GENDER-SPECIFIC T CELL HOMING AND AUTOIMMUNITY

描述：（改编自申请人的摘要）-妇女更多 易患自身免疫性疾病，原因不明。女性 性激素似乎在这种倾向中发挥作用， 自身免疫，但广泛的分析的影响，女性 类固醇对体外免疫反应的影响未能确定 机制。理查森博士的团队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，D10细胞，一种克隆的Th 2细胞系，通过以下方法使其产生自身反应性： 用有丝分裂原和DNA甲基化抑制剂治疗，然后注射 同基因小鼠。自身反应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， 因卵巢切除而减少明显更多的细胞，处理或 未经治疗，积累在女性脾脏，这种选择性 卵巢切除术后尿潴留也减少。最后是脾切除术 防止自身免疫的发展。这些结果证明 男性和女性的T细胞脾归巢不同， 脾是疾病发展的关键。这些结果 这表明，女性疾病的严重程度更高是由于 自体反应细胞在女性脾脏中聚集观察 卵巢切除术可以逆转这些影响， 激素在这些差异中的作用。理查森博士假设性别- 由于女性性别的影响，T细胞归巢的特定差异 激素对粘附分子表达的影响，有助于增加 通过修饰淋巴细胞检测女性自身免疫性疾病的严重程度 贩卖模式贩运人口的性别差异可能是 重要的是在诱导疾病以及后来在 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 内皮细胞粘附分子表达和淋巴细胞归巢，以及 将这些发现与以下疾病的发展和严重程度联系起来： 自身免疫具体目标是：（1）描述 性激素对体内T细胞归巢的影响;（2）确定性别的影响 激素和其他信号对T细胞和内皮细胞粘附的影响 体外表达和功能;并确定这些的作用 粘附分子，其表达被性激素改变， 脾归巢和疾病过程。理查森博士预计， 这些研究将确定新的重要机制， 女性自身免疫性疾病的发病率和严重程度增加。

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.