RESIDENT SKIN CELLS AND THEIR CYTOKINES IN AUTOIMMUNITY

自身免疫中的常驻皮肤细胞及其细胞因子

• 批准号: 2376370
• 负责人: SUSAN H JACKMAN
• 金额: $ 9.85万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2376370
• 关键词: apoptosis; autoimmunity; cellular pathology; cytokine; disease /disorder model; immunocytochemistry; immunopathology; immunosuppression; in situ hybridization; isoantigen; keratinocyte; laboratory mouse; passive immunization; polymerase chain reaction; skin

It has been recognized that most autoimmune diseases have a multifaceted etiology. Both a dysregulated immune process, as well as, the local environment within the involved organ-system appear to contribute to pathogenesis. Using a murine model targeted against the epidermal cell alloantigens, Skn, we can induce an autoimmune response by the adoptive transfer of CD4+ Skn-immune lymphocytes to previously immunosuppressed recipients expressing the appropriate Skn alleles who subsequently develop lesions in areas of mild epidermal trauma. The overall hypothesis to be evaluated is that epidermal trauma concomitant with immunosuppression elicits dysfunctional resident skin cells which alter the local microenvironment of the skin, subsequently contributing to the immune-mediated autoaggressive processes. First, we will characterize the sequence of molecular and cellular events that occur in the local skin environment after superficial trauma by analyzing skin-derived cytokine mRNA using PCR and by correlating those cytokines found with several site-modified alterations associated with immunopathology: the induction of adhesion molecules for leukocyte migration into the skin, changes in epidermal cell cycling, and appearance of apoptotic keratinocytes. Another study will address autoregulatory properties of resident skin gamma/delta T-cells and/or circulating lymphocytes, which appear to be inactivated by immunosuppression thereby rendering the recipient susceptible to autoaggressive attack. This will be determined by cotransfer of normal skin cells and/or lymphocytes along with Skn- immune cells to recipients who will be evaluated for reduced incidence of skin lesions and for altered skin cytokine profiles. In addition we will identify the cells expressing cytokines within lesional skin by detection of cytokine mRNA and protein using in situ hybridization and immunohistochemistry. In that Skn antigen appears to have a human counterpart, this animal model can provide information essential for understanding both the immune and the environmental pathogenic processes thought to contribute to human autoimmune dermatoses.

人们已经认识到，大多数自身免疫性疾病具有多方面的 病因学。无论是失控的免疫过程，还是局部的 受累器官系统内的环境似乎有助于 发病机制。以表皮细胞为靶点的小鼠模型 同种异体抗原，SKN，我们可以通过过继的方式诱导自身免疫反应 CD4+SKN免疫淋巴细胞向先前免疫抑制状态的转移 表达适当SKN等位基因的接受者随后 在轻微的表皮创伤区域形成皮损。整体而言 需要评估的假设是，表皮创伤伴随着 免疫抑制引起功能失调的常驻皮肤细胞改变 皮肤的局部微环境，从而导致 免疫介导的自攻性过程。首先，我们将描述 发生在当地的分子和细胞事件的顺序 从皮肤来源分析浅表创伤后皮肤环境 使用聚合酶链式反应并通过将发现的细胞因子与 与免疫病理学相关的几种部位修饰的改变： 诱导白细胞迁移到皮肤中的黏附分子， 表皮细胞周期的改变和细胞凋亡的出现 角质形成细胞。另一项研究将解决自动调节特性 常驻皮肤伽马/德尔塔T细胞和/或循环淋巴细胞， 似乎被免疫抑制灭活，从而使 易受自动攻击攻击的收件人。这一点将被确定 通过将正常皮肤细胞和/或淋巴细胞与SKN- 向接受者提供免疫细胞，以评估其发病率是否降低 对于皮肤损伤和皮肤细胞因子图谱的改变。此外，我们还 将通过以下方法鉴定皮损内表达细胞因子的细胞 原位杂交法检测细胞因子mRNA和蛋白 免疫组织化学。在SKN抗原中似乎有一个人 相应地，这种动物模型可以提供必要的信息 了解免疫和环境致病过程 被认为与人类自身免疫性皮肤病有关。