RESUMO
OBJECTIVE: Repair of demyelinated axons in diseases such as multiple sclerosis requires activation of the myelination program in existing or newly recruited oligodendrocyte precursor cells (OPCs). The control of OPC differentiation and initiation of myelination during repair is poorly understood. In this study, we test the ability of anti-LINGO-1 reagents to promote myelination in vitro and remyelination in the rodent adult central nervous system in vivo. METHODS: The effects of LINGO-1 antagonists on the differentiation of OPCs and the promotion of myelination has been assayed using a combination of coculture and slice culture preparations. Using three different animal models of demyelination and remyelination, we morphologically and functionally assessed the effects of LINGO-1 antagonists on OPC differentiation and myelin repair. RESULTS: The data indicate that in vitro treatment with antagonists of LINGO-1 promote OPC differentiation and myelination, whereas in vivo remyelination is accelerated in lysophosphatidylcholine- or cuprizone-induced demyelination. This remyelination is associated with enhanced OPC differentiation and functional recovery of conduction velocities in demyelinated axons. INTERPRETATION: Our studies demonstrate that LINGO-1 antagonism promotes OPC differentiation and remyelination, and suggest LINGO-1 functions as an inhibitor of OPC differentiation to retard central nervous system remyelination.
Assuntos
Diferenciação Celular/fisiologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/fisiopatologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Oligodendroglia/fisiologia , Células-Tronco/fisiologia , Animais , Animais Recém-Nascidos , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Cuprizona/toxicidade , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/induzido quimicamente , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/tratamento farmacológico , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Gânglios Espinais/citologia , Lisofosfatidilcolinas/toxicidade , Proteínas de Membrana/imunologia , Proteínas de Membrana/fisiologia , Camundongos , Proteínas da Mielina/metabolismo , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/fisiologia , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/fisiologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley , Células-Tronco/efeitos dos fármacosRESUMO
The TAPR locus containing the TIM gene family is implicated in the development of atopic inflammation in mouse, and TIM-1 allelic variation has been associated with the incidence of atopy in human patient populations. In this study, we show that manipulation of the TIM-1 pathway influences airway inflammation and pathology. Anti-TIM-1 mAbs recognizing distinct epitopes differentially modulated OVA-induced lung inflammation in the mouse. The epitopes recognized by these Abs were mapped, revealing that mAbs to both the IgV and stalk domains of TIM-1 have therapeutic activity. Unexpectedly, mAbs recognizing unique epitopes spanning exon 4 of the mucin/stalk domains exacerbated immune responses. Using Ag recall response studies, we demonstrate that the TIM-1 pathway acts primarily by modulating the production of T(H)2 cytokines. Furthermore, ex vivo cellular experiments indicate that TIM-1 activity controls CD4(+) T cell activity. These studies validate the genetic hypothesis that the TIM-1 locus is linked to the development of atopic disease and suggest novel therapeutic strategies for targeting asthma and other atopic disorders.
Assuntos
Anticorpos Monoclonais/farmacologia , Epitopos/imunologia , Proteínas de Membrana/imunologia , Pneumonia/imunologia , Células Th2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Asma/tratamento farmacológico , Asma/genética , Asma/imunologia , Asma/patologia , Células Cultivadas , Citocinas/imunologia , Mapeamento de Epitopos , Epitopos/genética , Feminino , Humanos , Pulmão/imunologia , Pulmão/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ovalbumina/toxicidade , Pneumonia/tratamento farmacológico , Pneumonia/genética , Pneumonia/patologia , Estrutura Terciária de Proteína/genética , Locos de Características Quantitativas/genética , Locos de Características Quantitativas/imunologia , Células Th2/patologiaRESUMO
The development of asthma and other atopic diseases is influenced by cytokines produced by Th2 effector T cells. How effector T cell responses are regulated once these cell populations are established remains unclear. The recently described T cell and airway phenotype regulator locus, containing the T cell, Ig domain, mucin domain (TIM) genes, is genetically associated with Th2 cytokine production and Th2-dependent immune responses. In this study, we report the phenotype of the TIM-2 gene-deficient mouse, and demonstrate exacerbated lung inflammation in an airway atopic response model. Immune responses in the TIM-2-deficient mouse reveal disregulated expression of Th2 cytokines, and adoptive transfer experiments show that the T cell compartment is responsible for the heightened inflammatory phenotype. These studies show that TIM-2 is a novel and critical regulator of effector T cell activity.
Assuntos
Inflamação/imunologia , Pulmão/imunologia , Proteínas de Membrana/deficiência , Células Th2/imunologia , Animais , Asma/imunologia , Diferenciação Celular , Modelos Animais de Doenças , Citometria de Fluxo , Pulmão/metabolismo , Pulmão/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Ovalbumina/imunologia , Ratos , Proteínas Recombinantes de Fusão/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/citologia , Linfócitos T/imunologia , Células Th2/citologiaRESUMO
Herein we demonstrate that B cell-activating factor of the TNF family (BAFF), a B cell survival factor, also regulates CD21/35 and CD23 expression. BAFF blockade in wild-type mice down-modulates CD21/35 and CD23 on B cells while survival remains intact, and BAFF exposure causes elevated CD21/35 and CD23 expression. Similar down-modulation is observed in bcl-2-transgenic mice treated with a BAFF inhibitor. This is the first evidence that BAFF has a function independent of B cell survival. Reports using CD21/35 and CD23 expression to assess splenic B cell subsets in BAFF-null mice concluded a lack of B cells beyond the immature stage. Since CD21/35 and CD23 are inadequate for delineating B cell subpopulations in BAFF-null mice, we used expression of BAFF-R and several B cell markers to identify more mature splenic B cells in these mice. These data broaden our understanding of BAFF function and correct the view that BAFF-null mice lack mature B cells.