Pearson C I, Smilek D E, Danska J S, McDevitt H O
Department of Microbiology and Immunology, Stanford University Medical Center, CA 94305, USA.
Mol Immunol. 1997 Aug;34(11):781-92. doi: 10.1016/s0161-5890(97)00058-8.
Experimental autoimmune encephalomyelitis (EAE) serves as a rodent model of the autoimmune disease multiple sclerosis. In mice, EAE is induced by immunizing with spinal cord homogenate, components of the myelin sheath, such as myelin basic protein (MBP) or proteolipid protein (PLP), or peptides derived from these components. EAE can be induced in H-2u or (H-2u x H-2s)F1 mice with the N-terminal peptide of MBP, Ac1-11. Coimmunization with Ac1-11 and Ac1-11[4A], an analog in which lysine at position four is substituted with alanine, prevents EAE. The mechanism of inhibition has not been elucidated, but probably does not work through MHC blockade, T cell anergy or clonal elimination of encephalitogenic T cells. We have isolated T cell clones and hybridomas from (PL/J x SJL/J)F1 mice immunized with either Ac1-11 alone or Ac1-11 and Ac1-11[4A] and analysed these cells for differences in their T cell receptor repertoire and in vitro response. Although T cells elicited by coinjection of Ac1-11 and Ac1-11[4A] expressed TCR that used V alpha and Vbeta gene elements similar to those elicited by Ac1-11 alone, they differed in the sequences of the junctional region of the alpha chain. Most of these T cells also responded less well to Ac1-11 in vitro, suggesting that coinjection of Ac1-11 and Ac1-11[4A] preferentially activates T cells bearing TCR of different affinity for Ac1-11 bound to I-A(u), and which may therefore be less encephalitogenic. Furthermore, our results show that a more diverse repertoire of V alpha and Vbeta genes are elicited by Ac1-11 in (PL/J x SJL/J)F1 mice compared to PL/J and B10.PL mice, providing further evidence that a restricted TCR repertoire is not required for the development of autoimmune disease.
实验性自身免疫性脑脊髓炎（EAE）是自身免疫性疾病多发性硬化的啮齿动物模型。在小鼠中，通过用脊髓匀浆、髓鞘成分（如髓鞘碱性蛋白（MBP）或蛋白脂蛋白（PLP））或这些成分衍生的肽进行免疫来诱导EAE。用MBP的N端肽Ac1-11可在H-2u或（H-2u×H-2s）F1小鼠中诱导EAE。将Ac1-11与Ac1-11[4A]（一种第4位赖氨酸被丙氨酸取代的类似物）共同免疫可预防EAE。抑制机制尚未阐明，但可能不是通过MHC阻断、T细胞无能或致脑炎性T细胞的克隆清除起作用。我们从单独用Ac1-11或Ac1-11与Ac1-11[4A]免疫的（PL/J×SJL/J）F1小鼠中分离出T细胞克隆和杂交瘤，并分析这些细胞在T细胞受体库和体外反应方面的差异。尽管同时注射Ac1-11和Ac1-11[4A]引发的T细胞表达的TCR使用的Vα和Vβ基因元件与单独用Ac1-11引发的T细胞相似，但它们在α链连接区的序列上有所不同。这些T细胞中的大多数在体外对Ac1-11的反应也较差，这表明同时注射Ac1-11和Ac1-11[4A]优先激活了对与I-A（u）结合的Ac1-11具有不同亲和力的TCR的T细胞，因此可能致脑炎性较低。此外，我们的结果表明，与PL/J和B10.PL小鼠相比，Ac1-11在（PL/J×SJL/J）F1小鼠中引发的Vα和Vβ基因库更多样化，这进一步证明自身免疫性疾病的发展不需要受限的TCR库。
