCs and a higher efficacy to induce antigen-specific T cell apoptosis than soluble peptides, irrespective of hydrophobicity. We show that intravenous injection of polymer-conjugated MOG peptide, but not soluble peptide, markedly treats the clinical symptoms of experimental autoimmune encephalomyelitis in mice. Together, these results demonstrate the potential for using amphiphilic HB polymers as antigen carriers to deliver peptides for pathogenic autoreactive T cell deletion/tolerance strategies to treat autoimmune disorders.


Assuntos
Membrana Celular/química , Sistemas de Liberação de Medicamentos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/uso terapêutico , Polímeros/química , Animais , Apoptose/efeitos dos fármacos , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/química , Glicoproteína Mielina-Oligodendrócito/imunologia , Linfócitos T/efeitos dos fármacos
7.
J Autoimmun ; 94: 110-121, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30061013

RESUMO

NF-κB inducing kinase (NIK) is the key protein of the non-canonical NF-κB pathway and is important for the development of lymph nodes and other secondary immune organs. We elucidated the specific role of NIK in T cells using T-cell specific NIK-deficient (NIKΔT) mice. Despite showing normal development of lymphoid organs, NIKΔT mice were resistant to induction of CNS autoimmunity. T cells from NIKΔT mice were deficient in late priming, failed to up-regulate T-bet and to transmigrate into the CNS. Proteomic analysis of activated NIK-/- T cells showed de-regulated expression of proteins involved in the formation of the immunological synapse: in particular, proteins involved in cytoskeleton dynamics. In line with this we found that NIK-deficient T cells were hampered in phosphorylation of Zap70, LAT, AKT, ERK1/2 and PLCγ upon TCR engagement. Hence, our data disclose a hitherto unknown function of NIK in T-cell priming and differentiation.


Assuntos
Actinas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Ativação Linfocitária , Proteínas Serina-Treonina Quinases/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Actinas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Linfonodos/imunologia , Linfonodos/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Fosfolipase C gama/genética , Fosfolipase C gama/imunologia , Fosfoproteínas/genética , Fosfoproteínas/imunologia , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais , Baço/imunologia , Baço/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Linfócitos T/patologia , Proteína-Tirosina Quinase ZAP-70/genética , Proteína-Tirosina Quinase ZAP-70/imunologia
8.
Sci China Life Sci ; 61(6): 675-687, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29931449

RESUMO

GPR54 is highly expressed in the central nervous system and plays a crucial role in pubertal development. However, GRP54 is also expressed in the immune system, implying possible immunoregulatory functions. Here we investigated the role of GPR54 in T cell and immune tolerance. GPR54 deficiency led to an enlarged thymus, an increased number of thymocytes, and altered thymic micro-architecture starting around puberty, indicating GPR54 function in T-cell development through its regulatory effect on the gonadal system. However, flow cytometry revealed a significant reduction in the peripheral regulatory T cell population and a moderate decrease in CD4 single-positive thymocytes in prepubertal Gpr54-/- mice. These phenotypes were confirmed in chimeric mice with GPR54 deficient bone marrow-derived cells. In addition, we found elevated T cell activation in peripheral and thymic T cells in Gpr54-/- mice. When intact mice were immunized with myelin oligodendrocyte glycoprotein, a more severe experimental autoimmune encephalomyelitis (EAE) developed in the Gpr54-/- mice. Interestingly, aggravated EAE disease was also manifested in castrated and bone marrow chimeric Gpr54-/- mice compared to the respective wild-type control, suggesting a defect in self-tolerance resulting from GPR54 deletion through a mechanism that bypassed sex hormones. These findings demonstrate a novel role for GPR54 in regulating self-tolerant immunity in a sex hormone independent manner.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Receptores de Kisspeptina-1/deficiência , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Feminino , Expressão Gênica , Tolerância Imunológica/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/toxicidade , Receptores de Kisspeptina-1/genética , Receptores de Kisspeptina-1/fisiologia , Baço/imunologia , Timo/imunologia
9.
Front Immunol ; 9: 836, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29770132

RESUMO

gp130 cytokines are differentially involved in regulating the T helper (H) 17-driven pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model of human multiple sclerosis. Interleukin (IL)-6 directly promotes the development of TH17 cells through the gp130/IL-6R complex. By contrast, IL-27 has been shown to suppress a TH17 immune response by gp130/IL-27R-alpha (α) receptor ligation. The IL-27-dependent regulation of a TH17 development could be mediated on the level of CD4 T cells. However, because IL-27 also suppresses the secretion of the TH17-driving cytokines IL-6 and IL-12/23p40 in accessory cells, TH17 immune responses may also be controlled by IL-27 on the level of macrophages and/or neutrophils. To analyze these opposing effects of gp130 engagement on the pathogenesis of EAE, we immunized CD4+ T cell-specific gp130-deficient (CD4creposgp130loxP/loxP) and macrophage/neutrophil-specific gp130-deficient (LysMcreposgp130loxP/loxP) mice with the myelin-oligodendrocyte-glycoprotein peptide MOG35-55. Whereas inflammatory immune responses, TH17 differentiation, and pathology in CD4creposgp130loxP/loxP mice were mitigated, disease progression was eventually enhanced in LysMcreposgp130loxP/loxP mice. Exacerbated disease in MOG35-55-immunized LysMcreposgp130loxP/loxP mice was associated with an elevated development of TH17 cells and increased infiltration of the central nervous system with leukocytes indicating a suppressive role of macrophage/neutrophil-gp130. To further prove IL-6 to be responsible for the control of inflammation during EAE through gp130 on macrophages/neutrophils, we immunized LysMcreposIL-6RloxP/loxP mice. In contrast to LysMcreposgp130loxP/loxP mice, neuropathology in MOG35-55-immunized macrophage/neutrophil-specific IL-6R-deficient mice was not enhanced indicating that the alleviation of EAE through macrophage/neutrophil-gp130 is mediated independently of IL-6. Together, this different pathology in macrophage/neutrophil- and CD4 T cell-specific gp130-deficient mice suggests that gp130 cytokines modulate TH17 inflammation differentially by targeting distinct cell types.


Assuntos
Receptor gp130 de Citocina/genética , Encefalomielite Autoimune Experimental/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular , Sistema Nervoso Central/imunologia , Receptor gp130 de Citocina/deficiência , Citocinas/imunologia , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/patologia , Inflamação , Camundongos , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Células Th1/imunologia
10.
J Pharm Sci ; 107(8): 2048-2054, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29649469

RESUMO

Phosphatidylserine (PS) exposure during apoptosis leads to silent clearance of cells without adverse immune reactions to self-proteins. Given the biological functions of PS in cellular cleanup and global immunosuppression, we hypothesized that administration of PS-protein complexes would reduce immunogenicity. Here, we report that exposing Pompe disease mice to acid alpha glucosidase (rhGAA) with PS or immunosuppressant dexamethasone resulted in lower anti-rhGAA antibodies than in animals receiving rhGAA alone. However, upon rechallenge with rhGAA, only PS-rhGAA pre-exposed mice displayed a durable hyporesponsiveness even after PS administration was ceased. Thus, pre-exposure of antigens administered together with PS were not silently cleared, but the immune system acquired memory about the antigen that averted mounting of a response during rechallenge. In hemophilia A mice, PS hyporesponsiveness toward Factor VIII was reversed by administration of function-blocking antibody against the PS receptor T-cell immunoglobulin and mucin 4, implicating this receptor in PS's effect. Moreover, pre-exposure of myelin oligodendrocyte glycoprotein peptide with PS delayed the onset and reduced the severity of experimental autoimmune encephalomyelitis. These observations suggest that PS's function in apoptosis is not limited to silent antigen clearance without immune responses toward self-proteins but shows that PS reduces immune response during rechallenge to several antigens that also involves initiation of antigen tolerance.


Assuntos
Dexametasona/imunologia , Doença de Depósito de Glicogênio Tipo II/imunologia , Imunossupressores/imunologia , Fosfatidilserinas/imunologia , alfa-Glucosidases/imunologia , Animais , Formação de Anticorpos , Apoptose , Dexametasona/administração & dosagem , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Fator VIII/administração & dosagem , Fator VIII/imunologia , Feminino , Hemofilia A/imunologia , Humanos , Tolerância Imunológica , Imunossupressores/administração & dosagem , Lipossomos/administração & dosagem , Lipossomos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Fosfatidilserinas/administração & dosagem , alfa-Glucosidases/administração & dosagem
11.
J Hand Surg Am ; 43(9): 873.e1-873.e4, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29526530

RESUMO

Accidental needlestick injuries are common in laboratory and health care workers. Injection of atypical pathogens, such as those encountered in the animal laboratory setting, may pose considerable problems at the site of inoculation. We present the case of an otherwise healthy laboratory worker who accidentally self-injected Freund complete adjuvant with heat-killed Mycobacterium tuberculosis into her hand, requiring multiple debridement operations over a prolonged treatment course.


Assuntos
Adjuvante de Freund/administração & dosagem , Traumatismos da Mão/terapia , Mycobacterium tuberculosis , Ferimentos Penetrantes Produzidos por Agulha/terapia , Acidentes de Trabalho , Adulto , Desbridamento , Feminino , Adjuvante de Freund/efeitos adversos , Glucocorticoides/uso terapêutico , Granuloma/etiologia , Granuloma/cirurgia , Humanos , Pessoal de Laboratório , Metilprednisolona/uso terapêutico , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/efeitos adversos , Ferimentos Penetrantes Produzidos por Agulha/complicações , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/efeitos adversos , Triancinolona Acetonida/uso terapêutico
12.
Mol Med Rep ; 17(3): 4163-4172, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29328415

RESUMO

The endogenous neurotransmitter, noradrenaline, exerts anti-inflammatory and neuroprotective effects in vivo and in vitro. Reduced noradrenaline levels results in increased inflammation and neuronal damage. The primary source of noradrenaline in the central nervous system is tyrosine hydroxylase (TH)­positive neurons, located in the locus coeruleus (LC). TH is the rate­limiting enzyme for noradrenaline synthesis; therefore, regulation of TH protein expression and intrinsic enzyme activity represents the central means for controlling the synthesis of noradrenaline. Catalpol is an iridoid glycoside purified from Rehmannia glutinosa Libosch, which exerts a neuroprotective effect in multiple sclerosis (MS). The present study used an experimental mouse model of autoimmune encephalomyelitis to verify the neuroprotective effects of catalpol. Significant improvements in the clinical scores were observed in catalpol­treated mice. Furthermore, catalpol increased TH expression and increased noradrenaline levels in the spinal cord. In primary cultures, catalpol exerted a neuroprotective effect in rat LC neurons by increasing the noradrenaline output. These results suggested that drugs targeting LC survival and function, including catalpol, may be able to benefit patients with MS.


Assuntos
Anti-Inflamatórios/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Glucosídeos Iridoides/farmacologia , Locus Cerúleo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Norepinefrina/biossíntese , Amidinas/antagonistas & inibidores , Amidinas/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Benzilaminas/administração & dosagem , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Feminino , Regulação da Expressão Gênica , Imunização , Injeções Intraperitoneais , Glucosídeos Iridoides/isolamento & purificação , Locus Cerúleo/imunologia , Locus Cerúleo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Neurônios/imunologia , Neurônios/patologia , Fármacos Neuroprotetores/isolamento & purificação , Neurotransmissores/agonistas , Neurotransmissores/biossíntese , Norepinefrina/agonistas , Oxidantes/antagonistas & inibidores , Oxidantes/farmacologia , Fragmentos de Peptídeos/administração & dosagem , Cultura Primária de Células , Rehmannia/química , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/imunologia
13.
J Immunol ; 200(3): 966-973, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29288202

RESUMO

GM-CSF has been portrayed as a critical cytokine in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and, ostensibly, in multiple sclerosis. C57BL/6 mice deficient in GM-CSF are resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG)35-55 The mechanism of action of GM-CSF in EAE is poorly understood. In this study, we show that GM-CSF augments the accumulation of MOG35-55-specific T cells in the skin draining lymph nodes of primed mice, but it is not required for the development of encephalitogenic T cells. Abrogation of GM-CSF receptor signaling in adoptive transfer recipients of MOG35-55-specific T cells did not alter the incidence of EAE or the trajectory of its initial clinical course, but it limited the extent of chronic CNS tissue damage and neurologic disability. The attenuated clinical course was associated with a relative dearth of MOG35-55-specific T cells, myeloid dendritic cells, and neutrophils, as well as an abundance of B cells, within CNS infiltrates. Our data indicate that GM-CSF drives chronic tissue damage and disability in EAE via pleiotropic pathways, but it is dispensable during early lesion formation and the onset of neurologic deficits.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Sistema Nervoso Central/citologia , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/patologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Transferência Adotiva , Animais , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/transplante , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Pulmão/patologia , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Neutrófilos/imunologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo
14.
Cell Rep ; 21(1): 195-207, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-28978473

RESUMO

Th17 cells are potent mediators in autoimmune diseases, and RORγt is required for their development. Recent studies have shown that RORγt+ Treg cells in the gut regulate intestinal inflammation by inhibiting effector T cell function. In the current study, we report that RORγt+ Treg cells were also found in lymph nodes following immunization. Not only distinct from intestinal RORγt+ Treg cells in their transcriptomes, peripheral RORγt+ Treg cells were derived from Foxp3+ thymic Treg cells in an antigen-specific manner. Development of these RORγt+ Treg cells, coined T regulatory 17 (Tr17) cells, depended on IL-6/Stat3 signaling. Tr17 cells showed suppressive activity against antigen-specific effector T cells in vitro. In addition, Tr17 cells efficiently inhibited myelin-specific Th17-cell-mediated CNS auto-inflammation in a passive EAE model. Collectively, our study demonstrates that Tr17 cells are effector Treg cells that potentially restrict autoimmunity.


Assuntos
Autoimunidade/genética , Encefalomielite Autoimune Experimental/genética , Fatores de Transcrição Forkhead/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Transferência Adotiva , Animais , Diferenciação Celular , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Fragmentos de Peptídeos/administração & dosagem , Receptores CCR6/genética , Receptores CCR6/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Transdução de Sinais , Linfócitos T Reguladores/patologia , Linfócitos T Reguladores/transplante , Células Th17/patologia
15.
J Cell Mol Med ; 21(12): 3795-3809, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28780774

RESUMO

Immunization of experimental autoimmune encephalomyelitis (EAE)-prone C57BL/6 mice with MOG35-55 (a model used to study aspects of human multiple sclerosis) is known to lead to the production of various abzymes. The production of catalytic IgGs that can efficiently hydrolyse myelin basic protein (MBP), MOG and DNA is associated with changes in the profile of differentiation and level of proliferation of mice bone marrow haematopoietic stem cells (HSCs). As MOG simulates the production of abzymes with high DNase activity, we compared the effects of DNA and MOG immunization on EAE-prone mice. In contrast to MOG, immunization with DNA leads to a suppression of proteinuria, a decrease in the concentrations of antibodies to MOG and DNA and a reduction in abzyme production. Immunization with DNA only resulted in a significant increase in DNase activity over 40 days where it became 122-fold higher than before immunization, and fivefold higher when comparing to the maximal activity obtained after MOG treatment. DNA and MOG immunization had different effects on the differentiation profiles of HSCs, lymphocyte proliferation, and the level of apoptosis in bone marrow and other organs of mice. The data indicate that for C57BL/6 mice, DNA may have antagonistic effects with respect to MOG immunization. The usually fast immune response following MOG injection in C57BL/6 mice is strongly delayed after immunization with DNA, which is probably due to a rearrangement of the immune system following the response to DNA.


Assuntos
Anticorpos Catalíticos/biossíntese , DNA/administração & dosagem , Encefalomielite Autoimune Experimental/imunologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Animais , Diferenciação Celular , Proliferação de Células , Ensaio de Unidades Formadoras de Colônias , DNA/imunologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/patologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Imunidade Humoral , Imunização/métodos , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia
16.
Iran J Allergy Asthma Immunol ; 16(3): 271-281, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28732440

RESUMO

The abnormal function of the T lymphocytes causes a range of autoimmune diseases, particularly multiple sclerosis; hence, several methods have been used to treat these disorders through the induction of antigen-specific tolerance in T cells. The present study aims to use a simple and low-cost method to produce poly (lactic-co-glycolic acid) (PLGA) nanoparticles for carrying antigens and inducing antigen-specific tolerance. In this study, PLGA nanoparticles were produced using the water/oil/water (W/O/W) method. The myelin oligodendrocyte glycoprotein (MOG) peptide and ovalbumin peptide(OVA) were covalently bound to the synthetic PLGA nanoparticles in the presence of 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) and were injected to six groups of C57BL/6 mice one week before the induction of the experimental autoimmune encephalomyelitis (EAE) intravenously or subcutaneously; one group was considered as control; finally, immunologic responses including delayed-type hypersensitivity (DTH) response and lymphocyte proliferation were investigated. The results showed that the intravenous injection of microparticles containing MOG peptides before the development of the EAE model, not only could delay the incidence of syndrome, but also increase the antigen-specific tolerance. Moreover, a reduced delayed-type hypersensitivity response was observed in the mice primed with microparticles containing MOG peptides. In addition, a reduced spleen lymphocyte proliferation was found in the same mice when challenged with antigens. The present study proposes a simple, inexpensive, effective and safe method for preparing MOG-conjugated PLGA microparticles with immune tolerance properties that can be used in the treatment or reducing clinical syndromes of EAE model.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Tolerância Imunológica , Glicoproteína Mielina-Oligodendrócito/imunologia , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Animais , Autoimunidade , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Feminino , Ativação Linfocitária/imunologia , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/química , Fragmentos de Peptídeos/imunologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Baço/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
17.
Nanomedicine (Lond) ; 12(11): 1231-1242, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28593827

RESUMO

AIM: Based on the ability of apoptosis to induce immunological tolerance, liposomes were generated mimicking apoptotic cells, and they arrest autoimmunity in Type 1 diabetes. Our aim was to validate the immunotherapy in other autoimmune disease: multiple sclerosis. MATERIALS & METHODS: Phosphatidylserine-rich liposomes were loaded with disease-specific autoantigen. Therapeutic capability of liposomes was assessed in vitro and in vivo. RESULTS: Liposomes induced a tolerogenic phenotype in dendritic cells, and arrested autoimmunity, thus decreasing the incidence, delaying the onset and reducing the severity of experimental disease, correlating with an increase in a probably regulatory CD25+ FoxP3- CD4+ T-cell subset. CONCLUSION: This is the first work that confirms phosphatidylserine-liposomes as a powerful tool to arrest multiple sclerosis, demonstrating its relevance for clinical application.


Assuntos
Autoantígenos/administração & dosagem , Imunoterapia/métodos , Lipossomos/química , Esclerose Múltipla/terapia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Peptídeos/administração & dosagem , Fosfatidilserinas/química , Animais , Autoantígenos/imunologia , Autoantígenos/uso terapêutico , Feminino , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Glicoproteína Mielina-Oligodendrócito/uso terapêutico , Peptídeos/imunologia , Peptídeos/uso terapêutico , Linfócitos T Reguladores/imunologia
18.
Hum Antibodies ; 25(3-4): 121-129, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28269761

RESUMO

A single peripheral dose of CNS-binding IgMs promote remyelination and preserve axons in a number of animal models of neurologic disease. A myelin-binding recombinant human IgM (rHIgM22) is presently in a safety trial in MS patients following an acute MS exacerbation. rHIgM22 (directed against oligodendrocytes) or rHIgM12 (directed against neurons) were administered to mice with MOG-induced experimental autoimmune encephalomyelitis (EAE) with study endpoints: clinical deficits and brain and spinal cord pathology. IgMs were administered at a therapeutic dose of 100 µ g intra peritoneal at the time of immunization (day -1, 0, +$1), disease onset (15 days) or peak of the disease (28 days). Disease course was not worsened by either human IgM regardless of the time of treatment. Of note, the human IgM that recognizes a carbohydrate epitope on gangliosides and NCAM, rHIgM12, reduced brain pathology when given at time of immunization or at onset of disease, but did not reduce clinical deficits or spinal cord disease burden. Hence, treatment with rHIgM12 resulted in marked reduction in meningeal inflammation. Data consistent with the hypothesis that in the EAE model this molecule has an immune-modulatory effect. Treatment with an anti-CD4 blocking IgG prevented both clinical course and CNS pathology. This pre-clinical study further supports the safety of therapeutic CNS-binding human IgMs in the presence of autoimmunity and clearly differentiates them from IgGs directed against MOG or aquaporin-4 that worsen neurologic disease.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Doenças Desmielinizantes/tratamento farmacológico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Imunoglobulina M/farmacologia , Fatores Imunológicos/farmacologia , Molécula L1 de Adesão de Célula Nervosa/imunologia , Fármacos Neuroprotetores/farmacologia , Ácidos Siálicos/imunologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/patologia , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/patologia , Esquema de Medicação , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Adjuvante de Freund/administração & dosagem , Humanos , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/imunologia , Bainha de Mielina/patologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Neurônios/patologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/imunologia , Oligodendroglia/patologia , Fragmentos de Peptídeos/administração & dosagem , Ligação Proteica , Proteínas Recombinantes/farmacologia , Ácidos Siálicos/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia
19.
Methods Mol Biol ; 1559: 321-332, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28063054

RESUMO

Autoimmune diseases like multiple sclerosis (MS) develop from the activation and complex interactions of a wide network of immune cells, which penetrate the central nervous system (CNS) and cause tissue damage and neurological deficits. Experimental autoimmune encephalomyelitis (EAE) is a model used to study various aspects of MS, including the infiltration of autoaggressive T cells and pathogenic, inflammatory myeloid cells into the CNS. Various signature landscapes of immune cell infiltrates have proven useful in shedding light on the causes of specific EAE symptoms in transgenic mice. However, single cell analysis of these infiltrates has thus far been limited in conventional fluorescent flow cytometry methods by 14-16 parameter staining panels. With the advent of mass cytometry and metal-tagged antibodies, a staining panel of 35-45 parameters is now possible. With the aid of dimensionality reducing and clustering algorithms to visualize and analyze this high dimensional data, this allows for a more comprehensive picture of the different cell populations in an inflamed CNS, at a single cell resolution level. Here, we describe the induction of active EAE in C56BL/6 mice and, in particular, the staining of microglia and CNS invading immune cells for mass cytometry with subsequent data visualization and analysis.


Assuntos
Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/imunologia , Citometria por Imagem/métodos , Microglia/imunologia , Análise de Célula Única/métodos , Linfócitos T/imunologia , Algoritmos , Animais , Biomarcadores/metabolismo , Movimento Celular , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/patologia , Feminino , Adjuvante de Freund/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/patologia , Redução Dimensional com Múltiplos Fatores , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Coloração e Rotulagem/métodos , Linfócitos T/patologia
20.
Sci Rep ; 6: 34594, 2016 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-27708418

RESUMO

Studies in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), have shown that regulatory B cells modulate the course of the disease via the production of suppressive cytokines. While data indicate a role for transforming growth factor (TGF)-ß1 expression in regulatory B cell functions, this mechanism has not yet been tested in autoimmune neuroinflammation. Transgenic mice deficient for TGF-ß1 expression in B cells (B-TGF-ß1-/-) were tested in EAE induced by recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG). In this model, B-TGF-ß1-/- mice showed an earlier onset of neurologic impairment compared to their littermate controls. Exacerbated EAE susceptibility in B-TGF-ß1-/- mice was associated with augmented CNS T helper (Th)1/17 responses. Moreover, selective B cell TGF-ß1-deficiency increased the frequencies and activation of myeloid dendritic cells, potent professional antigen-presenting cells (APCs), suggesting that B cell-derived TGF-ß1 can constrain Th1/17 responses through inhibition of APC activity. Collectively our data suggest that B cells can down-regulate the function of APCs, and in turn encephalitogenic Th1/17 responses, via TGF-ß1, findings that may be relevant to B cell-targeted therapies.


Assuntos
Linfócitos B Reguladores/imunologia , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/genética , Células Th1/imunologia , Células Th17/imunologia , Fator de Crescimento Transformador beta1/genética , Animais , Linfócitos B Reguladores/patologia , Comunicação Celular/imunologia , Células Dendríticas/patologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Deleção de Genes , Expressão Gênica , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Células Th1/patologia , Células Th17/patologia , Fator de Crescimento Transformador beta1/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA