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2.
J Clin Invest ; 125(2): 699-714, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25607842

RESUMO

A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell-mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4-producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4-deficient animals had decreased functional recovery following CNS injury; however, transfer of CD4+ T cells from wild-type mice, but not from IL-4-deficient mice, enhanced neuronal survival. Using a culture-based system, we determined that T cell-derived IL-4 protects and induces recovery of injured neurons by activation of neuronal IL-4 receptors, which potentiated neurotrophin signaling via the AKT and MAPK pathways. Together, these findings demonstrate that damage-associated molecules from the injured CNS induce a neuroprotective T cell response that is independent of MHCII/TCR interactions and is MyD88 dependent. Moreover, our results indicate that IL-4 mediates neuroprotection and recovery of the injured CNS and suggest that strategies to enhance IL-4-producing CD4+ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration.


Assuntos
Axônios/imunologia , Lesões Encefálicas/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Interleucina-4/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Doenças Neurodegenerativas/imunologia , Animais , Axônios/patologia , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Linfócitos T CD4-Positivos/patologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Interleucina-4/genética , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia
3.
Brain Behav Immun ; 35: 58-63, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24012647

RESUMO

Numerous methods of T cell depletion lead to impairment of learning and memory function in mice. While adoptive transfer of whole splenocytes rescues learning behavior impairments, the precise sub-population and antigenic specificity of the T cells mediating the rescue remains unknown. Using several transgenic mouse models in combination with adoptive transfers, we demonstrate the necessity of an antigen-specific CD4(+) T cell compartment in normal spatial learning and memory, as measured by the Morris water maze (MWM). Moreover, transfer of a monoclonal T cell population reactive to the central nervous system (CNS) antigen, myelin oligodendrocyte glycoprotein (MOG), was sufficient to improve cognitive task performance in otherwise impaired OTII mice, raising the possibility that the antigen-specificity requirement of pro-cognitive T cells may be directed against CNS-derived self-antigens.


Assuntos
Encéfalo/imunologia , Linfócitos T CD4-Positivos/imunologia , Aprendizagem em Labirinto/fisiologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Proteínas de Ligação a DNA/genética , Genes MHC da Classe II , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
4.
Eur J Pharmacol ; 567(1-2): 67-76, 2007 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-17490635

RESUMO

MRL/MpJ-Fas(lpr) (MRL/lpr) mice are an accepted animal model to study human systemic lupus erythematosus. We tested if a commonly used analgesic (buprenorphine hydrochloride) would reduce pain and distress in these mice without impacting the progression of autoimmune disease. Female MRL/lpr mice were randomly separated into four groups. Experimental groups received cyclophosphamide (25 mg/kg i.p. weekly), buprenorphine (0.09 mg/kg/mouse/day via drinking water), or cyclophosphamide+buprenorphine from 11 to 21 weeks of age. Controls received no treatments. Mice were monitored daily by a licensed veterinarian (blinded observer) and assigned a score weekly on parameters associated with pain and distress as well as progression of disease. Proteinuria was measured weekly, and serum anti-dsDNA antibody levels were determined at 11, 15, and 18 weeks of age. At 21 weeks of age, the animals were euthanized and the kidneys and spleens were removed for evaluation. Regardless of the parameter observed, buprenorphine did not significantly decrease distress when compared to the controls. Buprenorphine did not alter the progression of autoimmune disease, based on characteristics of splenic architecture and splenocyte cell profiles, development of lymphadenopathy, or kidney histology as compared to controls. This study indicates that buprenorphine at this dose and route of administration was ineffective in reducing distress associated with disease progression in the MRL/lpr strain. More studies are needed to determine if, at a different dose or route, buprenorphine would be useful as adjunctive therapy in reducing distress in MRL/lpr mice.


Assuntos
Analgésicos/administração & dosagem , Bem-Estar do Animal , Buprenorfina/administração & dosagem , Camundongos Endogâmicos MRL lpr , Dor/prevenção & controle , Animais , Autoanticorpos/sangue , Biomarcadores/sangue , Biomarcadores/urina , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Proteinúria/urina , Distribuição Aleatória , Baço/efeitos dos fármacos , Baço/patologia
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