Immunopathogenesis of Lupus

狼疮的免疫发病机制

• 批准号: 8197177
• 负责人: Charles S. Via
• 金额: $ 37.71万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197177
• 关键词: Acute Graft Versus Host Disease; Address; Adverse effects; Animal Model; Antibodies; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; B-Cell Activation; B-Lymphocytes; Biological; CD4 Positive T Lymphocytes; CD80 gene; CD8B1 gene; Cells; Characteristics; Clinical; Complex; Cytotoxic T-Lymphocytes; Defect; Deposition; Development; Disease; Down-Regulation; Ethics; Funding; Gene Mutation; Genetic; Goals; HIV; Heterogeneity; Human; Immune system; Immunologics; Interferon Type II; Interleukin-15; Interleukin-2; Kidney; Knockout Mice; Longevity; Lupus; Measures; Methods; Minor; Modeling; Morbidity - disease rate; Mus; Mutation; Nature; Nuclear Antigens; Parents; Pathogenesis; Pathway interactions; Patients; Principal Investigator; Process; Production; Property; Protocols documentation; Resource Sharing; Role; Skin; Source; Specificity; System; Systemic Lupus Erythematosus; T-Lymphocyte; TNF gene; Testing; Text; Therapeutic; Toxin; Tropism; Woman; autoreactive B cell; body system; child bearing; chronic graft versus host disease; cytokine; disease characteristic; disorder control; graft vs host disease; human disease; in vivo; innovation; insight; killings; lupus-like; mortality; mouse model; novel; pathogen; perforin; prevent; research study; response

DESCRIPTION (provided by applicant): Systemic lupus erythematosus is a multi-system disease with significant morbidity and mortality. Current treatment is associated with significant side effects. This application pursues the novel hypothesis that cytotoxic T lymphocytes (CTL) are an important early mechanism that limits breaks in tolerance to nuclear antigens and prevents lupus development by eliminating activated autoreactive B cells. This hypothesis is tested using the parent-into-F1 model in which lupus-like disease is induced in normal F1 mice by the transfer of parental strain CD4+ T cells. Lupus is not observed with the transfer of both CD4+ and CD8+ T parental cells due to donor CD8+ CTL elimination of activated autoreactive host B cells. During the previous funding period, the Principal Investigator observed that perforin deficient donor cells result in impaired CTL elimination of host B cells leading to lupus long term. These results support a new paradigm in which defects in CTL killing are a final common pathway in lupus development due to incomplete elimination of activated autoreactive B cells which, in the setting of CD4 driven B cell activation, allows autoantibody production to persist and result in lupus. This paradigm is directly tested in this application. The long-term goal of the Principal Investigator is to develop a protocol for therapeutic induction of endogenous CTL which target and eliminate activated autoreactive B cells as treatment in lupus patients. This application will establish the underlying mechanisms required for this approach and test several promising strategies in the parent-into-F1 model. Aim 1. Determine whether impaired elimination of autoreactive B cells by CTL is a final common pathway for the development of lupus regardless of the nature of the initial CTL defect. Sub-aims will evaluate whether perforin or Fas dominates. Aim 2. Determine whether promoting CTL longevity by blocking downregulation will prevent lupus. The role of Fas, perforin, CD80, IL-2 and host T cells will be tested using knock out mice or mAb blockade. Aim 3. Determine whether promoting CTL expansion by cytokine administration will prevent lupus. These experiments use an innovative method of TNF administration in the form of cytokine:anti-cytokine antibody complexes that prolongs biological activity in vivo. IL-15 will be tested as uncomplexed cytokine. Sub-aims will define the mechanisms by which TNF, IFN-g and IL-2 exert critical roles in the maturation of CTL effectors. Project Narrative Relevance. Systemic lupus erythematosus is an autoimmune disease that attacks major organ systems resulting in significant morbidity and mortality, particularly in women during their child bearing years. Current treatment is associated with significant side effects. This application examines a novel method of harnessing one's own immune system to help control disease.

描述（由申请人提供）：系统性红斑狼疮是一种具有显着发病率和死亡率的多系统疾病。目前的治疗与显着的副作用相关。本申请提出了一个新的假设，即细胞毒性 T 淋巴细胞 (CTL) 是一种重要的早期机制，可限制核抗原耐受性的破坏，并通过消除活化的自身反应性 B 细胞来预防狼疮的发展。使用亲本进入 F1 模型测试了这一假设，其中通过亲本品系 CD4+ T 细胞的转移在正常 F1 小鼠中诱导狼疮样疾病。由于供体 CD8+ CTL 消除了激活的自身反应性宿主 B 细胞，因此在 CD4+ 和 CD8+ T 亲代细胞的转移中未观察到狼疮。在之前的资助期间，首席研究员观察到，穿孔素缺陷的供体细胞会导致宿主 B 细胞的 CTL 消除受损，从而导致长期狼疮。这些结果支持了一种新的范式，其中 CTL 杀伤缺陷是狼疮发展的最终常见途径，这是由于激活的自身反应性 B 细胞的不完全消除，在 CD4 驱动的 B 细胞激活的情况下，使得自身抗体的产生持续存在并导致狼疮。该范例在此应用程序中直接进行了测试。首席研究员的长期目标是开发一种治疗诱导内源性 CTL 的方案，该方案靶向并消除激活的自身反应性 B 细胞，作为狼疮患者的治疗方法。该应用程序将建立该方法所需的底层机制，并在“parent-into-F1”模型中测试几种有前景的策略。目标 1. 确定 CTL 对自身反应性 B 细胞的消除受损是否是狼疮发展的最终常见途径，无论初始 CTL 缺陷的性质如何。子目标将评估穿孔素或 Fas 是否占主导地位。目标 2. 确定通过阻止下调来促进 CTL 寿命是否可以预防狼疮。 Fas、穿孔素、CD80、IL-2 和宿主 T 细胞的作用将使用基因敲除小鼠或 mAb 阻断进行测试。目标 3. 确定通过细胞因子施用促进 CTL 扩增是否可以预防狼疮。这些实验采用了一种以细胞因子：抗细胞因子抗体复合物形式施用 TNF 的创新方法，可延长体内生物活性。 IL-15 将作为未复合的细胞因子进行测试。子目标将定义 TNF、IFN-g 和 IL-2 在 CTL 效应子成熟中发挥关键作用的机制。项目叙述相关性。系统性红斑狼疮是一种自身免疫性疾病，会攻击主要器官系统，导致显着的发病率和死亡率，特别是在育龄期的妇女中。目前的治疗与显着的副作用相关。该应用研究了一种利用自身免疫系统帮助控制疾病的新方法。

项目成果

Donor CD8 T cell activation is critical for greater renal disease severity in female chronic graft-vs.-host mice and is associated with increased splenic ICOS(hi) host CD4 T cells and IL-21 expression.

• DOI: 10.1016/j.clim.2010.01.005
• 发表时间: 2010-07
• 期刊: Clinical immunology (Orlando, Fla.)
• 作者: Foster AD;Haas M;Puliaeva I;Soloviova K;Puliaev R;Via CS
• 通讯作者: Via CS

Both perforin and FasL are required for optimal CD8 T cell control of autoreactive B cells and autoantibody production in parent-into-F1 lupus mice.

• DOI: 10.1016/j.clim.2018.06.007
• 发表时间: 2018-09
• 期刊: Clinical immunology (Orlando, Fla.)
• 作者: Soloviova K;Puliaiev M;Puliaev R;Puliaeva I;Via CS
• 通讯作者: Via CS

CTL-promoting effects of CD40 stimulation outweigh B cell-stimulatory effects resulting in B cell elimination and disease improvement in a murine model of lupus.

• DOI: 10.4049/jimmunol.181.1.47
• 发表时间: 2008-07-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Puliaev, Roman;Puliaeva, Irina;Welniak, Lisbeth A.;Ryan, Abigail E.;Haas, Mark;Murphy, William J.;Via, Charles S.
• 通讯作者: Via, Charles S.

In vivo maturation of allo-specific CD8 CTL and prevention of lupus-like graft-versus-host disease is critically dependent on T cell signaling through the TNF p75 receptor but not the TNF p55 receptor.

• DOI: 10.4049/jimmunol.1300091
• 发表时间: 2013-05-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Soloviova K;Puliaiev M;Haas M;Via CS
• 通讯作者: Via CS

B cell depletion in murine lupus using cytotoxic T lymphocytes in vivo: Feasibility and benefit.

使用体内细胞毒性 T 淋巴细胞去除小鼠狼疮中的 B 细胞：可行性和益处。

• DOI: 10.1016/j.cellimm.2020.104117
• 发表时间: 2020
• 期刊: Cellular immunology
• 影响因子: 4.3
• 作者: Soloviova,Kateryna;Puliaeva,Irina;Puliaiev,Maksym;Puliaev,Roman;Via,CharlesS
• 通讯作者: Via,CharlesS