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1.
Neuropathol Appl Neurobiol ; 49(1): e12851, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36181265

RESUMO

AIMS: Axonal injury in multiple sclerosis (MS) and experimental models is most frequently detected in acutely demyelinating lesions. We recently reported a compensatory neuronal response, where mitochondria move to the acutely demyelinated axon and increase the mitochondrial content following lysolecithin-induced demyelination. We termed this homeostatic phenomenon, which is also evident in MS, the axonal response of mitochondria to demyelination (ARMD). The aim of this study is to determine whether ARMD is consistently evident in experimental demyelination and how its perturbation relates to axonal injury. METHODS: In the present study, we assessed axonal mitochondrial content as well as axonal mitochondrial respiratory chain complex IV activity (cytochrome c oxidase or COX) of axons and related these to axonal injury in nine different experimental disease models. We used immunofluorescent histochemistry as well as sequential COX histochemistry followed by immunofluorescent labelling of mitochondria and axons. RESULTS: We found ARMD a consistent and robust phenomenon in all experimental disease models. The increase in mitochondrial content within demyelinated axons, however, was not always accompanied by a proportionate increase in complex IV activity, particularly in highly inflammatory models such as experimental autoimmune encephalomyelitis (EAE). Axonal complex IV activity inversely correlated with the extent of axonal injury in experimental disease models. CONCLUSIONS: Our findings indicate that ARMD is a consistent and prominent feature and emphasise the importance of complex IV activity in the context of ARMD, especially in autoimmune inflammatory demyelination, paving the way for the development of novel neuroprotective therapies.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Esclerose Múltipla/patologia , Axônios/patologia , Encefalomielite Autoimune Experimental/patologia , Neurônios/patologia , Mitocôndrias/patologia
2.
Acta Neuropathol ; 140(2): 143-167, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32572598

RESUMO

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.


Assuntos
Doenças Desmielinizantes/patologia , Mitocôndrias/patologia , Esclerose Múltipla/patologia , Degeneração Neural/patologia , Neuroproteção/fisiologia , Animais , Axônios/patologia , Humanos , Camundongos , Biogênese de Organelas
3.
J Immunol ; 201(11): 3229-3243, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30341184

RESUMO

Experimental autoimmune encephalomyelitis (EAE) in common marmosets is a translationally relevant model of the chronic neurologic disease multiple sclerosis. Following the introduction of a new dietary supplement in our purpose-bred marmoset colony, the percentage of marmosets in which clinically evident EAE could be induced by sensitization against recombinant human myelin oligodendrocyte glycoprotein in IFA decreased from 100 to 65%. The reduced EAE susceptibility after the dietary change coincided with reduced Callitrichine herpesvirus 3 expression in the colony, an EBV-related γ1-herpesvirus associated with EAE. We then investigated, in a controlled study in marmoset twins, which disease-relevant parameters were affected by the dietary change. The selected twins had been raised on the new diet for at least 12 mo prior to the study. In twin siblings reverted to the original diet 8 wk prior to EAE induction, 100% disease prevalence (eight out of eight) was restored, whereas in siblings remaining on the new diet the EAE prevalence was 75% (six out of eight). Spinal cord demyelination, a classical hallmark of the disease, was significantly lower in new-diet monkeys than in monkeys reverted to the original diet. In new-diet monkeys, the proinflammatory T cell response to recombinant human myelin oligodendrocyte glycoprotein was significantly reduced, and RNA-sequencing revealed reduced apoptosis and enhanced myelination in the brain. Systematic typing of the marmoset gut microbiota using 16S rRNA sequencing demonstrated a unique, Bifidobacteria-dominated composition, which changed after disease induction. In conclusion, targeted dietary intervention exerts positive effects on EAE-related parameters in multiple compartments of the marmoset's gut-immune-CNS axis.


Assuntos
Bifidobacterium/genética , Encéfalo/fisiologia , Células/imunologia , Suplementos Nutricionais , Encefalomielite Autoimune Experimental/dietoterapia , Esclerose Múltipla/dietoterapia , Medula Espinal/patologia , Animais , Apoptose , Callithrix , Células Cultivadas , Doenças Desmielinizantes , Dietoterapia , Modelos Animais de Doenças , Microbioma Gastrointestinal/genética , Herpesvirus Humano 3 , Humanos , Glicoproteína Mielina-Oligodendrócito/imunologia , RNA Ribossômico 16S/genética , Análise de Sequência de RNA
4.
J Immunol ; 192(9): 4242-53, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24696233

RESUMO

Depleting mAbs against the pan B cell marker CD20 are remarkably effective in the treatment of autoimmune-mediated inflammatory disorders, but the underlying mechanisms are poorly defined. The primary objective of this study was to find a mechanistic explanation for the remarkable clinical effect of the anti-CD20 mAbs in a representative nonhuman primate autoimmune-mediated inflammatory disorder model, experimental autoimmune encephalomyelitis (EAE) in common marmosets, allowing detailed analysis of secondary lymphoid organs (SLO). We observed that the depletion of CD20(+) B cells creates a less immunostimulatory environment in the SLO reflected by reduced expression of MHC class II, CD40, CD83, and CD80/CD86. APCs isolated from SLO of B cell-depleted EAE monkeys were also less responsive to mitogenic stimulation. The depleted B cell areas were replenished by T cells, of which the majority expressed CD127 (IL-7R) and CCR7. Such effects were not detected in EAE marmosets treated with mAb against BLyS or APRIL, where B cell depletion via withdrawal of essential survival cytokines was not associated with a marked clinical effect. We propose that at least part of the efficacy of anti-CD20 mAb therapy is attributable to the sustained CCR7 expression on T cells within SLO, limiting their release into the circulation.


Assuntos
Anticorpos Monoclonais/farmacologia , Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD20/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Callithrix , Quimiotaxia de Leucócito/efeitos dos fármacos , Citometria de Fluxo , Imuno-Histoquímica , Depleção Linfocítica/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Sci Rep ; 13(1): 5074, 2023 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-36977691

RESUMO

Influenza virosomes serve as antigen delivery vehicles and pre-existing immunity toward influenza improves the immune responses toward antigens. Here, vaccine efficacy was evaluated in non-human primates with a COVID-19 virosome-based vaccine containing a low dose of RBD protein (15 µg) and the adjuvant 3M-052 (1 µg), displayed together on virosomes. Vaccinated animals (n = 6) received two intramuscular administrations at week 0 and 4 and challenged with SARS-CoV-2 at week 8, together with unvaccinated control animals (n = 4). The vaccine was safe and well tolerated and serum RBD IgG antibodies were induced in all animals and in the nasal washes and bronchoalveolar lavages in the three youngest animals. All control animals became strongly sgRNA positive in BAL, while all vaccinated animals were protected, although the oldest vaccinated animal (V1) was transiently weakly positive. The three youngest animals had also no detectable sgRNA in nasal wash and throat. Cross-strain serum neutralizing antibodies toward Wuhan-like, Alpha, Beta, and Delta viruses were observed in animals with the highest serum titers. Pro-inflammatory cytokines IL-8, CXCL-10 and IL-6 were increased in BALs of infected control animals but not in vaccinated animals. Virosomes-RBD/3M-052 prevented severe SARS-CoV-2, as shown by a lower total lung inflammatory pathology score than control animals.


Assuntos
COVID-19 , Vacinas contra Influenza , Influenza Humana , Animais , Humanos , Macaca mulatta , Virossomos , SARS-CoV-2 , Receptor 7 Toll-Like , COVID-19/prevenção & controle , Adjuvantes Imunológicos , Anticorpos Amplamente Neutralizantes , Vacinas contra COVID-19 , Anticorpos Antivirais , Anticorpos Neutralizantes
6.
J Immunol ; 185(7): 3990-4003, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20739677

RESUMO

Depletion of CD20(+) B cells has been related to reduced clinical activity in relapsing-remitting multiple sclerosis. The underlying mechanism is not understood, because serum IgG levels were unaltered by the treatment. We report the effect of late B cell depletion on cellular and humoral immune mechanisms in a preclinical multiple sclerosis model (i.e., experimental autoimmune encephalomyelitis [EAE] in the common marmoset). We used a novel human anti-human CD20 IgG1κ mAb (HuMab 7D8) that cross-reacts with marmoset CD20. EAE was induced in 14 marmosets by immunization with recombinant human myelin oligodendrocyte glycoprotein (MOG) in CFA. After 21 d, B cells were depleted in seven monkeys by HuMab 7D8, and seven control monkeys received PBS. The Ab induced profound and long-lasting B cell depletion from PBMCs and lymphoid organs throughout the observation period of 106 d. Whereas all of the control monkeys developed clinically evident EAE, overt neurologic deficits were reduced substantially in three HuMab 7D8-treated monkeys, and four HuMab 7D8-treated monkeys remained completely asymptomatic. The effect of HuMab 7D8 was confirmed on magnetic resonance images, detecting only small lesions in HuMab 7D8-treated monkeys. The infusion of HuMab 7D8 arrested the progressive increase of anti-MOG IgG Abs. Although CD3(+) T cell numbers in lymphoid organs were increased, their proliferation and cytokine production were impaired significantly. Most notable were the substantially reduced mRNA levels of IL-7 and proinflammatory cytokines (IL-6, IL-17A, IFN-γ, and TNF-α). In conclusion, B cell depletion prevents the development of clinical and pathological signs of EAE, which is associated with impaired activation of MOG-reactive T cells in lymphoid organs.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfócitos B/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Depleção Linfocítica/métodos , Animais , Anticorpos Monoclonais/imunologia , Antígenos CD20/imunologia , Linfócitos B/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Callithrix , Separação Celular , Citocinas/biossíntese , Citocinas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Citometria de Fluxo , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/uso terapêutico , Cadeias kappa de Imunoglobulina/imunologia , Cadeias kappa de Imunoglobulina/uso terapêutico , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Reação em Cadeia da Polimerase
7.
J Infect Dis ; 201(7): 1072-80, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20170375

RESUMO

Background. Synthetic human chorionic gonadotropin (hCG)-related oligopeptides are potent inhibitors of pathogenic inflammatory responses induced by in vivo lipopolysaccharide exposure or hemorrhagic shock-induced injury. In this study, we tested whether hCG-related oligopeptide treatment similarly altered inflammatory responses and innate host defenses in mice during experimental Listeria monocytogenes infection. Methods. Mice were infected with L. monocytogenes and treated with hCG-related oligopeptides (LQGV, VLPALP, or AQGV) or phosphate-buffered saline. Subsequently, mice were analyzed for bacterial loads, cytokine and chemokine responses, and inflammatory cell infiltrates in target organs. Results. Oligopeptide administration increased bacterial numbers in the spleen and liver at 6 h after infection. Simultaneously, CXCL1/KC and CCL2/MCP-1 plasma levels as well as neutrophil numbers in the spleen, blood, and peritoneal cavity decreased. In contrast, at 18 h after infection, systemic tumor necrosis factor alpha, interleukin 12 p70, interleukin 6, and interferon gamma levels increased statistically significantly in oligopeptide-treated mice compared with controls, which correlated with increased bacterial numbers. Conclusion. These data show that treatment with hCG-related oligopeptides (LQGV, VLPALP, and AQGV) inhibits early innate immune activation by reducing initial chemokine secretion following infection. This leads to bacterial overgrowth with subsequent enhanced systemic inflammation. Our data underscore the importance of early innate immune activation and suggest a role for hCG-derived oligopeptides at the placenta that increases the risk of L. monocytogenes infections.


Assuntos
Gonadotropina Coriônica/farmacologia , Listeria monocytogenes/imunologia , Listeriose/tratamento farmacológico , Listeriose/imunologia , Oligopeptídeos/farmacologia , Animais , Quimiocinas/sangue , Quimiocinas/imunologia , Contagem de Colônia Microbiana , Citocinas/sangue , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Imunidade Inata/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Infiltração de Neutrófilos/efeitos dos fármacos , Proteínas Recombinantes/farmacologia
8.
Expert Opin Drug Discov ; 13(5): 387-397, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29465302

RESUMO

INTRODUCTION: The translation of scientific discoveries made in animal models into effective treatments for patients often fails, indicating that currently used disease models in preclinical research are insufficiently predictive for clinical success. An often-used model in the preclinical research of autoimmune neurological diseases, multiple sclerosis in particular, is experimental autoimmune encephalomyelitis (EAE). Most EAE models are based on genetically susceptible inbred/SPF mouse strains used at adolescent age (10-12 weeks), which lack exposure to genetic and microbial factors which shape the human immune system. Areas covered: Herein, the authors ask whether an EAE model in adult non-human primates from an outbred conventionally-housed colony could help bridge the translational gap between rodent EAE models and MS patients. Particularly, the authors discuss a novel and translationally relevant EAE model in common marmosets (Callithrix jacchus) that shares remarkable pathological similarity with MS. Expert opinion: The MS-like pathology in this model is caused by the interaction of effector memory T cells with B cells infected with the γ1-herpesvirus (CalHV3), both present in the pathogen-educated marmoset immune repertoire. The authors postulate that depletion of only the small subset (<0.05%) of CalHV3-infected B cells may be sufficient to limit chronic inflammatory demyelination.


Assuntos
Descoberta de Drogas/métodos , Encefalomielite Autoimune Experimental/fisiopatologia , Esclerose Múltipla/fisiopatologia , Animais , Linfócitos B/imunologia , Callithrix , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Humanos , Camundongos , Esclerose Múltipla/tratamento farmacológico , Primatas , Especificidade da Espécie , Linfócitos T/imunologia
9.
Clin Pharmacol Ther ; 103(2): 262-270, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28748631

RESUMO

The poor predictive quality of currently used animal models in preclinical research is an important cause of the high attrition of promising drug candidates for human autoimmune disease in clinical trials. Examples from own work in a primate multiple sclerosis (MS) model illustrate that important lessons can be learned from a critical reassessment of failed drugs in the animal model, which can help improve the animal model and better understand the targeted disease.


Assuntos
Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Medicina Baseada em Evidências/métodos , Fatores Imunológicos/farmacologia , Esclerose Múltipla/tratamento farmacológico , Pesquisa Translacional Biomédica/métodos , Animais , Mineração de Dados , Bases de Dados Factuais , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/fisiopatologia , Humanos , Esclerose Múltipla/imunologia , Esclerose Múltipla/fisiopatologia , Segurança do Paciente , Medição de Risco
10.
J Neuroimmunol ; 182(1-2): 135-52, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17126916

RESUMO

Rhesus monkeys immunized with MOG(34-56), a dominant T-cell epitope from myelin/oligodendrocyte glycoprotein, develop an acute neurological disease resembling acute disseminated encephalomyelitis (ADEM) in humans. The typical large demyelinated lesions and mononuclear infiltrates in the monkey brains are caused by MOG(34-56) T-cells. We show that MOG(34-56)-reactive CD4+ and CD8+ T-cells are induced in monkeys immunized with a peptide from the human CMV major capsid protein (UL86; 981-1003), that shares sequence similarity with MOG(34-56). Monkeys sensitized against the viral peptide and subsequently challenged with MOG(34-56) display histological signs of encephalitis, but do not show overt neurological signs.


Assuntos
Proteínas do Capsídeo/imunologia , Colesterol/análogos & derivados , Encefalomielite Autoimune Experimental/imunologia , Epitopos de Linfócito T/imunologia , Glicoproteínas/imunologia , Macaca mulatta/imunologia , Fragmentos de Peptídeos/imunologia , Animais , Anticorpos/sangue , Encéfalo/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas do Capsídeo/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Colesterol/imunologia , Reações Cruzadas , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Feminino , Humanos , Ativação Linfocitária , Masculino , Monócitos/patologia , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Associada a Mielina/farmacologia , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/farmacologia , Polietilenoglicóis , Proteínas Recombinantes/imunologia , Medula Espinal/patologia
11.
Mult Scler J Exp Transl Clin ; 3(1): 2055217317690184, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28607749

RESUMO

Infection with Epstein-Barr virus (EBV) has been associated with an enhanced risk of genetically susceptible individuals to develop multiple sclerosis (MS). However, an explanation for the contrast between the high EBV infection prevalence (60-90%) and the low MS prevalence (0.1%) eludes us. Here we propose a new concept for the EBV-MS association developed in the experimental autoimmune encephalomyelitis model in marmoset monkeys, which are naturally infected with the EBV-related γ1-herpesvirus CalHV3. The data indicate that the infection of B cells with a γ1-herpesvirus endows them with the capacity to activate auto-aggressive CD8+ T cells specific for myelin oligodendrocyte glycoprotein.

12.
PLoS One ; 12(11): e0188013, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29136024

RESUMO

Oxidative stress is increasingly implicated as a co-factor of tissue injury in inflammatory/demyelinating disorders of the central nervous system (CNS), such as multiple sclerosis (MS). While rodent experimental autoimmune encephalomyelitis (EAE) models diverge from human demyelinating disorders with respect to limited oxidative injury, we observed that in a non-human primate (NHP) model for MS, namely EAE in the common marmoset, key pathological features of the disease were recapitulated, including oxidative tissue injury. Here, we investigated the presence of oxidative injury in another NHP EAE model, i.e. in rhesus macaques, which yields an acute demyelinating disease, which may more closely resemble acute disseminated encephalomyelitis (ADEM) than MS. Rhesus monkey EAE diverges from marmoset EAE by abundant neutrophil recruitment into the CNS and destructive injury to white matter. This difference prompted us to investigate to which extent the oxidative pathway features elicited in MS and marmoset EAE are reflected in the acute rhesus monkey EAE model. The rhesus EAE brain was characterized by widespread demyelination and active lesions containing numerous phagocytic cells and to a lesser extent T cells. We observed induction of the oxidative stress pathway, including injury, with a predilection of p22phox expression in neutrophils and macrophages/microglia. In addition, changes in iron were observed. These results indicate that pathogenic mechanisms in the rhesus EAE model may differ from the marmoset EAE and MS brain due to the neutrophil involvement, but may in the end lead to similar induction of oxidative stress and injury.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Estresse Oxidativo , Animais , Encéfalo/metabolismo , Ferro/metabolismo , Macaca mulatta
13.
Clin Transl Immunology ; 6(2): e127, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28243437

RESUMO

Despite the well-known association of Epstein-Barr virus (EBV), a lymphocryptovirus (LCV), with multiple sclerosis, a clear pathogenic role for disease progression has not been established. The translationally relevant experimental autoimmune encephalomyelitis (EAE) model in marmoset monkeys revealed that LCV-infected B cells have a central pathogenic role in the activation of T cells that drive EAE progression. We hypothesized that LCV-infected B cells induce T-cell functions relevant for EAE progression. In the current study, we examined the ex vivo cross-talk between lymph node mononuclear cells (MNCs) from EAE marmosets and (semi-) autologous EBV-infected B-lymphoblastoid cell lines (B-LCLs). Results presented here demonstrate that infection with EBV B95-8 has a strong impact on gene expression profile of marmoset B cells, particularly those involved with antigen processing and presentation or co-stimulation to T cells. At the cellular level, we observed that MNC co-culture with B-LCLs induced decrease of CCR7 expression on T cells from EAE responder marmosets, but not in EAE monkeys without clinically evident disease. B-LCL interaction with T cells also resulted in significant loss of CD27 expression and reduced expression of IL-23R and CCR6, which coincided with enhanced IL-17A production. These results highlight the profound impact that EBV-infected B-LCL cells can have on second and third co-stimulatory signals involved in (autoreactive) T-cell activation.

14.
Front Immunol ; 8: 804, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28744286

RESUMO

The absence of pathological hallmarks of progressive multiple sclerosis (MS) in commonly used rodent models of experimental autoimmune encephalomyelitis (EAE) hinders the development of adequate treatments for progressive disease. Work reviewed here shows that such hallmarks are present in the EAE model in marmoset monkeys (Callithrix jacchus). The minimal requirement for induction of progressive MS pathology is immunization with a synthetic peptide representing residues 34-56 from human myelin oligodendrocyte glycoprotein (MOG) formulated with a mineral oil [incomplete Freund's adjuvant (IFA)]. Pathological aspects include demyelination of cortical gray matter with microglia activation, oxidative stress, and redistribution of iron. When the peptide is formulated in complete Freund's adjuvant, which contains mycobacteria that relay strong activation signals to myeloid cells, oxidative damage pathways are strongly boosted leading to more intensive pathology. The proven absence of immune potentiating danger signals in the MOG34-56/IFA formulation implies that a narrow population of antigen-experienced T cells present in the monkey's immune repertoire is activated. This novel pathway involves the interplay of lymphocryptovirus-infected B cells with MHC class Ib/Caja-E restricted CD8+ CD56+ cytotoxic T lymphocytes.

15.
J Neuropathol Exp Neurol ; 76(6): 467-478, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28505283

RESUMO

Oxidative damage and iron redistribution are associated with the pathogenesis and progression of multiple sclerosis (MS), but these aspects are not entirely replicated in rodent experimental autoimmune encephalomyelitis (EAE) models. Here, we report that oxidative burst and injury as well as redistribution of iron are hallmarks of the MS-like pathology in the EAE model in the common marmoset. Active lesions in the marmoset EAE brain display increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p22phox, p47phox, and gp91phox) and inducible nitric oxide synthase immunoreactivity within lesions with active inflammation and demyelination, coinciding with enhanced expression of mitochondrial heat-shock protein 70 and superoxide dismutase 1 and 2. The EAE lesion-associated liberation of iron (due to loss of iron-containing myelin) was associated with altered expression of the iron metabolic markers FtH1, lactoferrin, hephaestin, and ceruloplasmin. The enhanced expression of oxidative damage markers in inflammatory lesions indicates that the enhanced antioxidant enzyme expression could not counteract reactive oxygen and nitrogen species-induced cellular damage, as is also observed in MS brains. This study demonstrates that oxidative injury and aberrant iron distribution are prominent pathological hallmarks of marmoset EAE thus making this model suitable for therapeutic intervention studies aimed at reducing oxidative stress and associated iron dysmetabolism.


Assuntos
Callithrix , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Ferro/metabolismo , Estresse Oxidativo , Animais , Doenças Desmielinizantes/patologia , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Imuno-Histoquímica , Masculino , Bainha de Mielina/metabolismo , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ferroproteínas não Heme/metabolismo , Superóxido Dismutase/metabolismo , Distribuição Tecidual
16.
Endocrinology ; 147(3): 1140-7, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16339209

RESUMO

The hypothalamus uses hormones and the autonomic nervous system to balance energy fluxes in the body. Here we show that the autonomic nervous system has a distinct organization in different body compartments. The same neurons control intraabdominal organs (intraabdominal fat, liver, and pancreas), whereas sc adipose tissue located outside the abdominal compartment receives input from another set of autonomic neurons. This differentiation persists up to preautonomic neurons in the hypothalamus, including the biological clock, that have a distinct organization depending on the body compartment they command. Moreover, we demonstrate a neuronal feedback from adipose tissue that reaches the brainstem. We propose that this compartment-specific organization offers a neuroanatomical perspective for the regional malfunction of organs in type 2 diabetes, where increased insulin secretion by the pancreas and disturbed glucose metabolism in the liver coincide with an augmented metabolic activity of visceral compared with sc adipose tissue.


Assuntos
Tecido Adiposo/metabolismo , Sistema Nervoso Autônomo/metabolismo , Encéfalo/patologia , Diabetes Mellitus Tipo 2/metabolismo , Fígado/metabolismo , Pâncreas/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Distribuição da Gordura Corporal , Encéfalo/metabolismo , Tronco Encefálico/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Homeostase , Hipotálamo/metabolismo , Insulina/metabolismo , Secreção de Insulina , Masculino , Síndrome Metabólica/patologia , Modelos Biológicos , Modelos Neurológicos , Neurônios Motores/metabolismo , Neurônios/metabolismo , Obesidade/metabolismo , Ratos , Ratos Wistar , Medula Espinal/metabolismo , Fatores de Tempo
17.
Drug Discov Today ; 21(8): 1200-5, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27060373

RESUMO

New drugs often fail in the translation from the rodent experimental autoimmune encephalomyelitis (EAE) model to human multiple sclerosis (MS). Here, we present the marmoset EAE model as an indispensable model for translational research into MS. The genetic heterogeneity of this species and lifelong exposure to chronic latent infections and environmental pathogens create a human-like immune system. Unique to this model is the presence of the pathological hallmark of progressive MS, in particular cortical grey matter lesions. Another great possibility of this model is systemic and longitudinal immune profiling, whereas in humans and mice immune profiling is usually performed in a single compartment (i.e. blood or spleen, respectively). Overall, the marmoset model provides unique opportunities for systemic drug-effect profiling.


Assuntos
Callithrix , Encefalomielite Autoimune Experimental/terapia , Imunoterapia , Esclerose Múltipla/terapia , Animais , Linfócitos B/imunologia , Linfócitos B/virologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Substância Cinzenta/patologia , Herpesvirus Humano 4/imunologia , Humanos , Linfonodos/imunologia , Camundongos , Baço/imunologia
18.
Methods Mol Biol ; 1304: 171-86, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25208751

RESUMO

Experimental autoimmune encephalomyelitis (EAE) in the common marmoset, a small-bodied Neotropical primate, is a well-known and validated animal model for multiple sclerosis (MS). This model can be used for exploratory research, i.e., investigating the pathogenic mechanisms involved in MS, and applied research, testing the efficacy of new potential drugs.In this chapter, we will describe a method to induce EAE in the marmoset. In addition, we will explain the most common immunological techniques involved in the marmoset EAE research, namely isolation of mononuclear cells (MNC) from peripheral blood and lymphoid tissue, assaying T cell proliferation by thymidine incorporation, MNC phenotyping by flow cytometry, antibody measurement by ELISA, generation of B cell lines and antigen-specific T cell lines, and assaying cytotoxic T cells.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Animais , Callithrix , Modelos Animais de Doenças , Imunofenotipagem , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo
19.
Trends Mol Med ; 22(12): 1012-1024, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27836419

RESUMO

Multiple sclerosis (MS) is thought to be initiated by the interaction of genetic and environmental factors, eliciting an autoimmune attack on the central nervous system. Epstein-Barr virus (EBV) is the strongest infectious risk factor, but an explanation for the paradox between high infection prevalence and low MS incidence remains elusive. We discuss new data using marmosets with experimental autoimmune encephalomyelitis (EAE) - a valid primate model of MS. The findings may help to explain how a common infection can contribute to the pathogenesis of MS. We propose that EBV infection induces citrullination of peptides in conjunction with autophagy during antigen processing, endowing B cells with the capacity to cross-present autoantigen to CD8+CD56+ T cells, thereby leading to MS progression.


Assuntos
Encefalomielite Autoimune Experimental/virologia , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/imunologia , Esclerose Múltipla/virologia , Animais , Apresentação de Antígeno , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos B/virologia , Citrulina/imunologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Humanos , Imunidade Celular , Complexo Principal de Histocompatibilidade , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Linfócitos T/virologia
20.
J Neuroimmune Pharmacol ; 11(1): 73-83, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26260924

RESUMO

Non-human primate models of human disease have an important role in the translation of a new scientific finding in lower species into an effective treatment. In this study, we tested a new therapeutic antibody against the IL-7 receptor α chain (CD127), which in a C57BL/6 mouse model of experimental autoimmune encephalomyelitis (EAE) ameliorates disease, demonstrating an important pathogenic function of IL-7. We observed that while the treatment was effective in 100 % of the mice, it was only partially effective in the EAE model in common marmosets (Callithrix jacchus), a small-bodied Neotropical primate. EAE was induced in seven female marmoset twins and treatment with the anti-CD127 mAb or PBS as control was started 21 days after immunization followed by weekly intravenous administration. The anti-CD127 mAb caused functional blockade of IL-7 signaling through its receptor as shown by reduced phosphorylation of STAT5 in lymphocytes upon stimulation with IL-7. Group-wise analysis showed no significant effects on the clinical course and neuropathology. However, paired twin analysis revealed a delayed disease onset in three twins, which were high responders to the immunization. In addition, we observed markedly opposite effects of the antibody on pathological changes in the spinal cord in high versus low responder twins. In conclusion, promising clinical effect of CD127 blockade observed in a standard inbred/SPF mouse EAE model could only be partially replicated in an outbred/non-SPF non-human primate EAE model. Only in high responders to the immunization we found a positive response to the treatment. The mechanism underpinning this dichotomous response will be discussed.


Assuntos
Anticorpos Monoclonais/farmacologia , Encefalomielite Autoimune Experimental/patologia , Subunidade alfa de Receptor de Interleucina-7/antagonistas & inibidores , Interleucina-7/imunologia , Animais , Callithrix , Encefalomielite Autoimune Experimental/imunologia , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Reação em Cadeia da Polimerase
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