GENDER-BASED REGULATION OF AUTOIMMUNE MEMORY

基于性别的自身免疫记忆调节

• 批准号: 6932323
• 负责人: VINCENT K TUOHY
• 金额: $ 30.6万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932323
• 关键词: T lymphocyte; autoimmune disorder; disease /disorder model; ganciclovir; gender difference; genetic susceptibility; idiopathic dilated cardiomyopathy; immunologic memory; immunopathology chemotherapy; laboratory mouse; myocarditis; nonhuman therapy evaluation

DESCRIPTION (provided by applicant): Gender differences in the immune response are particularly evident in autoimmunity where females show increased susceptibility for developing autoimmune disease but males are predisposed to a poorer prognosis. This sex-based divergence in both disease susceptibility and disease outcome is not well understood yet is clearly evident in several diseases having prominent autoimmune features, including multiple sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Graves' disease, and DCM. The experiments proposed in the current application are designed to address the basis for the differential prognosis of males versus females with autoimmune disease. To this end we have developed a murine EAMC model in which male SWXJ mice show prolonged maintenance of cardiac self- recognition and develop a high incidence of DCM, whereas female mice show aborted maintenance of T cell autoimmune memory and significant protection from the development of DCM. Thus, we hypothesize that the poor prognosis in males with autoimmune disease is due to their enhanced ability to maintain autoimmune T cell memory and persistence of inflammatory self-recognition. In Specific Aim 1, we will determine the mechanism by which differential gender- based maintenance of self-recognition occurs in male versus female SWXJ mice with EAMC. In Specific Aim 2, we will determine how the patterns of autoimmune memory may be altered by immune and non-immune manipulations. In addition, we will determine whether persistence of memory causes DCM and whether the gender-based differential development of autoimmune memory may be therapeutically manipulated to alter disease outcome. We believe that our proposed studies will lead to a better understanding of how autoimmune memory is maintained or aborted by gender-defined conditions. Such information may ultimately serve as a basis for therapeutic intervention during the development of autoimmune disease.

描述（由申请人提供）：免疫方面的性别差异 反应在自身免疫中尤其明显，女性表现出增加 易患自身免疫性疾病，但男性更容易患上自身免疫性疾病 预后较差。 这两种疾病易感性的性别差异 疾病的结果尚不清楚，但在一些疾病中却很明显 具有显着自身免疫特征的疾病，包括多发性硬化症 (MS)、系统性红斑狼疮 (SLE)、类风湿性关节炎 (RA)、格雷夫斯氏病 疾病和 DCM。 当前申请中提出的实验是 旨在解决男性与男性预后差异的基础 患有自身免疫性疾病的女性。 为此，我们开发了小鼠 EAMC 在该模型中，雄性 SWXJ 小鼠表现出心脏自体功能的长期维持 DCM 的发病率很高，而雌性小鼠则表现出 T 细胞自身免疫记忆和重要保护的维持中止 从DCM的发展来看。 因此，我们假设预后不良 男性患有自身免疫性疾病是因为他们的维持能力增强 自身免疫 T 细胞记忆和炎症自我识别的持续性。 在 具体目标 1，我们将确定性别差异的机制 雄性 SWXJ 小鼠与雌性 SWXJ 小鼠中发生基于自我识别的维持 与 EAMC。 在具体目标 2 中，我们将确定 自身免疫记忆可能会通过免疫和非免疫操作而改变。 在 此外，我们将确定记忆的持久性是否会导致 DCM 和 自身免疫记忆的性别差异发展是否可能与 进行治疗操作以改变疾病结果。 我们相信我们的 拟议的研究将有助于更好地理解自身免疫记忆如何 由性别定义的条件维持或终止。 此类信息可能 最终作为治疗干预的基础 自身免疫性疾病的发展。

项目成果

Autoimmune cardiac-specific T cell responses in dilated cardiomyopathy.

• DOI: 10.1016/j.ijcard.2006.05.007
• 发表时间: 2006-09
• 期刊: International journal of cardiology
• 影响因子: 3.5
• 作者: Dan Jane-wit;V. Tuohy

An autoimmune-mediated strategy for prophylactic breast cancer vaccination.

• DOI: 10.1038/nm.2161
• 发表时间: 2010-07
• 期刊: NATURE MEDICINE
• 影响因子: 82.9
• 作者: Jaini, Ritika;Kesaraju, Pavani;Johnson, Justin M.;Altuntas, Cengiz Z.;Jane-Wit, Daniel;Tuohy, Vincent K.
• 通讯作者: Tuohy, Vincent K.