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） - 女性更多 容易受到自身免疫性疾病的影响，原因是未知的。女性 性激素似乎在这种倾向中起作用 自身免疫性，但对女性的影响进行了广泛的分析 体外免疫反应的类固醇未能鉴定 机理。理查森博士的小组使用了一种新的药物模型 诱发狼疮以鉴定新型性别特异性免疫机制。在 该模型D10单元格（克隆的Th2系）由 用有丝分裂原和DNA甲基化抑制剂治疗，然后注射 进入合成小鼠。自动反应性细胞会导致更严重 女性的自身免疫性疾病多于男性，疾病的严重程度是 通过卵巢切除术减少。明显更多的细胞处理或 未经治疗，积聚在雌性脾脏中，这种选择性 卵巢切除术后，保留率也减少。最后，脾切除术 防止自身免疫的发展。这些结果表明 T细胞脾hous住在男性和女性之间，并且 脾脏对于疾病的发展至关重要。这些结果 表明女性的疾病严重程度较大是由于更多 雌性脾脏积聚的自动反应性细胞。观察 这些作用被卵形切除术逆转，这意味着女性 这些差异中的激素。理查森博士假设性别 由于女性的影响，T细胞寄养的特定差异 激素在粘附分子表达上，有助于增加 通过修饰淋巴细胞的女性自身免疫性疾病的严重程度 贩运模式。性别特定的贩运差异可能是 在疾病的诱导以及后期都重要 疾病过程。理查森博士的模型提供了一个独特的机会， 他相信，直接测试性激素在调节中的作用 内皮细胞粘附分子的表达和淋巴细胞的寄养，以及 将这些发现与发展和严重性 自身免疫性。具体目的是（1）表征 体内T细胞归巢上的性激素； （2）定义性别的影响 T细胞和内皮细胞粘附上的激素和其他信号 体外表达和功能；并定义这些角色 粘附分子的表达是通过性激素在 脾归住和疾病过程。理查森博士预计 这些研究将确定促成新颖和重要的机制 女性自身免疫性疾病的发病率和严重程度增加。