T cell diversity in the induction of autoimmunity

描述(申请人提供)：移植物抗宿主病(GVHD) 复杂异基因骨髓移植以器官为特征 损害包括皮炎、肠炎和肝炎。大多数人 移植后的患者也会产生针对自身抗原的抗体，包括 抗dsDNA，它模仿系统性红斑狼疮的dsDNA。最新进展 这两种表现都需要CD4+T细胞；然而， 激发T细胞在很大程度上是未知的。我们建议利用转基因模型来 检查CD4细胞-抗原提呈细胞(APC)的相互作用 小鼠GVHD。K14小鼠是胸腺发育异常的模型，在该模型中 由于阴性选择失败，T细胞发生自身反应。 H2-DM缺陷型胸腺选择限制性类自身反应性CD4+细胞 II相关多肽。K14CD_4细胞在同基因小鼠体内诱导抗双链DNA抗体 宿主；缺乏H2-DM的CD4+则不能。2-2-3小鼠携带TCR转基因 来自B6反应性K14 T细胞杂交瘤2-2-3的基因。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，2-2-31K14 CD4+细胞不能诱导 同基因小鼠的自身抗体。因此，皮肤移植物抗宿主病是由单抗诱导的。 与角质形成细胞相互作用的T细胞；而产生 GVHD期间的自身抗体需要激活不同的T细胞 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细胞 在转移到同基因宿主后诱导不同的自身抗体谱。 我们将研究细胞的定位、分裂和细胞因子的产生。 转移的CD4+细胞和B细胞活化及生发中心产生。 SPICAL AIM II将扩展这些研究以研究抗DNA抗体的生产 在GVHD期间，一只小鼠转基因获得一种抗DNA抗体的重链。 在特定的目标III中，角质形成细胞/CD4+细胞相互作用所需的 将解剖2-2-3/K14小鼠的皮肤移植物抗宿主病。的时间要求 皮肤中造血型APC、炎性细胞因子和MHC-II类的表达 将会被确定。最后，在特定的目标IV中，我们将鉴定多肽 自身反应性2-2-3细胞对APC和APC反应的特异性 移植物抗宿主病的角质形成细胞。了解T细胞多样性的要求和 移植物T细胞与宿主抗原提呈细胞的相互作用 为预防骨髓移植后移植物抗宿主病提供改进的免疫靶点 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.