GENDER-SPECIFIC T CELL HOMING AND AUTOIMMUNITY

性别特异性 T 细胞归巢和自身免疫

• 批准号: 6626340
• 负责人: BRUCE C. RICHARDSON
• 金额: $ 32.96万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6626340
• 关键词: autoimmune disorder; cell adhesion molecules; cell migration; disease /disorder etiology; female; gender difference; helper T lymphocyte; laboratory mouse; sex hormones; spleen; women's health

DESCRIPTION: (Adapted from the applicant's abstract) - Women are more susceptible to autoimmune diseases, and the reason is unknown. Female sex hormones appear to play a role in this predisposition to autoimmunity, but extensive analysis of the effects of the female sex steroids on immune responses in vitro have failed to identify the mechanism(s). Dr. Richardson's group has used a new model of drug- induced lupus to identify novel gender-specific immune mechanisms. In this model, D10 cells, a cloned Th2 line, are made autoreactive by treatment with a mitogen and DNA methylation inhibitors, then injected into syngeneic mice. The autoreactive cells cause a more severe autoimmune disease in females than in males, and disease severity is diminished by oophorectomy. Significantly more of the cells, treated or untreated, accumulate in the female spleens, and this selective retention also decreases following oophorectomy. Finally, splenectomy prevents the development of autoimmunity. These results demonstrate that T cell splenic homing differs between males and females, and that the spleen is essential for the development of the disease. These results suggest that the greater disease severity in females is due to more autoreactive cells accumulating in the female spleens. The observation that these effects are reversed by oophorectomy implicates female sex hormones in these differences. Dr. Richardson hypothesizes that gender- specific differences in T cell homing, due to effects of female sex hormones on adhesion molecule expression, contribute to increased severity of autoimmune diseases in females by modifying lymphocyte trafficking patterns. Gender-specific trafficking differences could be important both in the induction of disease as well as later in the disease process. Dr. Richardson's model provides a unique opportunity, he believes, to test the role of sex hormones directly in modulating endothelial cell adhesion molecule expression and lymphocyte homing, and to relate these findings to the development and severity of autoimmunity. The specific aims are to (1) characterize the effects of sex hormones on T cell homing in vivo; (2) define the effects of sex hormones and other signals on T cell and endothelial cell adhesion expression and function in vitro; and to define the role of these adhesion molecules whose expression is modified by sex hormones in splenic homing and in disease processes. Dr. Richardson anticipates that these studies will identify novel and important mechanisms contributing to the increased incidence and severity of autoimmune disease in women.

描述：（改编自申请人的摘要）- 女性更重要 易患自身免疫性疾病，其原因尚不清楚。女性 性激素似乎在这种倾向中发挥了作用 自身免疫，但对女性的影响进行了广泛分析 体外类固醇对免疫反应的影响未能确定 机制。理查森博士的研究小组使用了一种新的药物模型—— 诱导狼疮以确定新的性别特异性免疫机制。在 该模型中，D10 细胞是克隆的 Th2 细胞系，通过以下方式使其具有自身反应性： 用有丝分裂原和 DNA 甲基化抑制剂治疗，然后注射 进入同系小鼠。自身反应性细胞会导致更严重的 女性自身免疫性疾病的发病率高于男性，且疾病严重程度 因卵巢切除术而减少。显着更多的细胞，经过处理或 未经治疗，会积聚在女性脾脏中，并且这种选择性 卵巢切除术后保留也会减少。最后进行脾切除 防止自身免疫的发展。这些结果表明 T 细胞脾归巢在男性和女性之间存在差异，并且 脾对于疾病的发生至关重要。这些结果 表明女性疾病更严重的原因是 自身反应细胞在女性脾脏中积聚。观察结果 卵巢切除术可以逆转这些影响，这表明女性性别 激素的这些差异。理查森博士假设性别 由于女性性别的影响，T 细胞归巢的具体差异 激素对粘附分子表达的影响，有助于增加 通过改变淋巴细胞来观察女性自身免疫性疾病的严重程度 贩运模式。特定性别的贩运差异可能是 对于疾病的诱发以及后期的发展都很重要 疾病过程。理查森博士的模型提供了一个独特的机会， 他认为，要直接测试性激素在调节中的作用 内皮细胞粘附分子表达和淋巴细胞归巢，以及 将这些发现与疾病的发展和严重程度联系起来 自身免疫。具体目标是（1）表征 性激素对体内 T 细胞归巢的影响； (2) 定义性别的影响 T 细胞和内皮细胞粘附的激素和其他信号 体外表达和功能；并定义这些角色的作用 其表达受性激素修饰的粘附分子 脾归巢和疾病过程。理查森博士预计 这些研究将确定有助于 女性自身免疫性疾病的发病率和严重程度增加。