Antibody induced T cell-mediated neonatal autoimmunity.

抗体诱导 T 细胞介导的新生儿自身免疫。

• 批准号: 8206614
• 负责人: KENNETH S.K. TUNG
• 金额: $ 37.12万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206614
• 关键词: Ablation; Address; Adoptive Transfer; Adult; Affect; Age; Aleurites; Antibodies; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; CD4 Positive T Lymphocytes; CD94 Antigen; Cell physiology; Complex; Cytolysis; Dendritic Cells; Disease; Disease model; Equilibrium; Event; Frequencies; Genes; Goals; Grant; Growth; IL2RA gene; Immune response; Immune system; Inflammatory; Infusion procedures; Injury; Interleukin-10; Investigation; Knockout Mice; Life; Ligands; Mediating; Modeling; Mus; Natural Immunity; Natural Killer Cells; Neonatal; Oocytes; Organ; Ovarian; Ovarian Diseases; Ovary; Pathogenesis; Physiology; Play; Predisposing Factor; Process; Regulation; Regulatory T-Lymphocyte; Relative (related person); Research Personnel; Resistance; Rheumatoid Arthritis; Role; Seminal; Specificity; T cell response; T-Lymphocyte; Testing; Time; Wild Type Mouse; Work; base; cytokine; insight; knockout gene; neonate; novel; perforin; programs; receptor; recombinase; response; zona pellucida glycoprotein

This is the competitive renewal application to extend our work supported by AI51420-01A. Significant progress has been made that greatly elucidate the mechanism of the unique neonatal autoimmune ovarian disease (nAOD). Autoantibody (Ab) to the ovarian ZP3 led to the formation of ovarian immune complex. This provokes an organ specific autoimmune disease that is regulated by FcgR+, and dependent on de novo activation of pathogenic CD4 T cells (TD-nAOD). Uniquely, nAOD affects only neonatal mice and spares mice beyond 5 days of age; therefore, the understanding neonatal propensity to autoimmunity is our major goal. We discovered that severe nAOD is also induced in the recombinase activating gene (RAG) knockout (KO) mice, thus innate immunity alone is also sufficient to induce nAOD (TI-nAOD). NK cells play multiple and pivotal roles in TI-nAOD. A seminal observation is the ontogenetic regulation of NK cell function in TI- nAOD. RAG KO mice deficient in perforin did not develop TI-nAOD, and the disease was restored by neonatal but not adult (or day 9) NK cells from wild type donors. NK function in TI-nAOD also depended on NKG2D - a major NK cell activating receptor. In AIM 1, we will test the hypothesis that the late ontogeny of expression of the Ly49 NK cell inhibitory receptors allows neonatal NK cells to escape from regulation between neonatal 1-5 days, and to induce neonatal ovarian injury. The pro-inflammatory cytokine IFNg and also FcgR played non-redundant roles in the pathogenesis of both TI-nAOD and TD-nAOD. In AIM 2, we will investigate the cellular basis for the IFNg- and NK cell- dependent functions in TI-nAOD of RAG KO mice. And in AIM 3, we will investigate how neonatal NK cells and IFNg promote de novo pathogenic T cell responses in TD-nAOD of wild type mice; in particular, determine the relative contribution of NK cells and dendritic cells in this process. Finally, the NK cell-dependent TI-nAOD was readily suppressed by adult CD4+CD25+ Treg, and it requires IL10. This finding documents, for the first time, Treg suppression of any form of neonatal immune response. In AIM 4, we will investigate the cellular mechanism of the IL10- dependent Treg suppression. Also, by comparing the mechanism of suppression between the adult and the neonatal hosts, we expect to obtain new insight into the physiology of neonatal immune system, and further elucidate the important observation of neonatal propensity to autoimmune disease.

这是AI51420-01A支持的扩展我们工作的竞争性续期申请。重要的