T cell diversity in the induction of autoimmunity

诱导自身免疫的 T 细胞多样性

• 批准号: 6698542
• 负责人: TERRI M. LAUFER
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6698542
• 关键词: B lymphocyte; MHC class II antigen; antibody formation; antigen presenting cell; antinuclear autoantibody; autoantibody; cell cell interaction; cell cycle; cell migration; cytokine; genetically modified animals; graft versus host disease; helper T lymphocyte; keratinocyte; laboratory mouse; leukocyte activation /transformation; protein biosynthesis

DESCRIPTION (provided by applicant): The graft-versus-host-disease (GVHD) which complicates allogeneic bone marrow transplantation is characterized by organ damage including dermatitis, enteritis, and hepatitis. A majority of post-transplant patients also develop antibodies to self-antigens, including anti-dsDNA, which mimic those in systemic lupus erythematosus. The development of both manifestations requires CD4+ T cells; however, the specificity of the inciting T cells is largely unknown. We propose to utilize transgenic models to examine the CD4 cell-antigen presenting cell (APC) interactions which initiate murine GVHD. K14 mice are a model of abnormal thymic development in which CD4+ T cells are autoreactive due to a failure of negative selection. H2-DM-deficient thymi select autoreactive CD4+ cells on restricted class II-associated peptides. K14 CD4 cells induce anti-dsDNA antibodies in syngeneic hosts; H2-DM-deficient CD4+ do not. 2-2-3 mice carry transgenes for the TCR genes from a B6-reactive K14 T cell hybridoma, 2-2-3. Double transgenic 2-2-3/K14 mice spontaneously develop skin disease which histologically resembles cutaneous GVHI); however, 2-2-31K14 CD4+ cells cannot induce autoantibodies in syngeneic mice. Thus, cutaneous GVHD is induced by monoclonal T cells which interact with keratinocytes; whereas, the production of autoantibodies during GVHD requires the activation of a diverse repertoire of T cells. In Specific Aim I, we will ask why K14, H2-DM, and 2-2-3/K14 CD4 cells induce different spectrums of autoantibodies after transfer to syngeneic hosts. We will examine the localization, division, and cytokine production of transferred CD4+ cells and B cell activation and germinal center production. Specific Aim II will extend these studies to investigate anti-DNA Ab production during GVHD in a mouse transgenic for the heavy chain of an anti-DNA antibody. In Specific Aim III, the keratinocyte/CD4+ cell interactions required for cutaneous GVHD in 2-2-3/K14 mice will be dissected. Temporal requirement for hematopoietic APC, inflammatory cytokines, and MHC class II expression in skin will be determined. Finally, in Specific Aim IV, we will identify the peptide specificity of the autoreactive 2-2-3 CD4 cell response to APC and keratinocytes in GVHD. Understanding the requirements for T cell diversity and the interactions between "graft" T cells and host antigen presenting cells offers improved immunologic targets for preventing GVHD following bone marrow transplant.

描述（由申请人提供）：移植物抗宿主病（GVHD） 异体骨髓移植的复杂性特点是器官 损害包括皮炎、肠炎和肝炎。大多数 移植后患者也会产生针对自身抗原的抗体，包括 抗 dsDNA，类似于系统性红斑狼疮中的抗 dsDNA。发展历程 这两种表现都需要 CD4+ T 细胞；然而，其特殊性 刺激 T 细胞的情况在很大程度上是未知的。我们建议利用转基因模型 检查 CD4 细胞-抗原呈递细胞 (APC) 相互作用，该相互作用启动 小鼠 GVHD。 K14 小鼠是胸腺发育异常的模型，其中 CD4+ 由于负选择失败，T 细胞会发生自身反应。 H2-DM 缺陷型胸腺选择限制类自身反应性 CD4+ 细胞 II 相关肽。 K14 CD4 细胞在同基因中诱导抗 dsDNA 抗体 主机； H2-DM 缺陷型 CD4+ 则不会。 2-2-3 小鼠携带 TCR 转基因 来自 B6 反应性 K14 T 细胞杂交瘤的基因，2-2-3。双转基因 2-2-3/K14 小鼠自发发生皮肤病，其组织学特征 类似于皮肤 GVHI）；然而，2-2-31K14 CD4+ 细胞不能诱导 同基因小鼠中的自身抗体。因此，皮肤 GVHD 是由单克隆抗体诱导的。 与角质形成细胞相互作用的 T 细胞；而，生产 GVHD 期间的自身抗体需要激活多种 T 细胞。在具体目标 I 中，我们会问为什么 K14、H2-DM 和 2-2-3/K14 CD4 细胞 转移至同基因宿主后诱导不同谱的自身抗体。 我们将检查定位、分裂和细胞因子的产生 转移的 CD4+ 细胞和 B 细胞激活和生发中心产生。 Specific Aim II 将扩展这些研究以调查抗 DNA 抗体的产生 抗 DNA 抗体重链转基因小鼠的 GVHD 期间。 在特定目标 III 中，角质形成细胞/CD4+ 细胞相互作用 将解剖 2-2-3/K14 小鼠的皮肤 GVHD。时间要求 皮肤中造血 APC、炎症细胞因子和 MHC II 类表达 将被确定。最后，在特定目标 IV 中，我们将鉴定肽 自身反应性 2-2-3 CD4 细胞对 APC 反应的特异性 GVHD 中的角质形成细胞。了解 T 细胞多样性的要求和 “移植”T 细胞和宿主抗原呈递细胞之间的相互作用 提供改进的免疫靶标，预防骨髓移植后移植物抗宿主病 (GVHD) 移植。