T CELL CONTROL OF AUTOREACTIVITY IN MURINE SLE

所提出的研究是针对定义细胞机制， 抗Sm抗体的产生，抗Sm抗体是一种在人和鼠中发现的自身抗体 系统性红斑狼疮（SLE）。 该实验室的研究表明， 表明T细胞在调节抗Sm产生中起关键作用， MRL小鼠。 应用体外培养系统研究自发性抗Sm抗体 这些调节性T细胞的产生、性质和作用机制 将建立。 将特别注意 T细胞的抗原表型，它们对辅助细胞的需求 和Ia编码的限制性元件，以及它们的抗原特异性。 的 T细胞对Sm抗原的识别也将使用免疫荧光法进行研究。 抗原特异性增殖试验。 的 由T细胞感知的Sm的抗原决定簇的性质将是 确定，以及巨噬细胞，Ia抗原和免疫的作用， 在SLE小鼠和正常人中的这种反应。 初步 数据表明，T细胞对鼠Sm的反应是在MHC连锁的 遗传控制，但SLE菌株MRL-Mp-+/+能够识别 Sm，尽管其无应答（H-2k）单倍型。 这一发现将是 通过研究T细胞的Sm反应的遗传学， 这些自身免疫小鼠 Sm的T细胞识别特异性 将通过检查克隆的T细胞对Sm的反应性来确定。 此类克隆细胞也将用于确定重组人肝癌细胞的功能活性。 Sm特异性T细胞调节抗Sm产生。 长期 这项研究的目的是确定细胞机制， 疾病特异性自身抗体抗Sm的产生，从而获得 了解SLE的发病机制。

The proposed studies are directed toward defining cellular mechanisms of production of anti-Sm, an autoantibody found both in human and in murine systemic lupus erythematosus (SLE). Studies from this laboratory have indicated a key role for T cells in the regulation of anti-Sm production in MRL mice. Using an in vitro culture system to study spontaneous anti-Sm production, the nature and mechanism of action of these regulatory T cells will be established. Particular attention will be directed toward the antigen phenotype of the T cells, their requirements for accessory cells and Ia-encoded restriction elements, and their antigen specificity. The recognition by T cells of the Sm antigen will also be investigated using an antigen-specific proliferation assay developed in this laboratory. The nature of the antigenic determinants of Sm perceived by T cells will be determined, as well as the roles of macrophages, Ia antigens, and immune response genes in this response in SLE mice and in normals. Preliminary data indicate that the T-cell response to murine Sm is under MHC-linked genetic control, yet the SLE strain, MRL-Mp-+/+ is capable of recognition of Sm despite its nonresponder (H-2k) haplotype. This finding will be pursued by investigating the genetics of the Sm response of the T cells of these autoimmune mice. The fine specificity of T cell recognition of Sm will be determined by examining the reactivity of cloned T cells to Sm. Such cloned cells will also be used to determine the functional activity of Sm-specific T cells in regulation of anti-Sm production. The long-term objective of this investigation is to define the cellular mechanisms of production of the disease-specific autoantibody, anti-Sm, and thus to gain insight into the pathogenesis of SLE.