O vírus linfotrópico de células T humanas do tipo 1 (HTLV-1) é o agente etiológico de duas principais manifestações clínicas, a mielopatia associada ao HTLV-1/paraparesia espástica tropical (HAM/TSP) e a leucemia/linfoma de células T do adulto (ATLL). O desenvolvimento de HAM/TSP, uma doença neuroinflamatória crônica é relacionada a uma complexa interação entre vírus e resposta imunológica do hospedeiro. A expressão do gene viral tax desempenha um papel importante na patogênese da HAM/TSP pela ativação de diversos genes celulares, incluindo genes das citocinas inflamatórias IFN-? e TNF- Recentemente, os exossomos surgiram como um importante fator na comunicação célula-célula contribuindo em diversos processos celulares, inclusive na modulação do sistema imunológico. Considerando o potencial papel dos exossomos na imunomodulação e no processo inflamatório, o objetivo deste trabalho foi avaliar se os exossomos produzidos por células infectadas pelo HTLV-1 carreiam moléculas virais e se poderiam participar dos processos de imunomodulação e inflamação crônica observados na HAM/TSP. Os exossomos foram isolados de células infectadas pelo HTLV-1 da linhagem celular C8166, avaliados quanto à presença de RNAm viral tax e testados quanto à capacidade de ativar células mononucleares do sangue periférico (PBMC) à indução de resposta inflamatória. Neste trabalho, foi observado que, após a exposição de PBMC aos exossomos contendo RNAm viral tax, a expressão da citocina inflamatória IFN-? foi aumentada em linfócitos T CD4+ e CD8+ quando comparado ao grupo não exposto aos exossomos. Foi observado um pequeno aumento de TNF-? no grupo exposto aos exossomos. Não houve diferença na expressão das citocinas IL-4, perforina e granzima B. Tomados em conjunto, estes resultados sugerem que exossomos contendo tax isolados de células infectadas pelo HTLV-1 induzem a produção de citocinas inflamatórias ativam a resposta imunológica de padrão Th1, e não Th2. Estes achados podem contribuir na elucidação do papel dos exossomos na infecção pelo HTLV-1 e nos estudos relacionados à patogênese da HAM/TSP e à resposta inflamatória envolvendo a apresentação clínica desta doença. / Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of HTLV-1 associated myelopathy/tropical paraparesis spastic (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). The development of HAM/TSP, a chronic neuroinflammatory disease, is correlated to a complex host-virus dynamic immune response interaction. Tax expression plays an important role in HAM/TSP pathogenesis by activating various cellular genes, including the cytokines IFN-? and TNF-?. Exosomes have emerged as an important factor of cell-to-cell communication contributing to diverse cellular processes, including immune modulation. Considering the potential role of exosomes in modulating the immune response and inflammation, the main objective of this study was to examine if HTLV-1-infected cells produce exosomes can carry viral tax mRNA, and if they can can participate in the chronic inflammation observed in patients with HAM/TSP. Exosomes were isolated from HTLV-1-infected cell line culture, evaluated for the tax mRNA presence and tested for the ability to activate peripheral mononuclear cells (PBMC) in inducing an inflammatory immune response. We observed that the proinflammatory cytokine IFN-? was upregulated in CD4 and CD8 T-cells after treatment of the PBMC with Tax carrying exosomes compared to the negative control. The expression of TNF-? was slightly upregulated. IL-4, Granzyme B and Perforin did not show alterations. Taken together, these results suggest that exosomes carrying Tax isolated from HTLV-1-infected cells might induce the production of proinflammatory cytokines and activate T helper (Th)1, and not Th2, immune response. This study may have important impact on the studies involving the pathogenesis of HAM-TSP and the inflammatory response involved in the clinical presentation of the disease.

Le syndrome de Gougerot-Sjögren (SGS) est une épithélite auto-immune caractérisée par des lésions des glandes exocrines et manifestations systémiques. Une des complications majeures est la survenue chez 5% des malades, d’un lymphome non-hodgkininen (NHL). La contribution majeure des lymphocytes B (LB) a récemment été démontrée. Dans ce travail, nous avons voulu aborder des sujets cliniques et fondamentaux concernant le rôle des LB dans le SGS. Dans un premier temps, nous avons démontré que des LB mémoires sont visibles dans des infiltrats des échantillons de la peau et sa présence peut aider au diagnostic. Dans un deuxième temps, nous avons démontré que la cytokine FLT3-L augmentée (une cytokine impliquée dans l’ontogenèse des LB et lympho-prolifération) est associée à une distribution anormale des LB dans les malades. En plus, le rôle prolifératif de FLT3-L sur les LB pourrait expliquer l’évolution vers le NHL. Dans un troisième temps, nous avons étudié une autre cytokine dérégulée dans le SGS (la cytokine BAFF) et nous avons confirmé le rôle d’un nouveau variant de BAFF produit par l’épissage alternatif de l’exon 4 (∆4BAFF) comme un facteur de transcription de son propre gène. Ce nouveau variant est beaucoup plus exprimé au cours des maladies autoimmunes, et son expression est contrôlée par l’interferon gamma et la protéine SC35. Tous ces données montrent pour la première fois, un nouveau concept à savoir la possibilité pour une cytokine d’être régulée par un variant provenant de l’épissage alternatif de son propre gène. Ensemble, ces résultats montrent le rôle des cytokines impliquées dans l’ontogenèse et la survie des LB, dans la physiopathologie du SGS. / Primary Sjögren’s Syndrome (pSS) is a systemic autoimmune disease characterized by sicca symptoms and a broad variety of systemic manifestations. The most severe complication of the disease is the development of non-Hodgkin’s lymphoma (NHL) in 5% of patients. Recent evidence indicates a major contribution of B cells. In this work, we developed clinical and basic research subjects, related to the role of B-cell in the pathogenesis of pSS. In the first section, we showed that memory B-cell infiltrates are present in pSS and may be used as an additional diagnostic and follow-up tool. In the second section, we showed that high serum levels of the cytokine called FLT3-L (a cytokine implicated in B-cell ontogenesis and lymphoproliferation) are associated with abnormal B-cell distribution, characteristic of pSS; and disease clinical activity. In addition, this cytokine may explain the development of lymphoma. In the third section, we demonstrated that ∆4BAFF (a new variant of BAFF, due to the alternative splicing of exon 4) is a transcription factor of its own gene. Interestingly, this new variant is mainly detected in autoimmune diseases and its expression is regulated by IFN-y and SC35 protein (one of the proteins implicated in the splicing machinery). This finding provides an expanded conceptual view of BAFF gene regulation in autoimmune diseases, and contributes to a better understanding of the mechanisms involved in BAFF up-regulation in autoimmunity. Collectively, these results are of clinical and fundamental basic interest in pSS, in the diagnostic, physiopathology and therapeutic contexts.

Au cours d’une infection, les cellules de l’immunité innée sont capables de reconnaître via les Toll-like receptors (TLR) des motifs appelés pathogen-associated molecular patterns. Les cellules natural killer (NK) contribuent au processus inflammatoire en produisant de nombreuses cytokines. Chez la souris, nous avons montré que l’expression du TLR2 et du TLR4 dans les cellules NK spléniques est intracellulaire, comme pour le TLR9. La réponse des NK aux agonistes des TLR2, 4 et 9 nécessite la présence de cytokines accessoires (IL-15 et IL-18), afin d’obtenir une production significative des cytokines pro-inflammatoires IFN- et GM-CSF. En revanche, dans un modèle de sepsis polymicrobial, les NK spléniques de souris présentent une diminution dramatique de leur production d’IFN- et de GM-CSF en réponse aux agonistes des TLR. Cette diminution est sous le contrôle des cellules T régulatrices (Treg) et due au TGF-1. L’analyse des voies de signalisation nous a permis de montrer que la production de GM-CSF est abolie chez les cellules NK de souris déficientes pour STING en réponse au CpG-DNA. Ces résultats mettent en lumière une voie alternative et cytoplasmique pour la détection de l’ADN bactérien dans les cellules NK, différente de la voie classique TLR9-MyD88 dépendante. De plus, nous avons montré un trafic du récepteur TLR2 depuis l’intérieur vers la surface des cellules NK. La migration du TLR2 à la surface des NK nécessite la molécule UNC93B1, précédemment décrite comme transporteur endosomal de TLR.Chez les cellules NK humaines circulantes (sous-populations CD3-CD56bright et CD3-CD56dim), nous avons montré que l’expression des TLR2 et 4 est majoritairement intracellulaire, comme pour le TLR9 et comme chez la souris. La production d’IFN- par les NK de sujets sains en réponse aux agonistes des TLR nécessite également la présence de cytokines accessoires. Nous montrons que cette production est fortement altérée pour les NK des patients admis en soins intensifs et ayant un sepsis ou un syndrome de réponse inflammatoire systémique (SIRS). De même nous avons trouvé des différences entre les patients et les sujets sains dans l’expression du CD69 (marqueur d’activation précoce) et des TLR eux-mêmes. Cette étude indique que les NK des patients sepsis et SIRS deviennent tolérants aux agonistes des TLR en terme de production d’IFN-, de manière similaire à ce qui a été décrit pour d’autres cellules comme les monocytes / As sensors of infection, innate immune cells are able to recognize pathogen-associated molecular patterns by receptors such as Toll-like receptors (TLR). NK cells contribute to inflammatory processes by the production of numerous cytokines. In mice, we have shown that the protein expression of TLR2 and TLR4 in naive NK cells from spleen is predominantly intracellular, similarly to TLR9. The responsiveness of purified NK cells to TLR2, 4 or 9 agonists in vitro requires the presence of accessory cytokines (IL-15 and 18) to trigger a significant production of IFN- and GM-CSF. In contrast, NK cells purified from a model of in vivo polymicrobial sepsis, showed a dramatic reduction in their capacity to respond to TLR agonists in terms of IFN- and GM-CSF release due an inhibitory cross talk with Treg cells mediated by TGF-1. Analyzing the signaling pathways involved in cytokine production in response to CpG-DNA, we found that GM-CSF production was abolished in NK cells from STING-deficient mice, revealing that this intracytoplasmic receptor acts as a TLR9/MyD88-independent alternative sensor to bacterial DNA in NK cells. Additionally we show that intracellularly expressed TLR2 traffics to the cell surface of NK cells, by a mechanism involving UNC93B1, a protein previous described as an endosomal TLR carrier.In human peripheral blood NK cells (CD3-CD56bright and CD3-CD56dim subsets), we show that TLR2 and 4 protein expression is primarily intracellular, similar to TLR9, and similar to our findings in murine NK cells. The ex vivo responsiveness of human blood NK cells to TLR2, 4 or 9 agonists also requires accessory cytokines, to promote secretion of IFN-. In intensive care patients diagnosed with systemic inflammatory response syndrome (SIRS) and sepsis, IFN- production was significantly decreased. We also discovered modulations in the expression of CD69 (early activation marker) and in that of TLR themselves. This study indicates that NK cells undergo tolerance in response to TLR agonists during SIRS or sepsis, similarly to other cells, such as monocytes.

No description available.

Made available in DSpace on 2015-04-11T13:54:31Z (GMT). No. of bitstreams: 1 Claudia Maria de Melo Silva.pdf: 2215806 bytes, checksum: c9afeecd5c357af061e1b38a8a31df56 (MD5) Previous issue date: 2014-04-28 / FAPEAM - Fundação de Amparo à Pesquisa do Estado do Amazonas / Tuberculosis (TB) is a chronic infection caused by Mycobacterium tuberculosis complex and remains a major worldwide public health problem, leading to almost 1.45 million deaths annually. The state of Amazonas has a high rate incidence of TB, about 68.3/100,000 inhabitants in 2012. Only 5 to 10% of infected individuals develop active TB. It has been suggested that host factors determine the immune response to pathogen. Thus, many immunogenetic researches have demonstrated TB associated genes, but in the north region, research in this field is still rare. This fact motivated the investigation of polymorphisms for IFNG, IL12B, CD80 and CD86 genes, which codify proteins for cellular immune response. Furthermore, IFN- concentration and its relation with genotypes found have been verified. A total of 177 patients and 224 controls (159 contacts and 65 non-contacts) were included in this study and DNA sequencing was performed for genes IFNG (SNP +874A/T and microsatellite +875), IL12B (SNPs +1030C/T, +1188A/C and +1254T/G), CD80 (SNPs -454 C/A, -387 T/C, -232 G/A, -79 C/G, -7T/C, +5C/A and an indel polymorphism -557_-561insCATGA) and CD86 (SNPs +1057G/A and +1079G/A). The IFN-y concentration was determined by enzyme-linked immunoassay. At IFNG, the presence of the allele +874A and the allele with 15 CA repeats were associated with susceptibility to pulmonary TB, while the allele +874T and the allele with 12 CA repeats were associated with protection from pulmonary TB. In addition, an association between genotype CC (SNP +1188A/C at IL12B) and increased risk of pulmonary TB was found. Furthermore, a significant difference between IFN- concentration and genotypes of SNP +1188A/C at IL12B and microsatellite at IFNG was observed, with decrease of IFN-at genotype CC and 15 CA repeats respectively. These outcomes lead to a better understanding of the immune response regulation for TB and help to determine the genetic profile of the Amazon population. Future researches are still needed for a better understanding of the role of other genes involved in the immune response to M. tuberculosis and their influence at the production of citokines like IFN-. / A Tuberculose (TB) é uma infecção crônica causada pelo complexo Mycobacterium tuberculosis sendo um importante problema de saúde pública mundial, levando a aproximadamente 1,45 milhões de mortes a cada ano. O estado do Amazonas possui uma alta incidência desta doença, atingindo 68,3 casos por 100 mil habitantes em 2012. Dos indivíduos infectados pelo bacilo, cerca de 5 a 10% desenvolvem a Tuberculose ativa, sugerindo que há fatores associados ao hospedeiro que determinam o destino da resposta imune ao patógeno. Neste contexto, diversos estudos em imunogenética têm demonstrado genes associados à TB, mas na região norte ainda são raras as pesquisas nesta área, fato que motivou a investigação da frequência dos polimorfismos nos genes IFNG, IL12B, CD80 e CD86, que codificam para proteínas fundamentais na resposta imune celular. Além disso, foi verificado se a concentração de IFN- está relacionada com o genótipo encontrado. Foram incluídas amostras de 177 pacientes e 224 controles (159 contatos e 65 não contatos) e realizado sequenciamento de DNA para os genes IFNG (SNP +874A/T e microssatélite +875), IL12B (SNPs +1030C/T, +1188A/C e +1254T/G), CD80 (SNPs -454 C/A, 454 C/A, 454 C/A, 454 C/A, -387 T/C, 387 T/C, 387 T/C, -232 G/A, 232 G/A, 232 G/A, -79 C/G, 79 C/G, 79 C/G, -7T/C e 7T/C e 7T/C e 7T/C e +5C/A+5C/A +5C/A e um polimorfismo indel -557_-561insCATGA) e CD86 (SNPs +1057G/A e +1079G/A). A determinação das concentrações de IFN-foi realizada através de ensaio imunoenzimático. Foi verificada uma associação do gene IFNG, entre a presença do alelo +874A e 15 repetições CA, como fator de risco para TB pulmonar assim como a presença do alelo +874T e 12 repetições CA como fatores de proteção contra TB pulmonar. Também foi encontrada uma associação do genótipo CC, do SNP +1188A/C no gene IL12B, como fator de risco ao desenvolvimento da TB pulmonar. Houve diferença significativa na concentração de IFN-entre os genótipos do SNP +1188A/C no gene IL12B e o microssatélite no gene IFNG, com menor produção no genótipo CC e 15 repetições CA respectivamente. Estes resultados contribuem para o melhor entendimento da regulação na resposta imune à TB e auxilia na determinação do perfil genético da população da região Amazônica. Estudos futuros são necessários para uma melhor compreensão do papel de outros genes envolvidos na resposta imunológica a M. tuberculosis e influência nos níveis de produção de citocinas como IFN-.

Physical exercise has been implicated in several immunophysiological improvements especially during the aging process when an immunocompromised status could be established. Toxoplasma gondii is a protozoan parasite that causes a widespread opportunistic infection, which may present severe consequences, particularly to the fetus and immunocompromised patients. It is estimated that one-third of the human population worldwide has been infected by this parasite, being the reactivation during immunesenescence an unexplored public health issue. The present study was designed to assess the immunophysiological differences between exercised versus sedentary C57BL/6 male mice that have been infected by T. gondii. Before the two key set of experiments, several other sets were carried out to the prospection of the main found data of this study. There were two main sets of experiments: in the first set, the animals were infected after exercising and three groups were formed: experimental groups - infected sedentary (IS, n=6); infected exercised (IEx, n=6) and control group - non-infected sedentary (NIS, n=6). When splenocytes were stimulated by T. gondii-soluble tachyzoite antigens, it was found an significant increasing (P<0.0001) in interferon-gamma (IFN-&#61543;) production concomitant with any changes in IL-10, allowing a greater IFN-&#61543;/IL-10 ratios, produced by the cells from exercised group compared to sedentary one. However, there was no difference concerning quantification of T. gondii genomic DNA by qPCR and immunohistochemistry analysis in brain cysts (P>0.05). In order to further investigate the consequences of these data for the host, a second set of experiments was performed, when the animals were infected before exercising and four groups of animals were established for comparison purpose, as follows: experimental groups - infected sedentary (IS, n=7); infected exercised (IEx, n=6) and control groups - non-infected sedentary (NIS, n=6) and non-infected exercised (NIEx, n=6). It was found that exercised group survived longer (P<0.05) than sedentary one. In both sets of experiments, mice have been submitted to moderate exercises: running (14m/min; 3x/week) and strength (60-80% of one-repetition maximum; 2x/week). In summary, moderated aerobic and strength exercises are able to modulate immune responses against T. gondii infection, being these immunological features beneficial to the host. / A prática regular de exercício físico tem sido relacionado com melhoras imunopatológicas, especialmente durante o processo de envelhecimento quando pode haver um estado de imunocomprometimento. O Toxoplasma gondii é um parasito protozoário que causa infecção oportunista de forma global, podendo apresentar consequências severas, particularmente ao feto e pacientes imunocomprometimentos. É estimado que um terço da população mundial esteja atualmente infectado por este parasito, sendo a reativação durante a imunossenescência um tópico em saúde pública não explorado. O presente estudo foi projetado para avaliar parâmetros de diferenças imunológicas entre camundongos machos C57BL/6 exercitados e sedentários que tenham sido infectados por T. gondii. Antes dos experimentos chaves vários outros conjuntos de experimentos foram realizados para prospecção dos principais achados desta tese. Houve dois conjuntos de experimentos principais: no primeiro conjunto de experimentos, os animais foram infectados após o início dos exercícios formando-se três grupos: um grupo controle - sedentário não infectado (NIS, IS, n=4); dois grupos infectados - um sedentário (IS, n=4) e um exercitado (IEx, n=6). Quando esplenócitos foram estimuladas com antígeno de taquizoíto solúvel de T gondii (STAg), encontrou-se uma maior produção de IFN-&#61543;, concomitante à uma manutenção das taxas de IL-10, que permitiu uma maior razão de IFN-&#61543;/IL10 (P<0,0001) para o grupo exercitado comparado com o sedentário. No entanto, não houve diferenças no que diz repeito a quantificação de DNA genômico de T. gondii pelas análises de qPCR e imunohistoquímica de cistos cerebrais (P>0,05). Com objetivo de se pesquisar posteriormente as consequências destes dados para o hospedeiro, um segundo conjunto de experimentos foram realizados, quando os animais foram infectados antes do início dos exercícios, e quatro grupos foram estabelecidos para comparação deste propósito, como se segue: dois grupos controles não infectados - sedentário (NIS, n=6) e exercitado (NIEx, n=6), e dois grupos infectados - sedentário (IS, n=7) e exercitado (IEx, n=6). Encontrou-se que o grupo infectado exercitado teve sua longevidade aumentada (P<0,05) comparado com o infectado sedentário. Em ambos os conjuntos de experimentos, os camundongos foram submetidos à exercícios moderados: de corrida (14 m/min; 3 x/semana) e resistido (60-80% de uma repetição máxima; 2x/semana). Em síntese, exercícios físicos aeróbicos e resistidos moderados são capazes de modular a resposta do sistema imune no combate da infecção por T. gondii sendo estas características imunológicas benéficas para o hospedeiro. / Doutor em Imunologia e Parasitologia Aplicadas

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No. of bitstreams: 1 sandrabertelliribeirodecastro.pdf: 21642592 bytes, checksum: ba2c7d8539f06b1e9a8e8f3ca1c34c08 (MD5) Previous issue date: 2011-12-08 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / A Esclerose Múltipla (EM) caracteriza-se por ser uma doença inflamatória crônica desmielinizante do Sistema Nervoso Central (SNC), que afeta aproximadamente um milhão de pessoas em todo o mundo. Entre os agentes terapêuticos aprovados atualmente para o tratamento da EM podemos citar o interferon beta (IFN-β) e o acetato de glatirâmer, entretanto, estes agentes não promovem a cura da doença ou a recuperação total dos pacientes que estão em fase avançada. Diversos estudos demonstram a propriedade que os hormônios sexuais, como o estradiol e progesterona possuem em diminuir a gravidade da Encefalomielite Autoimune Experimental (EAE). Estruturalmente, as isoflavonas compartilham muitas similaridades com os estrógenos endógenos. Estudos realizados com genisteína mostram os efeitos benéficos deste isoflavonóide na EAE. Entretanto, alguns fatores limitam sua aplicação clínica, como por exemplo, sua rápida excreção e declínio dos níveis séricos, sendo que estas características podem estar relacionadas à sua estrutura química. Dentro deste contexto, este trabalho teve por objetivo avaliar o efeito de sete derivados lipofílicos da genisteína na modulação da resposta in vitro de macrófagos murinos J774.A1 ativados com lipopolissacarídeo e IFN-g, e verificar a atuação de um análogo selecionado na etapa in vitro na modulação da resposta imune in vivo no modelo de EAE. Na etapa in vitro foi avaliada a citotoxicidade dos compostos, no sobrenadante da cultura foram dosados óxido nítrico, IL-12 e TNF-α. Na etapa in vivo foi investigado o uso do derivado da genisteína 3 (7-Otetradecanoil-genisteína – TDG) na evolução da EAE induzida em camundongos C57Bl/6 através da aplicação do MOG35–55. No 14° dia após a indução com o MOG, os camundongos foram tratados com TDG por sete dias. No 21° dia após a indução, as porcentagens de células mononucleares isoladas de cérebro expressando marcadores de superfície (CD4+, CD3+ e CTLA-4) e produzindo citocinas IL- 17+CD4+, IL-10+CD4+ ou fator de transcrição Foxp3+CD4+ foram determinadas por citometria de fluxo. A concentração de IL-6, IFN-γ e IL-10 em macerado de cérebro e medula foram determinadas por ELISA. As análises histológicas de cérebro e medulas foram realizadas por coloração de Hematoxilina e Eosina. Os resultados apresentados indicam que a modificação estrutural da genisteína originou derivados não citotóxicos, com elevada capacidade de inibir a concentração de IL-12. Entretanto, estes derivados da genisteína não foram capazes de inibir TNF-α. A produção de NO foi significativamente inibida pelos derivados monoésteres (2,3) e monoéter (6,7) de maneira dose-dependente. Os dados obtidos in vivo indicam que o tratamento com o TDG melhora os sinais clínicos da EAE e isto pode ser correlacionado com uma redução na porcentagem de células produzindo IL-17 e um aumento de células Foxp3+CD4+ no cérebro. Além disso, o tratamento com o TDG aumentou a liberação de IL-10 e a expressão de CTLA-4 além de reduzir a liberação de IFN-γ e IL-6. Desta forma, os dados sugerem um papel imunomodulatório do TDG na EAE e possivelmente na EM / Multiple Sclerosis (MS) is a severe and disabling chronic autoimmune inflammatory demyelinating disease of the central nervous system (CNS), that affect around one million people at entire world. Among the therapeutic agents currently approved for the treatment of MS can be cited the interferon beta (IFN-β) and the glatiramer acetate, however, these agents do not promote the cure or full recovery of patients in advanced stages. Several studies showed that hormones, such as estradiol and progesterone, could reduce the severity of experimental autoimmune encephalomyelitis (EAE). The isoflavones share many structural similarities with endogenous estrogens. Studies with genistein showed the beneficial effects of isoflavones in EAE. However, the chemical structure of genistein has characteristics that limit its clinical application, such as rapid excretion and decreased serum levels. This study aimed evaluate the effect of seven lipophilic derivatives of genistein in the modulation of in vitro response of murine J774A.1 macrophages activated with lipopolysaccharide and IFN-g, and verify the performance of one in vitro selected analogue on modulating in vivo the immune response in EAE. The lipophilic derivatives were evaluated in LPS+IFN-g-activated J774A.1 macrophage cultures to their effects on cytotoxicity and nitric oxide, IL-12 and TNF-α production. The effects of the selected genistein derivative 3 (7-O-genistein-tetradecanoil - TDG) on the development of EAE induced in C57BL/6 mice immunized with MOG35-55 were performed. At 14th day after induction, mice were treated with TDG for seven days. At 21st day the percentage of mononuclear cells isolated from brains expressing CD4+, CD3+, CTLA-4+ and Foxp3+ and producing IL-17+ and IL-10+ were determined by flow cytometry. The concentration of IL-6, IFN-g and IL-10 in brain and spinal cord were determined by ELISA. Histological analysis of brain and spinal cord were performed by hematoxylin and eosin staining. The results showed that the modification of genistein enables the generation of non-cytotoxic compounds with increased IL-12 inhibition, despite of failed TNF-α inhibition. The NO production was inhibited by the monoester (2,3) and monoether (6,7) compounds in a dose-dependent manner. The in vivo data indicated that treatment with TDG improved the clinical signs of EAE which can be correlated with a reduction in the percentage of cells producing IL-17 and the increment of Foxp3+CD4+ cell population at brain. Furthermore, treatment with TDG increased the release of IL-10 and expression of CTLA-4 and reduced the release of IFN-g and IL-6. Altogether, the data suggest an immunomodulatory role of the TDG in EAE and possibly MS.