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1.
J Immunol ; 187(1): 274-82, 2011 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-21646293

RESUMEN

Mast cells (MCs) have been thought to play a pathogenic role in the development of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, an immunoregulatory function of these cells has recently been suggested. We investigated the role of MCs in EAE using the W(-sh) mouse strain, which is MC deficient. W(-sh) mice developed earlier and more severe clinical and pathological disease with extensive demyelination and inflammation in the CNS. The inflammatory cells were mainly composed of CD4(+) T cells, monocyte/macrophages, neutrophils, and dendritic cells. Compared with wild-type mice, MC-deficient mice exhibited an increased level of MCP-1/CCR2 and CD44 expression on CD4(+) T cells in addition to decreased production of regulatory T cells, IL-4, IL-5, IL-27, and IL-10. We also found that levels of IL-17, IFN-γ, and GM-CSF were significantly increased in peripheral lymphocytes from immunized W(-sh) mice compared with those in peripheral lymphocytes from wild-type mice. Reconstitution of W(-sh) mice downregulated susceptibility to EAE, which correlated with MC recruitment and regulatory T cell activation in the CNS. These findings indicate that responsiveness is not required in the pathogenesis of inflammatory demyelination in the CNS and that, in the absence of MCs, increased MCP-1, CCR2, IL-17, IFN-γ, CD44, and other inflammatory molecules may be responsible for increased severity of EAE.


Asunto(s)
Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Mastocitos/inmunología , Mastocitos/patología , Proteínas Proto-Oncogénicas c-kit/deficiencia , Índice de Severidad de la Enfermedad , Animales , Encefalomielitis Autoinmune Experimental/patología , Femenino , Predisposición Genética a la Enfermedad , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/toxicidad , Glicoproteína Mielina-Oligodendrócito , Proteínas Proto-Oncogénicas c-kit/genética , Médula Espinal/inmunología , Médula Espinal/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología
2.
Eur J Immunol ; 41(2): 313-23, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21268002

RESUMEN

Stimulation of Ag-specific inducible Treg can enhance resolution of autoimmune disease. Conventional methods to induce Treg often require induction of autoimmune disease or subjection to infection. Reovirus adhesin, protein σ1 (pσ1), can successfully facilitate tolerance when fused to a tolerogen. We tested whether myelin oligodendrocyte glycoprotein (MOG) fused to pσ1 (MOG-pσ1) can stimulate Ag-specific Treg. We show that C57BL/6 mice treated nasally with MOG-pσ1 fail to induce MOG-specific Abs and delayed-type hypersensitivity (DTH) responses and resist EAE. Such resistance was attributed to stimulation of Foxp3(+) Treg, as well as Th2 cells. MOG-pσ1's protective capacity was abrogated in IL-10(-/-) mice, but restored when adoptively transferred with MOG-pσ1-induced Treg. As a therapeutic, MOG-pσ1 diminished EAE within 24 h of nasal application, unlike recombinant MOG (rMOG), pσ1, or pσ1+rMOG, implicating the importance of Ag specificity by pσ1-based therapeutics. MOG-pσ1-treated mice showed elevated IL-4, IL-10, and IL-28 production by CD4(+) T cells, unlike rMOG treated or control mice that produced elevated IFN-γ or IL-17, respectively. These data show the feasibility of using pσ1 as a tolerogen platform for Ag-specific tolerance induction and highlight its potential use as an immunotherapeutic for autoimmunity.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/terapia , Interleucina-10/inmunología , Linfocitos T Reguladores/inmunología , Vacunación/métodos , Traslado Adoptivo , Animales , Proteínas de la Cápside/administración & dosificación , Proteínas de la Cápside/genética , Proteínas de la Cápside/inmunología , Recuento de Células , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/diagnóstico , Femenino , Glicoproteínas/inmunología , Hipersensibilidad Tardía/inmunología , Tolerancia Inmunológica/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Interleucina-10/genética , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/genética , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos/inmunología , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Médula Espinal/citología , Médula Espinal/inmunología , Bazo/citología , Bazo/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/trasplante , Células Th2/inmunología , Células Th2/metabolismo , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología
3.
J Immunol ; 186(5): 2750-6, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21270409

RESUMEN

Ab-mediated blockade of the adhesion molecule VLA-4 has been shown to ameliorate disease in human multiple sclerosis patients and experimental autoimmune encephalomyelitis (EAE) animal models. We wanted to determine whether anti-VLA-4 Ab treatment affected the function and persistence of autoreactive T cells in mice with EAE. Unexpectedly, we observed a high level of mortality in anti-VLA-4 mAb (PS/2)-treated mice with actively induced EAE despite decreased disease severity. Investigation of the underlying mechanism showed that injection of PS/2 mAb in combination with pertussis toxin resulted in anaphylaxis and mortality. Furthermore, the data showed that CD4(+) T cells were required for this effect and suggested a role for IL-1ß and TNF-α in the underlying pathology. The results reveal a previously not appreciated deleterious effect of anti-VLA-4 Ab treatment in combination with exposure to pertussis toxin.


Asunto(s)
Anafilaxia/inmunología , Anafilaxia/mortalidad , Anticuerpos Monoclonales/administración & dosificación , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/mortalidad , Integrina alfa4beta1/inmunología , Toxina del Pertussis/administración & dosificación , Anafilaxia/genética , Animales , Anticuerpos Bloqueadores/administración & dosificación , Combinación de Medicamentos , Encefalomielitis Autoinmune Experimental/genética , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Análisis de Supervivencia , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/deficiencia , Factor de Necrosis Tumoral alfa/genética
4.
Immunol Lett ; 122(2): 145-9, 2009 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-18824198

RESUMEN

To elucidate the role of antibodies in development of chronic non-remitting experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, which is a well-established Th1-mediated autoimmune disease, and the involvement of activation-induced cytidine deaminase (AID) in Th1-mediated function, we have investigated the myelin oligodendrocyte glycoprotein (MOG)-induced EAE in mice deficient of AID, which is absolutely required for class switching and somatic hypermutation. Following immunization with MOG, AID(-/-) had completely same levels of clinical and pathological severity of EAE when compared with AID(+/-) and AID(+/+), although AID(-/-) did not produce IgG and anti-MOG IgG. Similar levels of T cell proliferation and a modest increase of anti-MOG IgM synthesis were found in spleen cells of AID(-/-) stimulated with MOG. These results indicate that antibodies are not involved in development of EAE in C57BL/6 mice.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/fisiopatología , Glicoproteína Asociada a Mielina/inmunología , Subgrupos de Linfocitos T/inmunología , Células TH1/inmunología , Animales , Formación de Anticuerpos , Proliferación Celular , Enfermedad Crónica , Citidina Desaminasa/genética , Encefalomielitis Autoinmune Experimental/patología , Glicoproteínas/administración & dosificación , Glicoproteínas/inmunología , Cambio de Clase de Inmunoglobulina , Inmunoglobulina G/sangre , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Hipermutación Somática de Inmunoglobulina , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Células TH1/metabolismo , Células TH1/patología
5.
Am J Pathol ; 172(4): 980-92, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18349128

RESUMEN

The Pten tumor suppressor gene is critical for normal intrathymic development of T cells; however, its role in mature antigen-activated T cells is less well defined. A genetically crossed mouse line, Pten(fl/fl) GBC, in which Pten gene deletions could be primarily confined to antigen-activated CD8+ T cells, enabled us to evaluate the consequences of Pten loss on the course of experimental autoimmune encephalomyelitis. Compared with Pten(fl/fl) controls, myelin oligodendrocyte glycoprotein (MOG) peptide-immunized Pten(fl/fl) GBC mice developed more severe and protracted disease. This was accompanied by increased spinal cord white matter myelin basic protein depletion and axonal damage, as well as a striking persistence of macrophage and granzyme B-expressing cellular neuroinfiltrates in the chronic phase of the disease. This persistence may be explained by the observation that anti-CD3 activated Pten(fl/fl) GBC T cells were more resistant to proapoptotic stimuli. Consistent with the predicted consequences of Pten loss, purified CD8+ T cells from Pten(fl/fl) GBC mice displayed augmented proliferative responses to anti-T-cell receptor stimulation, and MOG-primed Pten(fl/fl) GBC T cells exhibited a reduced activation threshold to MOG peptide. Pten(fl/fl) GBC mice also developed atypical central nervous system disease, manifested by prominent cervical cord and forebrain involvement. Collectively, our findings indicate that the phosphatidylinositol 3-kinase signaling pathway is an essential regulator of CD8+ T-cell effector function in experimental autoimmune encephalomyelitis.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Eliminación de Gen , Glicoproteína Asociada a Mielina/inmunología , Fosfohidrolasa PTEN/genética , Animales , Apoptosis/efectos de los fármacos , Axones/efectos de los fármacos , Axones/inmunología , Complejo CD3/inmunología , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/patología , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Genes Reporteros , Granzimas/metabolismo , Inmunización , Inflamación , Integrasas/metabolismo , Interleucina-2/inmunología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Ratones , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/farmacología , Glicoproteína Mielina-Oligodendrócito , Péptidos/administración & dosificación , Péptidos/farmacología , Prosencéfalo/efectos de los fármacos , Prosencéfalo/inmunología , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/patología
6.
Exp Anim ; 57(1): 45-55, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18256518

RESUMEN

Dendritic cells (DCs) are the most potent antigen-presenting cells (APC) of the immune system, and are critically involved in initiation of immune responses in autoimmune diseases. They can modulate the nature of immune responses to stimulatory or tolerogenic fashion. Previous studies have demonstrated that the administration route of DCs is an important variable in eliciting anti-tumor immunity. In this study we used experimental autoimmune encephalomyelitis (EAE) as an animal model of multiple sclerosis to compare different protocols of DC delivery in autoimmunity or tolerance induction. Dendritic cells were generated from bone marrow cells of C57BL/6 mice by culturing in the presence of GM-CSF and IL-4 for 7 days, followed by 2 days culture with TNF-alpha. The obtained DCs were pulsed in vitro with myelin oligodendrocyte glycoprotein (MOG) peptide and injected (5 x 10(5) cells/mouse) via the intravenous (i.v.), intraperitoneal (i.p.) or subcutaneous (s.c.) route into female C57BL/6 mice. In some instances pertussis toxin was also injected zero and 48 hours after DC injection. After follow up of the mice pretreated in this way for 4 weeks, in the i.v. group in which no clinical signs of EAE occurred, the mice were immunized with MOG peptide for EAE induction via the common method and the results were compared with mice that were not pre-immunized. Only after three s.c. DC injections with pertussis toxin, the mice showed mild clinical signs of EAE, whereas mice given i.v. or i.p. injections with or without pertussis toxin failed to develop EAE after 4 weeks. Induction of EAE via the common method after three injections of TNF-alpha treated DCs, in i.v. injected groups showed no protection from EAE. It seems that several factors influence the tolerance versus immunity induction by DCs. Our results showed that the administration route of DCs is one of the pivotal factors in DC-based induction of autoimmune diseases.


Asunto(s)
Antígenos/inmunología , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Animales , Antígenos/administración & dosificación , Femenino , Inyecciones , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Toxina del Pertussis/administración & dosificación , Factor de Necrosis Tumoral alfa/farmacología
7.
Int Immunol ; 18(10): 1473-85, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16914508

RESUMEN

BAFF [B cell-activating factor of the tumour necrosis factor (TNF) family] and APRIL (a proliferation-inducing ligand) are two TNF family members with shared receptors. While, physiological roles for APRIL are not fully understood, BAFF is critical for B cell homeostasis and also acts as a co-stimulator of T cells. Using a B and T cell-mediated mouse model of multiple sclerosis (MS), myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), we observed that a BAFF/APRIL antagonist (soluble BCMA-Fc) inhibited central nervous system inflammation and demyelination such that it suppressed the onset and progression of clinical symptoms of EAE. In addition to dramatically reducing the titre of MOG-specific auto-antibodies, this treatment also induced a switch in the subtype of the T(h) cell population characterized by marked alterations in cytokine production following re-stimulation with MOG in vitro. Indeed, hBCMA-Fc therapy led to significant increases in the level of transforming growth factor beta, while the levels of T(h)1 cytokines were markedly diminished. These results not only identify BAFF as a critical factor in maintaining humoral immunity in EAE but also support its role in T lymphocyte responses. Our findings demonstrate that hBCMA-Fc acts on both effector arms of the immune response in EAE, a characteristic that may be of significant therapeutic value in the treatment of MS.


Asunto(s)
Formación de Anticuerpos/efectos de los fármacos , Factor Activador de Células B/antagonistas & inhibidores , Antígeno de Maduración de Linfocitos B/administración & dosificación , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Esclerosis Múltiple/tratamiento farmacológico , Animales , Formación de Anticuerpos/inmunología , Factor Activador de Células B/inmunología , Linfocitos B/inmunología , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/inmunología , Ratones , Ratones Endogámicos NOD , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple/inmunología , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/toxicidad , Glicoproteína Mielina-Oligodendrócito , Proteínas Recombinantes de Fusión/administración & dosificación , Linfocitos T/inmunología , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/antagonistas & inhibidores , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/inmunología
8.
Brain ; 129(Pt 12): 3196-208, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16931536

RESUMEN

Axonal degeneration is a major contributor to non-remitting deficits in multiple sclerosis, and there is thus considerable current interest in the development of strategies that might prevent axonal loss in neuroinflammatory disease. Dysregulation of sodium ion homeostasis has been implicated in mechanisms leading to axonal degeneration, and several studies have shown that blockade of sodium channels can ameliorate axon damage following anoxic, traumatic and nitric oxide-induced CNS injury. Two sodium channel blockers, phenytoin and flecainide, have been reported to protect axons in experimental autoimmune encephalomyelitis (EAE) for 30 days, but long-term protective effects have not been studied. We demonstrate here that oral administration of phenytoin provides long-term (up to 180 days) protection for spinal cord corticospinal tract (CST) and dorsal column (DC) axons in both monophasic (C57/BL6 mice) and chronic-relapsing (Biozzi mice) murine EAE. Untreated C57/BL6 mice exhibit a 40-50% loss of CST and DF axons at 90 and 180 days post-EAE induction via myelin-oligodendrocyte glycoprotein (MOG) injection. In contrast, only 4% of DF axons are lost at 90 days, and only 8% are lost at 180 days in phenytoin-treated C57/BL6 mice with EAE; only 21-29% of CST axons are lost at 90 and 180 days in phenytoin-treated C57/BL6 mice with EAE. Attenuation of dorsal column compound action potentials was ameliorated and clinical status was also significantly enhanced with phenytoin treatment at 90 and 180 days in this model. In addition, inflammatory cell infiltration into the dorsal columns was reduced in phenytoin-treated mice with EAE compared with untreated mice with EAE. Similar results were obtained in Biozzi mice with chronic-relapsing EAE followed for 120 days post-injection. These observations demonstrate that phenytoin provides long-term protection of CNS axons and improves clinical status in both monophasic and chronic-relapsing models of neuroinflammation.


Asunto(s)
Axones/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Fenitoína/administración & dosificación , Bloqueadores de los Canales de Sodio/administración & dosificación , Médula Espinal/efectos de los fármacos , Potenciales de Acción/fisiología , Administración Oral , Animales , Recuento de Células/métodos , Vértebras Cervicales , Enfermedad Crónica , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Inmunohistoquímica/métodos , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos C57BL , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Mielina-Oligodendrócito , Conducción Nerviosa , Recurrencia , Médula Espinal/patología , Médula Espinal/fisiopatología , Resultado del Tratamiento
9.
J Neuroimmunol ; 178(1-2): 1-8, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16872684

RESUMEN

We have shown previously that intranasal administration of encephalitogenic peptides in soluble form to H-2u and H-2s mice affords protection from experimental autoimmune encephalomyelitis (EAE). Here we demonstrate that this method of disease protection can be induced in C57BL/6 mice by administration of the soluble peptide 35-55 from myelin oligodendrocyte glycoprotein. This protective effect was demonstrated by the evaluation of both clinical EAE scores and central nervous system histopathology; the latter showing minimal inflammatory infiltrates in treated mice. The employment of an IL-10-/- congenic strain allowed an appraisal of the involvement of IL-10 in this process. The lack of disease protection in these mice clearly demonstrates the non-redundant role of IL-10 in this process.


Asunto(s)
Encefalomielitis Autoinmune Experimental/prevención & control , Tolerancia Inmunológica , Interleucina-10/metabolismo , Glicoproteína Asociada a Mielina/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Administración Intranasal , Animales , Encéfalo/patología , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Interleucina-10/inmunología , Masculino , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos/inmunología , Médula Espinal/patología
10.
Infect Immun ; 74(8): 4841-8, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16861672

RESUMEN

The course of autoimmune inflammatory diseases of the central nervous system (CNS) can be influenced by infections. Here we assessed the disease-modulating effects of the most frequent respiratory pathogen Streptococcus pneumonia on the course of experimental autoimmune encephalomyelitis (EAE). Mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG(35-55)) peptide, challenged intraperitoneally with live S. pneumoniae type 3, and then treated with ceftriaxone. EAE was monitored by a clinical score for 35 days after immunization. EAE was unaltered in mice infected with S. pneumoniae 2 days before and 21 days after the first MOG(35-55) injection but was more severe in animals infected 7 days after the first MOG(35-55) injection. The antigen-driven systemic T-cell response was unaltered, and the intraspinal Th1 cytokine mRNA concentrations at the peak of disease were unchanged. The composition of CNS-infiltrating cells and subsequent tissue destruction were only slightly increased after S. pneumoniae infection. In contrast, the serum levels of tumor necrosis factor alpha and interleukin-6 and spinal interleukin-6 levels were elevated, and the expression of major histocompatibility complex class II molecules, CD80, and CD86 on splenic dendritic cells were enhanced early after infection. Serum cytokine concentrations were not elevated, and EAE was not aggravated by S. pneumoniae infection in Toll-like receptor 2 (TLR2)-deficient mice. In conclusion, infection with S. pneumoniae worsens EAE probably by elevation of proinflammatory cytokines and activation of dendritic cells in the systemic circulation via TLR2 and cross talk through the blood-brain barrier.


Asunto(s)
Encefalomielitis Autoinmune Experimental/fisiopatología , Infecciones Neumocócicas/complicaciones , Índice de Severidad de la Enfermedad , Receptor Toll-Like 2/metabolismo , Animales , Citocinas/metabolismo , Células Dendríticas/inmunología , Femenino , Humanos , Inflamación/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Mielina-Oligodendrócito
11.
Brain ; 129(Pt 8): 1972-83, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16714315

RESUMEN

Recent studies have revealed widespread demyelination in the cortex of patients with chronic multiple sclerosis. In contrast to white matter lesions, cortical multiple sclerosis lesions are accompanied by only minor inflammation. Research into the pathogenesis of cortical lesion formation has been hampered by the fact that the conventional rodent model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), does not regularly affect the cortex. To overcome this limitation we developed a new rat model of cortical multiple sclerosis. Lesions were stereotactically targeted to the cerebral cortex by injection of pro-inflammatory mediators in animals that were immunized subclinically with myelin oligodendrocyte glycoprotein (MOG). We thus generated highly reproducible demyelinated lesions in the neocortex with remarkable histological similarities to cortical multiple sclerosis lesions. The focal cortical EAE model led to the typical pattern of intracortical and subpial demyelination, infiltration with inflammatory cells, complement deposition, acute axonal damage and neuronal cell death. Surprisingly, extensive cortical inflammation largely resolved within 2 weeks. Furthermore, cortical demyelination was readily compensated by rapid remyelination. Our data thus suggest that cortical inflammation is a transient phenomenon, and that remyelination of cortical inflammatory-demyelinating lesions may occur rapidly.


Asunto(s)
Corteza Cerebral/patología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Esclerosis Múltiple/patología , Vaina de Mielina/patología , Animales , Citocinas/administración & dosificación , Encefalomielitis Autoinmune Experimental/etiología , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Mediadores de Inflamación/administración & dosificación , Esclerosis Múltiple/etiología , Esclerosis Múltiple/inmunología , Proteínas de la Mielina , Vaina de Mielina/fisiología , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Mielina-Oligodendrócito , Ratas , Ratas Endogámicas Lew , Remisión Espontánea , Técnicas Estereotáxicas
12.
Int Immunol ; 17(6): 721-8, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15899926

RESUMEN

The immune system has co-evolved with the infectious agents that challenge it, and in response pathogens have developed different mechanisms to subvert host immunity. A wealth of evidence suggests that infections are important components in the development of a functional immune system, and understanding the modulation of the host immune system by pathogens may offer new therapeutic strategies in a non-infectious setting. We investigated how infection with the protozoan parasite Trypanosoma brucei brucei (Tbb) modulates the autoimmune response to recombinant myelin oligodendrocyte glycoprotein (rMOG) in DBA/1 mice. Mice harbouring a Tbb infection did not develop experimental autoimmune encephalomyelitis (EAE) induced by immunization with rMOG in CFA, an animal model for the human autoimmune disease multiple sclerosis. Additionally, mice infected with the parasite at the time of immunization or 1 week later developed less severe EAE than uninfected controls. Protected mice displayed a markedly diminished rMOG-specific proliferation and IFNgamma production in lymph node cells and had correspondingly low titres of serum anti-rMOG IgG. Antigen-presenting cells (APCs) from spleens of Tbb-infected mice presented rMOG less efficiently to rMOG-specific T cells in vitro than did splenic APCs from uninfected mice and could also inhibit antigen-specific proliferation in control in vitro cultures. This suppressive effect is at least in part due to increased release of IL-10. Transfer of splenic APCs from Tbb-infected mice into mice immunized with rMOG-CFA 7 days previously abrogated disease significantly. These findings indicate that infections can prevent autoimmunity and that APCs might be used as immunomodulants.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Glicoproteína Asociada a Mielina/inmunología , Trypanosoma brucei brucei/inmunología , Tripanosomiasis Africana/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Proliferación Celular , Células Cultivadas , Técnicas de Cocultivo , Medios de Cultivo Condicionados , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/etiología , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Inmunoglobulina G/sangre , Terapia de Inmunosupresión , Interferón gamma/metabolismo , Interleucina-10/inmunología , Interleucina-10/metabolismo , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos DBA , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Mielina-Oligodendrócito , Bazo
13.
J Neuroimmunol ; 160(1-2): 122-34, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15710465

RESUMEN

We induced experimental allergic encephalomyelitis (EAE) in SJL/J mice, an animal model for multiple sclerosis (MS), using myelin oligodendrocyte glycoprotein (MOG)(92-106) peptide, following ultraviolet (UV) irradiation. While all control mice developed relapsing-remitting (RR)-EAE, UV irradiation induced secondary progressive (SP)-EAE in some of the mice. Although mild demyelination was observed with T cell infiltration in RR-EAE, large demyelinating lesions developed in SP-EAE with massive macrophage and neutrophil infiltration and immunoglobulin deposition, but with little T cell infiltration. UV irradiation induced higher anti-MOG antibody responses. In SP-EAE, lymphoproliferative responses and interferon-gamma production were decreased without alteration of interleukin-4.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Esclerosis Múltiple Crónica Progresiva/etiología , Esclerosis Múltiple Crónica Progresiva/patología , Esclerosis Múltiple Recurrente-Remitente/etiología , Esclerosis Múltiple Recurrente-Remitente/patología , Rayos Ultravioleta , Secuencia de Aminoácidos , Animales , Movimiento Celular/inmunología , Movimiento Celular/efectos de la radiación , Sistema Nervioso Central/patología , Sistema Nervioso Central/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/sangre , Inmunoglobulina G/efectos de la radiación , Inmunoglobulinas/metabolismo , Inmunoglobulinas/efectos de la radiación , Activación de Linfocitos/efectos de la radiación , Macrófagos/patología , Macrófagos/efectos de la radiación , Ratones , Datos de Secuencia Molecular , Esclerosis Múltiple Crónica Progresiva/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Proteínas de la Mielina , Vaina de Mielina/patología , Vaina de Mielina/efectos de la radiación , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Índice de Severidad de la Enfermedad , Linfocitos T/patología , Linfocitos T/efectos de la radiación
14.
Cell Death Differ ; 11 Suppl 2: S181-92, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15459752

RESUMEN

In multiple sclerosis (MS), long-term disability is primarily caused by axonal and neuronal damage. We demonstrated in a previous study that neuronal apoptosis occurs early during experimental autoimmune encephalomyelitis, a common animal model of MS. In the present study, we show that, in rats suffering from myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis, systemic application of erythropoietin (Epo) significantly increased survival and function of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. We identified three independent intracellular signaling pathways involved in Epo-induced neuroprotection in vivo: Protein levels of phospho-Akt, phospho-MAPK 1 and 2, and Bcl-2 were increased under Epo application. Using a combined treatment of Epo together with a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K) prevented upregulation of phospho-Akt and consecutive RGC rescue. We conclude that in MOG-EAE the PI3-K/Akt pathway has an important influence on RGC survival under systemic treatment with Epo.


Asunto(s)
Eritropoyetina/farmacología , Esclerosis Múltiple/tratamiento farmacológico , Glicoproteína Asociada a Mielina/farmacología , Fármacos Neuroprotectores/farmacología , Células Ganglionares de la Retina/efectos de los fármacos , Transducción de Señal/fisiología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Caspasas/efectos de los fármacos , Caspasas/metabolismo , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Modelos Animales de Enfermedad , Electrorretinografía , Eritropoyetina/administración & dosificación , Femenino , Etiquetado Corte-Fin in Situ/métodos , Esclerosis Múltiple/fisiopatología , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Mielina-Oligodendrócito , Fármacos Neuroprotectores/administración & dosificación , Nervio Óptico/fisiopatología , Fosforilación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt , Ratas , Ratas Endogámicas BN , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Células Ganglionares de la Retina/fisiología , Transducción de Señal/efectos de los fármacos
15.
Methods Mol Med ; 102: 363-75, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15286395

RESUMEN

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyleinating disease of the central nervous system that is induced in laboratory animals by the generation of an immune response against myelin epitopes. It has been used as a prototype of Th1-driven, organ-specific autoimmunity and as a model for the human disease multiple sclerosis. This chapter describes two classic protocols for EAE induction (active immunization and adoptive transfer). Subheading 3.3. describes methods for rating clinical disease in symptomatic animals. Subheading 3.4. includes instructions for the isolation of mononuclear cells from the inflamed spinal cords from mice with EAE.


Asunto(s)
Encefalomielitis Autoinmune Experimental/etiología , Traslado Adoptivo , Secuencia de Aminoácidos , Animales , Autoantígenos/administración & dosificación , Autoantígenos/genética , Encefalomielitis Autoinmune Experimental/inmunología , Humanos , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Esclerosis Múltiple/etiología , Esclerosis Múltiple/inmunología , Proteína Básica de Mielina/administración & dosificación , Proteína Básica de Mielina/genética , Proteína Básica de Mielina/inmunología , Proteínas de la Mielina , Proteína Proteolipídica de la Mielina/administración & dosificación , Proteína Proteolipídica de la Mielina/genética , Proteína Proteolipídica de la Mielina/inmunología , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/genética , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Células TH1/inmunología , Vacunación
16.
J Exp Med ; 200(1): 79-87, 2004 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-15238607

RESUMEN

The transcription factors signal transducer and activator of transcription (STAT)1 and T-bet control the differentiation of interferon (IFN)-gamma-producing T helper type (Th)1 cells. Here we compare the role of T-bet and STAT1 in the initiation and regulation of experimental autoimmune encephalomyelitis (EAE), a disease initiated by Th1 cells. T-bet-deficient mice immunized with myelin oligodendrocyte glycoprotein (MOG) were resistant to the development of EAE. This protection was also observed when T-bet(-/-) mice were crossed to the MOG-specific 2D2 T cell receptor transgenic strain. In contrast, although T-bet is downstream of STAT1, STAT1(-/-) mice were highly susceptible to EAE and developed more severe and accelerated disease with atypical neuropathologic features. The function of T-bet was dominant as mice deficient in both T-bet and STAT1 were also protected from EAE. CD4(+) CD25(+) regulatory T cells from these two mice strains were fully competent and do not explain the difference in disease susceptibility. However, enhanced EAE in STAT1(-/-) mice was associated with continued generation of IFN-gamma-producing Th1 cells and up-regulation of selective chemokines responsible for the increased recruitment of macrophages and neutrophils in the central nervous system. Although the two transcription factors, STAT1 and T-bet, both induce IFN-gamma gene transcription, our results demonstrate marked differences in their function in regulating pathogenic Th1 cell responses.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Animales , Encéfalo/inmunología , Encéfalo/metabolismo , Linfocitos T CD4-Positivos/inmunología , Quimiocinas/metabolismo , Citocinas/metabolismo , Proteínas de Unión al ADN/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Receptores de Interleucina-2/inmunología , Factor de Transcripción STAT1 , Médula Espinal/citología , Médula Espinal/metabolismo , Médula Espinal/patología , Proteínas de Dominio T Box , Células TH1/inmunología , Transactivadores/genética , Factores de Transcripción/genética
17.
J Immunol ; 172(5): 2878-84, 2004 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-14978089

RESUMEN

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is primarily mediated by CD4 T cells specific for Ags in the CNS. Using MHC class II tetramers, we assessed expansion and phenotypic differentiation of polyclonal self-reactive CD4 T cells during EAE after primary and secondary challenge with the specific Ag. After EAE induction in SJL mice with proteolipid protein 139-151, CNS-specific T cells up-regulated activation markers and expanded in the draining lymph nodes and in the spleen. Less than 20% of total autoreactive T cells entered the CNS simultaneously with Th cells of other specificities. Almost all tetramer-positive cells in the CNS were activated and phenotypically distinct from the large peripheral pool. When EAE was induced in Ag-experienced mice, disease symptoms developed earlier and persisted longer; autoreactive T cells were more rapidly activated and invaded the CNS earlier. In striking contrast to specific CTLs that respond after secondary viral challenge, the absolute numbers of autoreactive CD4 T cells were not increased, indicating that the accelerated autoreactivity in Ag-experienced mice is not related to higher frequencies of autoreactive CD4 T cells.


Asunto(s)
Autoantígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Proteína Proteolipídica de la Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Animales , Autoantígenos/metabolismo , Linfocitos T CD4-Positivos/citología , Diferenciación Celular/inmunología , División Celular/inmunología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Encefalomielitis Autoinmune Experimental/patología , Epítopos de Linfocito T/inmunología , Femenino , Adyuvante de Freund/administración & dosificación , Adyuvante de Freund/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunización , Inmunización Secundaria , Inmunofenotipificación , Activación de Linfocitos , Recuento de Linfocitos , Ratones , Proteínas de la Mielina , Proteína Proteolipídica de la Mielina/inmunología , Proteína Proteolipídica de la Mielina/metabolismo , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Asociada a Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo
18.
J Immunol ; 172(1): 302-9, 2004 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-14688338

RESUMEN

The skin is both an essential barrier for host defense and an important organ of immunity. In this study, we show that the application of cholera toxin to intact mouse skin induces and enhances autoimmune diseases affecting organs at distant anatomic sites, whereas its administration by the mucosal route has been reported to have the opposite effect. First, the CNS autoantigen myelin oligodendrocyte glycoprotein 35-55, when applied repeatedly with cholera toxin to the intact skin of healthy C57BL/6 mice, induced relapsing paralysis with demyelinating immunopathologic features similar to multiple sclerosis. Second, the application of cholera toxin in the absence of autoantigen exacerbated the severity of conventional experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein in CFA. Third, the application of cholera toxin to the intact skin of NOD/Lt mice, with or without insulin B peptide 9-23, exacerbated insulitis and T lymphocyte-derived IFN-gamma and IL-4 production in the islets of Langerhans, resulting in an increased incidence and rate of onset of autoimmune diabetes. The data presented in this study highlight the different outcomes of adjuvant administration by different routes. Because dermal application of cholera toxin, and other bacterial products with similar adjuvant activities, is being developed as a clinical vaccination strategy, these data raise the possibility that it could precipitate autoimmune disease in genetically susceptible humans.


Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Toxina del Cólera/administración & dosificación , Toxina del Cólera/inmunología , Diabetes Mellitus Tipo 1/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Piel/inmunología , Piel/microbiología , Administración Cutánea , Secuencia de Aminoácidos , Animales , Anticuerpos Antibacterianos/biosíntesis , Diabetes Mellitus Tipo 1/microbiología , Diabetes Mellitus Tipo 1/patología , Encefalomielitis Autoinmune Experimental/microbiología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Inmunoglobulina G/biosíntesis , Insulina/administración & dosificación , Insulina/inmunología , Anticuerpos Insulínicos/biosíntesis , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/microbiología , Islotes Pancreáticos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Datos de Secuencia Molecular , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Especificidad de Órganos/inmunología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Índice de Severidad de la Enfermedad , Piel/citología , Vacunas Combinadas/administración & dosificación , Vacunas Combinadas/inmunología
19.
J Neuroimmunol ; 144(1-2): 105-15, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14597104

RESUMEN

To investigate the possible role of molecular mimicry to bacterial components in multiple sclerosis (MS) pathogenesis we examined antibody responses to mimicry peptide sequences of Acinetobacter, Pseudomonas aeruginosa and myelin components. Antibodies to mimicry peptides from Acinetobacter (p<0.001), P. aeruginosa (p<0.001), myelin basic protein (MBP) (p<0.001) and myelin oligodendrocyte glycoprotein (MOG) (p<0.001) were significantly elevated in MS patients compared to controls. Antisera against MBP (residues 110-124) reacted with both Acinetobacter and Pseudomonas peptides from 4- and gamma-carboxymuconolactone decarboxylase, respectively. MOG (residues 43-57) antisera reacted with Acinetobacter peptide from 3-oxo-adipate-CoA-transferase subunit A. The role of these bacteria in MS is unclear but demonstrates that molecular mimicry is not restricted to viruses suggesting bacterial infections could play a role in MS pathogenesis. Further work is required to evaluate the relevance of these cross-reactive antibodies to the neuropathology of MS.


Asunto(s)
Acinetobacter/inmunología , Anticuerpos Antibacterianos/metabolismo , Antígenos Bacterianos/metabolismo , Esclerosis Múltiple/inmunología , Proteína Básica de Mielina/inmunología , Glicoproteína Asociada a Mielina/inmunología , Pseudomonas aeruginosa/inmunología , Homología de Secuencia de Aminoácido , Acinetobacter/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Animales , Anticuerpos Antibacterianos/biosíntesis , Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/inmunología , Carboxiliasas/administración & dosificación , Carboxiliasas/inmunología , Carboxiliasas/metabolismo , Coenzima A Transferasas/inmunología , Coenzima A Transferasas/metabolismo , Reacciones Cruzadas , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/microbiología , Femenino , Humanos , Sueros Inmunes/metabolismo , Masculino , Ratones , Ratones Biozzi , Persona de Mediana Edad , Imitación Molecular/inmunología , Datos de Secuencia Molecular , Esclerosis Múltiple/microbiología , Proteína Básica de Mielina/administración & dosificación , Proteína Básica de Mielina/metabolismo , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Pseudomonas aeruginosa/enzimología
20.
J Neuroimmunol ; 141(1-2): 10-9, 2003 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12965249

RESUMEN

Experimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein (MOG(1-125)) in CD4(-/-) and CD8(-/-) DBA/1 mice. Both gene-deleted mice developed clinical signs of EAE, albeit milder than in wild-type mice, suggesting that both CD4(+) and CD8(+) cells participate in disease development. Demyelination and inflammation in the central nervous system was reduced in the absence of CD8(+) T cells. Antibody depletion of CD4(+) cells completely protected CD8(-/-) mice from MOG-induced EAE while depletion of CD8(+) cells in CD4(-/-) mice resulted in fewer EAE incidence compared to that in control antibody-treated mice. Antibody depletion of CD4(+) cells in wild-type mice protected from EAE, but not depletion of CD8(+) cells, although demyelination was reduced on removal of CD8(+) T cells. Immunization with immunodominant MOG(79-96) peptide led to EAE only in the presence of pertussis toxin (PT) in the inoculum. PT also triggered an earlier onset and more severe EAE in CD8(-/-) mice. We interpret our findings such that in an ontogenic lack of CD4(+) T cells, EAE is mediated by CD8(+) and elevated levels of alphabetaCD4(-)CD8(-) cells, and that CNS damage is partly enacted by the activity of CD8(+) T cells.


Asunto(s)
Antígenos CD4/genética , Linfocitos T CD4-Positivos/inmunología , Antígenos CD8/genética , Linfocitos T CD8-positivos/inmunología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Eliminación de Gen , Animales , Autoanticuerpos/biosíntesis , Antígenos CD4/inmunología , Linfocitos T CD4-Positivos/patología , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/patología , Enfermedades del Sistema Nervioso Central/genética , Enfermedades del Sistema Nervioso Central/inmunología , Enfermedades del Sistema Nervioso Central/patología , Enfermedades Desmielinizantes/prevención & control , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Incidencia , Inyecciones Intradérmicas , Depleción Linfocítica , Linfopenia/genética , Linfopenia/inmunología , Linfopenia/patología , Ratones , Ratones Endogámicos DBA , Ratones Noqueados , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/administración & dosificación , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología
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