T cell diversity in the induction of autoimmunity

描述（由申请人提供）：移植物抗宿主病（GVHD）， 复杂的异基因骨髓移植的特点是器官 损伤包括皮炎、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 抗双链DNA，其模拟系统性红斑狼疮中的那些。发展 这两种表现都需要CD 4 + T细胞;然而， 刺激T细胞的机制还不清楚我们建议利用转基因模型， 检测CD 4细胞-抗原呈递细胞（APC）相互作用， 小鼠GVHD。K14小鼠是胸腺发育异常的模型，其中CD 4 + 由于阴性选择失败，T细胞是自身反应性的。 H2-DM缺陷型胸腺选择自身反应性CD 4+细胞限制类 II相关肽。K14 CD 4细胞诱导抗dsDNA抗体的同源性 宿主; H2-DM缺陷型CD 4+则没有。2-2-3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小鼠自发发生皮肤病， 类似于皮肤GVHI）;然而，2-2- 31 K14 CD 4+细胞不能诱导 同源小鼠体内的自身抗体。因此，皮肤GVHD由单克隆抗体诱导。 与角质形成细胞相互作用的T细胞;然而， GVHD期间的自身抗体需要激活不同的T细胞库， 细胞在具体目标I中，我们将询问为什么K14、H2-DM和2-2-3/K14 CD 4细胞 在转移到同源宿主后诱导不同谱的自身抗体。 我们将研究的定位，分裂，和细胞因子的生产， 转移的CD 4+细胞和B细胞活化和生发中心产生。 Specific Aim II将扩展这些研究，以研究抗DNA抗体的产生 在抗DNA抗体的重链转基因小鼠中的GVHD期间。 在特定目标III中，角质形成细胞/CD 4+细胞相互作用需要 解剖2-2-3/K14小鼠的皮肤GVHD。时间要求 皮肤中造血APC、炎性细胞因子和MHC II类表达 将被确定。最后，在特定目标IV中，我们将识别肽 自身反应性2-2-3 CD 4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， “移植物”T细胞和宿主抗原呈递细胞之间的相互作用 为预防骨髓移植后GVHD提供了改进的免疫靶点 移植

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.