T CELL ABNORMALITIES IN AUTOIMMUNE 1PR/1PR MICE

描述(改编自申请人的摘要)：MRL/MP-LPR/LPR小鼠 发生一种类似人类的系统性红斑狼疮(SLE)样疾病 SLE并发展为一种年龄依赖性淋巴增生性疾病 通过大量聚集异常的T淋巴细胞亚群。这个 异常的LPR T细胞对许多有丝分裂刺激无反应。 表型正常的CD4+T细胞，仅占5%至10% 在LPR小鼠的淋巴细胞中，也在 自身免疫性疾病的发病机制。这些携带CD4的细胞可能会识别 自身Ia抗原或某些加工过的与Ia结合的自体多肽。相互作用 这些自身反应性T细胞与B细胞之间的相互作用可能导致产生 自身抗体。因此，T细胞和自身抗原可能是导致 这些小鼠的自身免疫性疾病。T细胞杂交瘤是由 将CD4+LPR T细胞与BW5147融合。这些杂交瘤将被用来 研究自身反应性T细胞的T细胞受体谱系。T 细胞杂交瘤或其上清液将与B细胞培养以 确定他们是否能激活B细胞产生抗体。同种异型 产生的抗体的特异性将被确定。B细胞来源 LPR小鼠可能具有一些内在特征，这些特征使它们 在激活自身反应性T细胞方面有刺激作用。虽然很明显， CD_4~+T细胞对小鼠淋巴增殖的发育是必不可少的 LPR小鼠，CD4+T细胞与异常T细胞的关系不明显 安全。CD4+T细胞可能是异常T细胞的前体细胞。 淋巴细胞渗入LPR小鼠的肾脏和唾液腺。这个 浸润性淋巴细胞以CD4+T细胞为主。T细胞克隆 T细胞杂交瘤将从浸润性淋巴细胞中产生 取自LPR小鼠的肾脏和唾液腺。T细胞 这些T细胞克隆和杂交瘤的受体(TCR)谱将是 特色化的。肾脏和唾液腺的抗原提呈细胞 也将分离出LPR小鼠及其激活T细胞的能力 克隆或杂交瘤将被确定。这些研究应该提供新的 自身反应性T细胞与异常T细胞关系的研究 细胞和淋巴细胞在lpr小鼠炎症器官中的浸润。

DESCRIPTION (Adapted from the applicant's abstract): MRL/Mp-lpr/lpr mice develop a systemic lupus erythematosus (SLE) like disease similar to human SLE and develop an age dependent lymphoproliferative disease characterized by massive accumulation of an abnormal subset of T lymphocytes. The abnormal lpr T cells are unresponsive to many mitogenic stimuli. Phenotypically normal CD4+ T cells, which account for only 5 to 10 percent of the lymphocytes in lpr mice, also play an important role in the pathogenesis of autoimmune disease. These CD4 bearing cells may recognize self Ia antigens or some processed self peptides bound to Ia. Interaction of these autoreactive T cells with B cells may result in production of autoantibodies. T cells and self-antigens may, therefore, be the cause of autoimmune diseases in these mice. T cell hybridomas were generated by fusing CD4+ lpr T cells with BW5147. These hybridomas will be used to investigate the T cell receptor repertoire of the autoreactive T cells. T cell hybridomas or their supernatants will be cultured with B cells to determine if they can activate B cells to produce antibodies. The isotype and specificities of antibodies produced will be determined. B cells from lpr mice may possess some intrinsic features which render them more stimulatory in activating autoreactive T cells. While it is clear that CD4+ T cells are essential for the development of lymphoproliferation in lpr mice, the relationship between CD4+ T cells and abnormal T cells is not clear. CD4+ T cells may be the precursors of the abnormal T cells. Lymphocytes infiltrate the kidneys and salivary glands in lpr mice. The majority of the infiltrating lymphocytes are CD4+ T cells. T cell clones and T cell hybridomas will be generated from infiltrating lymphocytes obtained from the kidneys and salivary glands of lpr mice. The T cell receptor (TCR) repertoire of these T cell clones and hybridomas will be characterized. Antigen presenting cells in the kidneys and salivary glands of lpr mice will also be isolated and their ability to activate the T cell clones or hybridomas will be determined. These studies should provide new insights into the relationship between autoreactive T cells, abnormal T cells and lymphocytes infiltrating inflamed organs in lpr mice.