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Immunization with pVAXhsp65 Decreases Inflammation and Modulates Immune Response in Experimental Encephalomyelitis

ZORZELLA-PEZAVENTO, Sofia Fernanda Goncalves; CHIUSO-MINICUCCI, Fernanda; FRANCA, Thais Graziela Donega; ISHIKAWA, Larissa Lumi Watanabe; MARTINS, Douglas Rodrigues; SILVA, Celio Lopes; SARTORI, Alexandrina
Fonte: KARGER Publicador: KARGER
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
36.34%
Background: A DNA vaccine (pVAXhsp65) containing the gene of a heat-shock protein (hsp65) from Mycobacterium leprae showed high immunogenicity and protective efficacy against tuberculosis in BALB/c mice. A possible deleterious effect related to autoimmunity needed to be tested because hsp65 is highly homologous to the correspondent mammalian protein. In this investigation we tested the effect of a previous immunization with DNAhsp65 in the development of experimental autoimmune encephalomyelitis (EAE), a rat model of multiple sclerosis. Methods: Female Lewis rats were immunized with 3 pVAXhsp65 doses by intramuscular route. Fifteen days after the last DNA dose the animals were evaluated for specific immunity or submitted to induction of EAE. Animals were evaluated daily for weight loss and clinical score, and euthanized during the recovery phase to assess the immune response and inflammatory infiltration at the central nervous system. Results: Immunization with pVAXhsp65 induced a specific immune response characterized by production of IgG(2b) anti-hsp65 antibodies and IFN-gamma secretion. Previous immunization with pVAXhsp65 did not change EAE clinical manifestations (weight and clinical score). However, the vaccine clearly decreased brain and lumbar spinal cord inflammation. In addition...

Tempol ameliorates murine viral encephalomyelitis by preserving the blood-brain barrier, reducing viral load, and lessening inflammation

TSUHAKO, Maria Heloisa; AUGUSTO, Ohara; LINARES, Edlaine; CHADI, Gerson; GIORGIO, Selma; PEREIRA, Carlos A.
Fonte: ELSEVIER SCIENCE INC Publicador: ELSEVIER SCIENCE INC
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
36.35%
Multiple sclerosis (MS) is a progressive inflammatory and/or demyelinating disease of the human central nervous system (CNS). Most of the knowledge about the pathogenesis of MS has been derived from murine models, such as experimental autoimmune encephalomyelitis and vital encephalomyelitis. Here, we infected female C57BL/6 mice with a neurotropic strain of the mouse hepatitis virus (MHV-59A) to evaluate whether treatment with the multifunctional antioxidant tempol (4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy) affects the ensuing encephalomyelitis. In untreated animals, neurological symptoms developed quickly: 90% of infected mice died 10 days after virus inoculation and the few survivors presented neurological deficits. Treatment with tempol (24 mg/kg, ip, two doses on the first day and daily doses for 7 days plus 2 mM tempol in the drinking water ad libitum) profoundly altered the disease outcome: neurological symptoms were attenuated, mouse survival increased up to 70%, and half of the survivors behaved as normal mice. Not Surprisingly, tempol substantially preserved the integrity of the CNS, including the blood-brain barrier. Furthermore, treatment with tempol decreased CNS vital titers, macrophage and T lymphocyte infiltration...

A ativação imune materna e os efeitos sobre a imunidade, neuroinflamação e desenvolvimento da encefalomielite autoimune experimental na prole de camundongos; Maternal immune activation and the effects on immunity, neuroinflammation and development of experimental autoimmune encephalomyelitis in the offspring

Zager, Adriano
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 15/10/2013 PT
Relevância na Pesquisa
36.36%
Experiências vivenciadas durante o período pré-natal são determinantes para a saúde do feto. A ocorrência de infecções maternas e a consequente ativação do sistema imune da mãe ocasionam uma série de alterações estruturais e funcionais no cérebro da prole, podendo predispor o indivíduo a transtornos psiquiátricos na vida pós-natal, como esquizofrenia e autismo. No entanto, estudos que investigam as alterações imunes na prole ainda são escassos na literatura. Dessa forma, o objetivo do presente estudo foi avaliar, na prole, o impacto da ativação imune materna sobre a atividade imune periférica, a resposta imune-inflamatória no sistema nervoso central (SNC), e sobre o desenvolvimento da encefalomielite autoimune experimental (EAE), o modelo murino de Esclerose Múltipla. Camundongos fêmeas prenhes receberam uma administração de salina ou lipopolissacarídeo (LPS) ao final da gestação (dia gestacional 17) e, quando adulta, a prole foi submetida a 3 experimentos principais, analisando: (1) produção de citocinas, atividade de células da periferia e desenvolvimento da hipersensibilidade do tipo tardia; (2) produção de mediadores inflamatórios por células residentes do SNC e; (3) desenvolvimento dos sintomas clínicos e da resposta imune no decorrer da EAE. Nossos resultados mostraram que a ativação imune materna provocou na prole alterações imunes periféricas...

Plasticidade sinaptica em motoneuronios alfa medulares de animais submetidos a encefalomielite autoimune experimental; Spinal motoneuron synaptic plasticity during the course of an animal model of multiple scierosis

Karina de Brito Marques
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 31/08/2007 PT
Relevância na Pesquisa
46.32%
Durante o curso da encefalomielite autoimmune experimental ocorre uma grave redução das funções motoras e sensitivas. Esses eventos têm sido classicamente atribuídos ao processo desmielinizante da doença. Em ratos, os sinais clínicos da doença desaparecem 5 dias após completa tetraplegia, indicando que o processo desmielinizante não é a única causa da rápida evolução da doença. Assim sendo, investigamos as alterações sinaptológicas e o processo inflamatório induzidos pela encefalomielite autoimune experimental (EAE) em motoneurônios medulares e sua relação com o surto e remissão da doença. Para esse estudo, foram utilizados ratos Lewis, fêmeas de 7 semanas. Os animais foram induzidos à EAE por meio de dose única de proteína básica de mielina emulsificada com adjuvante completo de Freund e sacrificados no 13º dia após indução (surto grau 3) e no 26º dia (remissão da doença). Também, para investigar a possibilidade de que o tratamento com acetato de glatirâmer, uma droga imunomoduladora baseada na estrutura de aminoácidos da proteína básica de mielina, interfira no processo de plasticidade sináptica, os animais foram induzidos à EAE, tratados com AG diariamente e sacrificados após 2 semanas. Os grupos experimentais foram divididos em: estudo da aposição sináptica durante surto e remissão da doença e tratamento dos animais induzidos à EAE com AG. Assim...

Influencia do acetato de glatiramer (AG) sobre a estabilidade sinaptica e reação glial durante o curso da EAE e apos avulsão de raizes motoras; Influence of Glatiramer acetate on the synaptic stability and glial reaction during the EAE and after motor root avulsion

Juliana Milani Scorisa
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 10/06/2009 PT
Relevância na Pesquisa
46.26%
A Esclerose múltipla (EM) é uma doença inflamatória, desmielinizante do sistema nervoso central (SNC). Sua etiologia é desconhecida, porém, sua progressão se deve a ocorrência de uma importante resposta auto-imune. O acetato de glatirâmer (AG) é um medicamento utilizado em pacientes com esclerose múltipla e é constituído por um copolímero de 4 peptídeos homólogos à proteína básica da mielina (MBP), capaz de diminuir a exacerbação e o número lesões da doença. Pouco se sabe sobre o impacto do tratamento com AG sobre o SNC, principalmente, se este medicamento influencia na estabilidade das sinapses medulares durante o curso da doença. Uma molécula importante para a manutenção do SNC é o complexo de histocompatibilidade principal de classe (MHC I), que participa na regulação homeostática e função sináptica. Para este estudo, utilizamos o modelo animal da EM, a Encefalomielite Autoimune Experimental (EAE) e a avulsão de raízes motoras da medula espinhal para investigar a plasticidade sináptica e reatividade glial sobre o efeito do AG no SNC. A doença (EAE) foi induzida em camundongos C57BL/06 que foram dividivos em 4 grupos. Trinta animais foram submetidos à EAE e tratados com AG, sendo 15 tratados até o surto da doença e 15 tratados até a fase de remissão dos sinais clínicos. Para o grupo placebo...

Desenvolvimento de estratégia terapêutica para neuroinflamação autoimune utilizando o antimalárico primaquina; Development of a therapeutic strategy for autoimmune neuroinflammation by the antimalarial drug primaquine

Fábio dos Santos Machado Zanucoli
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 25/03/2015 PT
Relevância na Pesquisa
46.24%
A esclerose múltipla (EM) é uma doença inflamatória crônica de origem autoimune que afeta o sistema nervoso central (SNC), provocando disfunções neurológicas em decorrência de desmielinização axonal, principalmente na substância branca dos órgãos do SNC. A doença acomete mais de 2 milhões de pessoas no mundo todo e não tem cura. As abordagens terapêuticas utilizadas com sucesso consistem na aplicação de anticorpos monoclonais, citocinas imunomoduladoras e fármacos antiinflamatórios. Ainda assim, tais estratégias são dependentes de produtos de alto custo e toxicidade. A utilização de fármacos antimaláricos no tratamento da Encefalomielite Autoimune Experimental (EAE, modelo experimental de EM), como cloroquina e diidroartemisinina, tem apresentado resultados promissores na atenuação do quadro clínico dos camundongos; entretanto, os efeitos tóxicos dessas substâncias constituem um importante fator limitante para a utilização clínica. Neste sentido, o presente trabalho teve por objetivo caracterizar os efeitos terapêuticos da primaquina (PQ), um fármaco antimalárico análogo à cloroquina mas com toxicidade reduzida, na EAE emvcamundongos C57BL/6. Para tanto, camundongos foram tratados com PQ por via intraperitoneal (i.p.) por cinco dias consecutivos e os efeitos da administração direta foram avaliados sobre as subpopulações de linfócitos T esplênicos. Semelhantemente...

Efeito do interferon tipo I na indução da função tolerogênica das células dendríticas plasmocitóides na encefalomielite experimental autoimune = : Effect of type I interferon induction of tolerogenic function of plasmacytoid dendritic cells in experimental autoimmune encephalomyelitis; Effect of type I interferon induction of tolerogenic function of plasmacytoid dendritic cells in experimental autoimmune encephalomyelitis

Mariana Peres Almeida Santos
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 05/08/2014 PT
Relevância na Pesquisa
46.31%
O Resumo poderá ser visualizado no texto completo da tese digital.; The Abstract is available with the full electronic digital document.

Impacto do tratamento com pregabalina sobre a plasticidade sináptica e reatividade glial durante o curso da encefalomielite autoimune experimental (EAE); Impact of pregabalin treatment on synaptic plasticity and glial reactivity during the course of experimental autoimmune encephalomyelitis (EAE)

Gleidy Ana Araujo Silva
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 27/03/2013 PT
Relevância na Pesquisa
56.39%
A esclerose múltipla se caracteriza por gerar uma inflamação esmielinizantecrônica e de caráter autoimune no sistema nervoso central, gerando uma série desinais e sintomas clínicos. Um modelo experimental para estudo da esclerosemúltipla é a encefalomielite autoimune experimental (EAE). Durante o curso da EAE, observa-se no SNC, perda de contatos sinápticos, bem como aumento da gliose reativa, envolvendo tanto astrócitos quanto células microgliais. Assim, a amenização dessas alterações, por tratamentos farmacológicos, pode ser útil no tratamento dos sintomas da EM. Neste sentido, o emprego da pregabalina, um ligante da proteína ?2-? associada a canais de cálcio voltagem-dependentes em neurônios, pode se constituir numa estratégia para o controle dos sintomas da doença. Assim, o presente estudo investigou o efeito da pregabalina sobre o curso da EAE, através da análise clínica de ratos Lewis imunizados com MBP e avaliação imunoistoquímica da medula espinal, utilizando marcadores para sinapses, astrogliose e reação microglial. Adicionalmente, através de RT-PCR, avaliou-se a expressão gênica de interleucinas pró e anti-inflamatórias, bem como a recuperação motora nos grupos placebo e tratado, foi avaliada pelo walking track test (CatWalk System). Os resultados demonstraram que o tratamento com pregabalina foi capaz de atrasar e amenizar os sinais clínicos e morfológicos da EAE...

A role for macrophage inflammatory protein-3 a/CC chemokine ligand 20 in immune priming during T cell-mediated inflammation of the central nervous system

Kohler, R.; Caon, A.; Willenborg, D.; Clark-Lewis, I.; McColl, S.
Fonte: Amer Assoc Immunologists Publicador: Amer Assoc Immunologists
Tipo: Artigo de Revista Científica
Publicado em //2003 EN
Relevância na Pesquisa
46.12%
Chemokines are a family of cytokines that exhibit selective chemoattractant properties for target leukocytes and play a significant role in leukocyte migration. In this study, we have investigated the role of the C-C chemokine, macrophage inflammatory protein (MIP)-3/CC chemokine ligand 20, in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model of T cell-dependent inflammation. Expression in the CNS of MIP-3, as determined by RT-PCR, increased in a time-dependent manner such that peak expression correlated with peak clinical disease. Similarly, levels of immunoreactive MIP-3 in the draining lymph nodes increased up to 10-fold 9 days postimmunization and remained elevated for up to 21 days postimmunization. The increased production of MIP-3 coincided with onset of clinical disease. Treatment of mice with specific neutralizing anti-MIP-3 Abs significantly reduced the severity of both clinical EAE and neuroinflammation by inhibiting the sensitization of lymphocytes to the specific Ag and release of lymphocytes from the draining lymph nodes. In contrast, adoptive transfer experiments indicated that MIP-3 was not essential for the effector phase of EAE. Together, these data demonstrate that MIP-3 plays a critical role in the sensitization phase of EAE.; Rachel E. Kohler...

Treatment with Anti-Granulocyte Antobodies Inhibits the Effector Phase of Experimental Autoimmune Envephalomyelitis

McColl, S.; Staykova, M.; Wozniak, A.; Fordham, S.; Bruce, J.; Willenborg, D.
Fonte: AMER ASSOC IMMUNOLOGISTS Publicador: AMER ASSOC IMMUNOLOGISTS
Tipo: Artigo de Revista Científica
Publicado em //1998 EN
Relevância na Pesquisa
56.24%
Emerging data suggest that polymorphonuclear leukocytes (PMNLs) can play an important role in Ag-dependent immune responses. Therefore, we have assessed the involvement of these cells in the development of an organ-specific autoimmune disease, experimental autoimmune encephalomyelitis (EAE), in the mouse. Depletion of peripheral blood PMNLs beginning day 8 after immunization significantly delayed and in some cases totally prevented the development of clinical EAE in mice. Depletion of PMNLs beginning 1 day before sensitization and continuing until day 7 postimmunization had no effect on the subsequent development of EAE, suggesting that depletion alters the efferent but not the afferent arm of the immune response. In vitro studies showed that lymphoid cells from mice protected from EAE by PMNL depletion beginning on day 8 postsensitization proliferated in response to specific Ag to a level equal to cells from sensitized animals treated with control serum, again indicating that treatment was not affecting the afferent limb of the immune response. Further evidence that PMNL may be necessary in initiating the pathology of EAE was seen in passive transfer experiments where PMNL-depleted recipients of MBP-specific lymphoid effector cells developed EAE much less effectively than did animals treated with control Ab. Taken together...

Expression of rat I-TAC/CXCL11/SCYA11 during central nervous system inflammation: comparison with other CXCR3 ligands

McColl, S.; Mahalingam, S.; Staykova, M.; Tylaska, L.; Fisher, K.; Strick, C.; Gladue, R.; Neote, K.; Willenborg, D.
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Publicado em //2004 EN
Relevância na Pesquisa
46.12%
The chemokines are a large gene superfamily with critical roles in development and immunity. The chemokine receptor CXCR3 appears to play a major role in the trafficking of activated Th1 lymphocytes. There are at least three major ligands for CXCR3: mig/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11, and of these three ligands, CXCL11 is the least well-characterized. In this study, we have cloned a rat ortholog of CXCL11, evaluated its function, and examined its expression in the Th-1-mediated disease, experimental autoimmune encephalomyelitis (EAE) in the rat. Based on its predicted primary amino-acid sequence, rat I-TAC/CXCL11 was synthesized and shown to induce chemotaxis of activated rat T lymphocytes in vitro and the in vivo migration of T lymphocytes when injected into the skin. I-TAC/CXCL11 expression, as determined by RT-PCR, increased in lymph node and spinal cord tissue collected from rats in which EAE had been actively induced, and in spinal cord tissue from rats in which EAE had been passively induced. The kinetics of expression were similar to that of CXCR3 and IP-10/CXCL10, although expression of both CXCR3 and IP-10/CXCL10 was more intense than that of I-TAC/CXCL11 and increased more rapidly in both lymph nodes and the spinal cord. Only minor levels of expression of the related chemokine mig/CXCL9 were observed. Immunohistochemistry revealed that the major cellular source of I-TAC/CXCL11 in the central nervous system (CNS) during EAE is likely to be the astrocyte. Together...

Antagonism of the chemokine receptors CXCR3 and CXCR4 reduces the pathology of experimental autoimmune encephalomyelitis

Kohler, R.; Comerford, I.; Townley, S.; Haylock-Jacobs, S.; Clark-Lewis, I.; McColl, S.
Fonte: Int Soc Neuropathology Publicador: Int Soc Neuropathology
Tipo: Artigo de Revista Científica
Publicado em //2008 EN
Relevância na Pesquisa
56.31%
Chemokines regulate lymphocyte trafficking under physiologic and pathologic conditions. In this study, we have investigated the role of CXCR3 and CXCR4 in the activation of T lymphocytes and their migration to the central nervous system (CNS) using novel mutant chemokines to antagonize CXCR3 and CXCR4 specifically. A series of truncation mutants of CXCL11, which has the highest affinity for CXCR3, were synthesized, and an antagonist, CXCL11((4-79)), was obtained. CXCL11((4-79)) strongly inhibited the migration of activated mouse T cells in response to all three high-affinity CXCR3 ligands, CXCL9, 10 and 11. CXCL12((P2G2)), while exhibiting minimal agonistic activity, potently inhibited the migration of activated mouse T cells in response to CXCL12. Interfering with the action of CXCR3 and CXCR4 with these synthetic receptor antagonists inhibited experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis and reduced the accumulation of CD4(+) T cells in the CNS. Further investigation demonstrated that CXCL12((P2G2)) inhibited the sensitization phase, whereas CXCL11((4-79)) inhibited the effector phase of the immune response. Our data suggest that simultaneous targeting of CXCR4 and CXCR3 may be of benefit in the treatment of the CNS autoimmune disease.; The definitive version may be found at www.wiley.com

Inhibition of CCR6 Function Reduces the Severity of Experimental Autoimmune Encephalomyelitis via Effects on the Priming Phase of the Immune Response

Liston, A.; Kohler, R.; Townley, S.; Haylock-Jacobs, S.; Comerford, I.; Caon, A.; Webster, J.; Harrison, J.; Swann, J.; Clark-Lewis, I.; Korner, H.; McColl, S.
Fonte: Amer Assoc Immunologists Publicador: Amer Assoc Immunologists
Tipo: Artigo de Revista Científica
Publicado em //2009 EN
Relevância na Pesquisa
56.28%
Chemokines are essential for homeostasis and activation of the immune system. The chemokine ligand/receptor pairing CCL20/CCR6 is interesting because these molecules display characteristics of both homeostatic and activation functions. These dual characteristics suggest a role for CCR6 in the priming and effector phases of the immune response. However, while CCR6 has been implicated in the effector phase in several models, a role in the priming phase is less clear. Herein we analyze the role of CCR6 in these two important arms of the immune response during experimental autoimmune encephalomyelitis (EAE). Both CCR6 and its chemokine ligand CCL20 were up-regulated in the draining lymph nodes and spinal cord during EAE, and CCR6 was up-regulated on CD4(+) T cells that had divided following induction of EAE. The functional role of this expression was demonstrated by impaired development of EAE in gene-targeted CCR6-deficient mice and in mice treated either with a neutralizing anti-CCR6 Ab or with a novel receptor antagonist. Inhibition of EAE was due to reduced priming of autoreactive CD4(+) T cells probably as a result of impaired late-stage influx of dendritic cells into draining lymph nodes. This was accompanied by reduced egress of activated lymphocytes from the lymph nodes. These results demonstrate a novel role for CCR6 in the mechanism of autoreactive lymphocyte priming and emigration to the efferent lymphatics.; Adrian Liston...

Transplantation of autoimmune regulator-encoding bone marrow cells delays the onset of experimental autoimmune encephalomyelitis

Ko, H.J.; Kinkel, S.; Hubert, F.X.; Nasa, Z.; Chan, J.; Siatskas, C.; Hirubalan, P.; Toh, B.H.; Scott, H.; Alderuccio, F.
Fonte: Wiley-V C H Verlag GMBH Publicador: Wiley-V C H Verlag GMBH
Tipo: Artigo de Revista Científica
Publicado em //2010 EN
Relevância na Pesquisa
36.38%
The autoimmune regulator (AIRE) promotes "promiscuous" expression of tissue-restricted antigens (TRA) in thymic medullary epithelial cells to facilitate thymic deletion of autoreactive T-cells. Here, we show that AIRE-deficient mice showed an earlier development of myelin oligonucleotide glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). To determine the outcome of ectopic Aire expression, we used a retroviral transduction system to over-express Aire in vitro, in cell lines and in bone marrow (BM). In the cell lines that included those of thymic medullary and dendritic cell origin, ectopically expressed Aire variably promoted expression of TRA including Mog and Ins2 (proII) autoantigens associated, respectively, with the autoimmune diseases multiple sclerosis and type 1 diabetes. BM chimeras generated from BM transduced with a retrovirus encoding Aire displayed elevated levels of Mog and Ins2 expression in thymus and spleen. Following induction of EAE with MOG(35-55), transplanted mice displayed significant delay in the onset of EAE compared with control mice. To our knowledge, this is the first example showing that in vivo ectopic expression of AIRE can modulate TRA expression and alter autoimmune disease development.; Hyun-Ja Ko...

PI3Kδ drives the pathogenesis of experimental autoimmune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17 differentiation; PI3Kdelta drives the pathogenesis of experimental autoimmune encephalomyelitis by inhibiting effector T cell apoptosis and promoting Th17 differentiation

Haylock-Jacobs, S.; Comerford, I.; Bunting, M.; Kara, E.; Townley, S.; Klingler-Hoffmann, M.; Vanhaesebroeck, B.; Puri, K.; McColl, S.
Fonte: Academic Press Ltd Publicador: Academic Press Ltd
Tipo: Artigo de Revista Científica
Publicado em //2011 EN
Relevância na Pesquisa
36.42%
The Class IA phosphoinositide 3-kinase delta (PI3Kδ) has been implicated in multiple signaling pathways involved in leukocyte activation and hence is an attractive target in many human autoimmune diseases, including multiple sclerosis (MS). Here, using mice expressing a catalytically inactive form of the PI3Kδ subunit p110δ, we show that signaling through PI3Kδ is required for full and sustained pathology of experimental autoimmune encephalomyelitis (EAE), a Th17-driven model of MS. In p110δ-inactivated mice, T cell activation and function during EAE was markedly reduced and fewer T cells were observed in the central nervous system (CNS). The decrease in T cell activation is unlikely to be due to defects in dendritic cell (DC) function, as p110δ-inactivated DCs migrate and present antigen normally. However, significant increases in the proportion of T cells undergoing apoptosis at early stages of EAE were evident in the absence of PI3Kδ activity. Furthermore, a profound defect in Th17 cellular responses during EAE was apparent in the absence of PI3Kδ activity while Th1 responses were less affected. A highly selective PI3Kδ inhibitor, IC87114, also had greater inhibitory effects on Th17 cell generation in vitro than it did on Th1 cell generation. Thus...

PI3Kγ drives priming and survival of autoreactive CD4⁺ T cells during experimental autoimmune encephalomyelitis; PI3Kgamma drives priming and survival of autoreactive CD4(+) T cells during experimental autoimmune encephalomyelitis

Comerford, I.; Litchfield, W.; Kara, E.; McColl, S.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em //2012 EN
Relevância na Pesquisa
56.38%
The class IB phosphoinositide 3-kinase γ enzyme complex (PI3Kc) functions in multiple signaling pathways involved in leukocyte activation and migration, making it an attractive target in complex human inflammatory diseases including MS. Here, using pik3cg2/2 mice and a selective PI3Kc inhibitor, we show that PI3Kc promotes development of experimental autoimmune encephalomyelitis (EAE). In pik3cg2/2 mice, EAE is markedly suppressed and fewer leukocytes including CD4+ and CD8+ T cells, granulocytes and mononuclear phagocytes infiltrate the CNS. CD4+ T cell priming in secondary lymphoid organs is reduced in pik3cg2/2 mice following immunisation. This is attributable to defects in DC migration concomitant with a failure of full T cell activation following TCR ligation in the absence of p110c. Together, this results in suppressed autoreactive T cell responses in pik3cg2/2 mice, with more CD4+ T cells undergoing apoptosis and fewer cytokineproducing Th1 and Th17 cells in lymphoid organs and the CNS. When administered from onset of EAE, the orally active PI3Kc inhibitor AS605240 caused inhibition and reversal of clinical disease, and demyelination and cellular pathology in the CNS was reduced. These results strongly suggest that inhibitors of PI3Kc may be useful therapeutics for MS.; Iain Comerford...

Distinct chemokine receptor axes regulate Th9 cell trafficking to allergic and autoimmune inflammatory sites

Kara, E.; Comerford, I.; Bastow, C.; Fenix, K.; Litchfield, W.; Handel, T.; McColl, S.
Fonte: Amer Assoc Immunologists Publicador: Amer Assoc Immunologists
Tipo: Artigo de Revista Científica
Publicado em //2013 EN
Relevância na Pesquisa
56.17%
Migration of Th cells to peripheral sites of inflammation is essential for execution of their effector function. The recently described Th9 subset characteristically produces IL-9 and has been implicated in both allergy and autoimmunity. Despite this, the migratory properties of Th9 cells remain enigmatic. In this study, we examined chemokine receptor usage by Th9 cells and demonstrate, in models of allergy and autoimmunity, that these cells express functional CCR3, CCR6, and CXCR3, chemokine receptors commonly associated with other, functionally opposed effector Th subsets. Most Th9 cells that express CCR3 also express CXCR3 and CCR6, and expression of these receptors appears to account for the recruitment of Th9 cells to disparate inflammatory sites. During allergic inflammation, Th9 cells use CCR3 and CCR6, but not CXCR3, to home to the peritoneal cavity, whereas Th9 homing to the CNS during experimental autoimmune encephalomyelitis involves CXCR3 and CCR6 but not CCR3. To our knowledge, these data provide the first insights into regulation of Th9 cell trafficking in allergy and autoimmunity.; Ervin E. Kara, Iain Comerford, Cameron R. Bastow, Kevin A. Fenix, Wendel Litchfield, Tracy M. Handel, and Shaun R. McColl

Quantitative proteome profiling of CNS-infiltrating autoreactive CD4⁺ cells reveals selective changes during experimental autoimmune encephalomyelitis; Quantitative proteome profiling of CNS-infiltrating autoreactive CD4(+) cells reveals selective changes during experimental autoimmune encephalomyelitis

Turvey, M.E.; Koudelka, T.; Comerford, I.; Greer, J.M.; Carroll, W.; Bernard, C.C.A.; Hoffmann, P.; McColl, S.R.
Fonte: American Chemical Society Publicador: American Chemical Society
Tipo: Artigo de Revista Científica
Publicado em //2014 EN
Relevância na Pesquisa
36.4%
Experimental autoimmune encephalomyelitis (EAE) is a murine model of multiple sclerosis, a chronic neurodegenerative and inflammatory autoimmune condition of the central nervous system (CNS). Pathology is driven by the infiltration of autoreactive CD4(+) lymphocytes into the CNS, where they attack neuronal sheaths causing ascending paralysis. We used an isotope-coded protein labeling approach to investigate the proteome of CD4(+) cells isolated from the spinal cord and brain of mice at various stages of EAE progression in two EAE disease models: PLP139-151-induced relapsing-remitting EAE and MOG35-55-induced chronic EAE, which emulate the two forms of human multiple sclerosis. A total of 1120 proteins were quantified across disease onset, peak-disease, and remission phases of disease, and of these 13 up-regulated proteins of interest were identified with functions relating to the regulation of inflammation, leukocyte adhesion and migration, tissue repair, and the regulation of transcription/translation. Proteins implicated in processes such as inflammation (S100A4 and S100A9) and tissue repair (annexin A1), which represent key events during EAE progression, were validated by quantitative PCR. This is the first targeted analysis of autoreactive cells purified from the CNS during EAE...

Behandlung mit CDK5 Inhibitor bei der Myelin Oligodendrozyten Glykoprotein (MOG) induzierten experimentellen autoimmunen Encephalomyelitis (EAE); Treatment with CDK5 inhibitor in myelin oligodendrocyte glycoprotein (MOG) induced experimental autoimmune encephalomyelitis (EAE)

Herlan, Stephan
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
Relevância na Pesquisa
36.4%
Die multiple Sklerose (MS) ist eine inflammatorisch-entzündliche Erkrankung des zentralen Nervensystems (ZNS), bei der Läsionen und Entmarkungsherde in der weißen, sowie der grauen Substanz des ZNS auftreten. Neben der Demyelinisierung, ist auch eine Axon- und Neurodegeneration Gegenstand aktueller Forschung, die bei den Patienten mit MS im Verlauf der Erkrankung bleibende neurologische Defizite hervorrufen und für das klinische Bild der MS verantwortlich gemacht werden können. Die Myelin Oligodendrozyten Glykoprotein (MOG) induzierte experimentelle autoimmune Encephalomyelitis (EAE), dient als Tiermodell der MS und kann einige relevante immunologische und pathogenetische Mechanismen reproduzieren. Eine Überaktivierung der Cyclin abhängigen Kinase 5 (CDK5), hervorgerufen durch eine proteolytische Spaltung des spezifischen Aktivators p35 zum potenteren Spaltprodukt p25, wurde bei verschiedenen neurodegenerativen Erkrankungen beobachtet. Die fehlregulierte Aktivierung von CDK5 kann zu einer Hyperphosphorylierung des mikrotubuli-assoziierten Proteins Tau führen, was mit einer Axon- und Neurodegeneration einhergeht. Diese pathologischen Veränderungen konnten auch bei der EAE bei kongenen LEW.1N Ratten gezeigt werden (Schneider et al....

Biomarkers for Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis: Possible mechanisms mediating neurodegeneration; Biomarker für Experimental Autoimmune Encephalomyelitis und Multiple Sklerose: Mögliche Mechanismen der Neurodegeneration

Jastorff, Archana Mary
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
EN
Relevância na Pesquisa
36.52%
Since the mid-1800s, Multiple Sclerosis (MS) has been considered an episodic-inflammatory disorder of the central nervous system (CNS) characterized by inflammatory plaques with demyelination and relative preservation of axons. MS is believed to be an autoimmune disorder driven by encephalitogenic T cells which can attack the myelin sheath after activation in the periphery of the immune system. However, recent studies have rediscovered neurodegenerative components of the disease like axonal loss, and neuronal atrophy which seem to be the histopathological correlates of progressive clinical disability in MS patients. For this reason the focus in MS research increasingly includes the study of neurobiological aspects in addition to the classical neuroimmunological features. Despite the profound understanding of the different aspects of the pathogenesis of MS there is still a major inadequacy of effective long-term therapeutic interventions and early diagnostic measures. Moreover, the vast majority of therapeutic agents used in clinical trials today are directed against the immunological features of the disease, leaving for the most part untreated the disease processes that lead to irreversible CNS dysfunction in the patients. Therefore developing new therapies for MS that are aimed at preventing or repairing one or more of these disease mechanisms is of great importance. The shortcoming of effective long term treatment can be partially ascribed to the oversimplification of MS as an inflammatory...