Interleukin 12 in inflammatory neurological diseases

描述(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，与多发性硬化症(MS)等炎症性神经疾病的发病机制密切相关。在以前的资助时期，我们发现IL-12可由小胶质细胞产生，少量由星形胶质细胞产生，提示定位的IL-12可能调节中枢神经系统的细胞免疫反应。为了进一步验证这一点，用星形胶质细胞产生的生物活性IL-12产生了转基因小鼠。这些GF-IL12小鼠的神经系统疾病与大脑中活跃的1型细胞免疫病理有关。这些和随后的发现证实，局部产生的IL-12可以启动和驱动中枢神经系统中自发的和靶向的外周诱导的I型适应性和先天细胞介导的免疫反应。GF-IL12小鼠是一个独特而有价值的新范式，我们现在建议研究IL-12在大脑中的基本作用机制，以及研究中枢神经系统免疫细胞定位、外渗和激活的特定过程，以及这些细胞之间随后导致中枢神经系统损伤的相互作用。根据这一目标，我们建议：(1)确定IL-12受体(IL-12R)、信号转导和转录激活因子(STAT)和细胞因子信号抑制因子(SOCs)在GF-IL12小鼠中枢神经系统临床、细胞和分子变化中的表达、调节和作用：(2)阐明IL-12诱导的单核细胞产生干扰素-γ在GF-IL12小鼠脑自发和诱导细胞免疫反应发育中的作用；(3)阐明NK细胞与抗原特异性自身免疫T细胞反应在GF-IL12小鼠中枢神经系统免疫介导性疾病病理发展中是否起作用，以及在其中起什么作用；以及(4)研究局部产生IL-12是否可以从大脑内部产生抗原递呈。在这个持续的提案中概述的研究将提供关于IL-12在调节涉及中枢神经系统细胞免疫反应的分子和细胞过程中的作用的有价值的新知识。它们与我们对涉及中枢神经系统细胞免疫反应的一系列神经系统疾病的发病机制的理解极其相关。最后，这些研究的结果可能为开发新的治疗方法奠定概念基础，以改善与IL-12有关的免疫性炎症性中枢神经系统疾病

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