T cell diversity in the induction of autoimmunity

诱导自身免疫的 T 细胞多样性

• 批准号: 6621628
• 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/6621628
• 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 - 疾病（GVHD），哪个 复杂的同种异体骨髓移植的特征是器官 损害包括皮炎，肠炎和肝炎。大部分 移植后患者还开发了对自我抗原的抗体，包括 抗DSDNA，模仿那些在全身性红斑狼疮中的人。发展 两种表现都需要CD4+ T细胞。但是， 煽动T细胞在很大程度上未知。我们建议将转基因模型用于 检查启动的CD4细胞抗原呈现细胞（APC）相互作用 Murine GVHD。 K14小鼠是一种异常胸腺发育模型，其中CD4+ 由于负选择的失败，T细胞具有自动反应性。 H2-DM缺陷的百里香选择自动反应性CD4+细胞在受限类上 II相关肽。 K14 CD4细胞诱导抗DSDNA抗体中的抗体 主持人； H2-DM缺陷CD4+没有。 2-2-3只小鼠携带TCR的转基因 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小鼠自发发展皮肤疾病，这在组织学上 类似皮肤GVHI）;但是，2-2-31K14 CD4+细胞无法诱导 合成小鼠的自身抗体。因此，皮肤GVHD由单克隆诱导 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T 细胞。在特定的目标I中，我们将询问为什么K14，H2-DM和2-2-3/K14 CD4 CYT 转移到同步宿主后诱导不同频谱自身抗体。 我们将研究的本地化，分裂和细胞因子的产生 转移CD4+细胞和B细胞活化和生发中心的产生。 特定的目标II将扩展这些研究以研究抗DNA AB的产生 在抗DNA抗体的重链小鼠转基因中GVHD期间。 在特定的AIM III中，需要的角质形成细胞/CD4+细胞相互作用 将解剖2-2-3/K14小鼠中的皮肤GVHD。时间要求 造血APC，炎症细胞因子和MHC II类表达 将确定。最后，在特定的目标IV中，我们将确定肽 自动反应性2-2-3 CD4细胞对APC的特异性和 GVHD中的角质形成细胞。了解T细胞多样性的要求和 “移植” T细胞与宿主抗原呈现细胞之间的相互作用 提供改进的免疫目标，以防止骨髓后GVHD 移植。