T CELL CONTROL OF AUTOREACTIVITY IN MURINE SLE

拟议的研究旨在定义细胞机制 抗Sm抗体的产生，这是一种在人和小鼠中都发现的自身抗体 系统性红斑狼疮(SLE)。这个实验室的研究已经 提示T细胞在调节抗Sm产生中起关键作用 MRL小鼠。利用体外培养系统研究自发抗Sm 这些调节性T细胞的产生、性质和作用机制 将会建立起来。将特别关注 T细胞的抗原表型及其对辅助细胞的要求 和Ia编码的限制性元件，以及它们的抗原特异性。这个 T细胞对Sm抗原的识别也将使用 本实验室建立的抗原特异性增殖试验。这个 T细胞感知的Sm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 系统性红斑狼疮小鼠和正常人这种反应中的反应基因。初步 数据表明，T细胞对小鼠Sm的反应是MHC连锁的 基因控制，然而SLE株MRL-MP-+/+能够识别 Sm的无应答(H-2k)单倍型。这一发现将是 通过研究人T细胞Sm反应的遗传学来追求 这些自身免疫的小鼠。Sm对T细胞识别的良好特异性 将通过检测克隆的T细胞对Sm的反应性来确定。 这种克隆的细胞也将被用来确定 Sm特异性T细胞在调节抗Sm产生中的作用。长期的 这项研究的目的是要明确的细胞机制 生产疾病特异性自身抗体，抗Sm，从而获得 深入了解系统性红斑狼疮的发病机制。

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.