GENDER-SPECIFIC T CELL HOMING AND AUTOIMMUNITY

描述：(改编自申请者的摘要)-女性比 易患自身免疫性疾病，原因不明。女性 性激素似乎在这种易感性中发挥了作用。 自身免疫，但对女性的影响进行了广泛的分析 类固醇对体外免疫反应的影响未能确定 机制(S)。理查森博士的团队使用了一种新的药物模型- 诱导狼疮识别新的性别特异性免疫机制。在……里面 这个模型，D10细胞，一种克隆的Th2细胞，通过 用有丝分裂原和DNA甲基化抑制剂治疗，然后注射 变成同基因的小鼠。自身反应性细胞会引起更严重的 自身免疫性疾病女性多于男性，且疾病严重程度 因卵巢切除而减少。明显更多的细胞，处理或 未经治疗，积聚在女性脾中，这是选择性的 卵巢切除后的滞留也会减少。最后，脾切除术 防止自身免疫力的发展。这些结果表明， T细胞脾归巢在男性和女性之间不同，而且 脾在疾病的发展中是必不可少的。这些结果 这表明女性的疾病严重程度更高是因为 自体反应细胞聚集在女性的脾中。观察到的 这些影响被卵巢切除术逆转，这与女性的性别有关 这些差异中的荷尔蒙。理查森博士假设性别- 由于女性性别的影响，T细胞归巢的特异性差异 激素对黏附分子的表达，有助于增加 淋巴细胞修饰对女性自身免疫性疾病严重程度的影响 人口贩运模式。不同性别的人口贩运差异可能是 无论是在疾病的诱发中，还是在后来的 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，为了直接测试性激素在调节 内皮细胞黏附分子表达与淋巴细胞归巢 将这些发现与疾病的发展和严重程度联系起来 自身免疫力。具体目标是(1)描述 性激素对体内T细胞归巢的影响；(2)确定性行为的影响 激素和其他信号对T细胞和内皮细胞黏附的影响 在体外的表达和功能；并确定它们的作用 黏附分子的表达受性激素的调节 脾归巢和在疾病过程中。理查森博士预计 这些研究将确定新的和重要的机制 妇女自身免疫性疾病发病率和严重性的增加。

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.