Interleukin 12 in inflammatory neurological diseases

描述（由申请人提供）：IL-12是一种细胞因子，对1型细胞免疫至关重要，与炎性神经系统疾病如多发性硬化症（MS）的发病机制密切相关。在之前的资助期间，我们表明IL-12可以由小胶质细胞产生，并且在较小程度上由星形胶质细胞产生，这表明局部化的IL-12可以调节CNS中的细胞免疫应答。为了进一步测试这一点，产生了星形胶质细胞产生生物活性IL-12的转基因小鼠。这些GF-IL 12小鼠发展出与脑中活跃的1型细胞免疫病理学相关的神经系统疾病。这些和随后的发现证实，IL-12的局部产生可以启动和驱动CNS中的自发性以及靶向外周诱导的I型适应性和先天性细胞介导的免疫应答。GF-IL-12小鼠是一种独特而有价值的新范例，我们现在建议研究IL-12在脑中的基本作用机制，并研究CNS中免疫细胞的定位、外渗和激活以及这些细胞之间导致CNS损伤的后续相互作用的具体过程。与此目标一致，我们在此提出：（1）确定IL-12受体（IL-12 R）和信号转导子和转录激活子（STAT）以及细胞因子信号转导抑制子（SOCS）在GF-IL 12小鼠CNS中的临床、细胞和分子改变的发展中的表达、调节和作用;（2）阐明IL-12诱导的单核细胞产生IFN-γ在GF-IL 12小鼠脑中自发和诱导的细胞免疫应答的发展中的作用;（3）阐明NK细胞相对于抗原特异性自身免疫T细胞应答在GF-IL-12小鼠CNS中免疫介导的疾病病理学的发展中是否起作用以及起什么作用;以及（4）研究是否可以由IL-12的局部产生驱动从脑内发生抗原呈递。本持续提案中概述的研究将提供有关IL-12在调节CNS中细胞免疫应答所涉及的分子和细胞过程中的作用的有价值的新知识。它们与我们对涉及CNS中细胞免疫应答的广泛神经系统疾病的发病机制的理解极其相关。最后，这些研究的结果可以为开发新的治疗方法以改善与IL-12有关的免疫炎性起源的CNS疾病奠定概念基础

DESCRIPTION (provided by applicant): IL-12 is a cytokine, critical for type 1 cellular immunity that is strongly implicated in the pathogenesis of inflammatory neurological diseases such as multiple sclerosis (MS). In the previous funding periods we showed that IL-12 can be produced by microglia and to a lesser extent by astrocytes, suggesting that localized IL-12 may regulate cellular immune responses in the CNS. To test this further, transgenic mice were generated with astrocyte-production of bioactive IL-12. These GF-IL12 mice develop neurologic disease in association with active type 1 cellular immune pathology in the brain. These and subsequent findings confirm that local production of IL-12 can initiate and drive spontaneous as well as target peripherally-induced type I adaptive and innate cell-mediated immune responses in the CNS. The GF-IL12 mice are a unique and valuable new paradigm in which we now propose to study basic mechanisms of action of IL-12 in the brain as well as investigate specific processes underlying the localization, extravasation and activation of immune cells in the CNS and the subsequent interactions between these cells that contribute to CNS damage. Consistent with this goal here we propose to:(1) determine the expression, regulation and role of the IL-12 receptor (IL-12R) and the signal transducers and activators of transcription (STAT) and suppressors of cytokine signaling (SOCS) in the development of the clinical, cellular and molecular alterations in the CNS of the GF-IL12 mice; (2) elucidate the role of IL-12-induced IFN-gamma production by mononuclear cells in the development of spontaneous and induced cellular immune responses in the brain of the GF-IL12 mice; (3) clarify whether or not and what role is played by NK cells versus antigen-specific autoimmune T cell responses in the development of immune-mediated disease pathology in the CNS of the GF-IL12 mice; and (4) investigate whether antigen presentation can occur from within the brain driven by the local production of IL-12. The studies outlined in this continuing proposal will provide valuable new knowledge concerning the role of IL-12 in regulating molecular and cellular processes involved in cellular immune responses in the CNS. They are extremely relevant to our understanding of the pathogenesis of a wide spectrum of neurologic disorders that involve cellular immune responses in the CNS. Finally, the results from these studies could lay the conceptual foundations for the development of novel therapeutic approaches to ameliorate CNS diseases of immunoinflammatory origin in which IL-12 is implicated