Development of TCR-CDR3 vaccine for multiple sclerosis

自身免疫性脑源性T细胞倾向于在T细胞受体α链和β链的CDR3区域表达有限的序列基序(Int.免疫系统。6：947,1994)。我们最近报道了一个脑源性克隆4b的α链CDR3的多肽序列。14A会增加实验性自身免疫性疾病的严重性，包括实验性自身免疫性脑脊髓炎(EAE)、佐剂性关节炎或自身免疫性糖尿病，而不考虑抗原/MHC的特异性(J.Neurosci)。结果45：706-713,1996)。在这里，我们澄清，观察到的自身免疫性脑脊髓炎的增强可能是由对CDR3肽起反应的调节性T细胞克隆介导的。我们通过制备对该多肽有反应性的T细胞杂交瘤，并对CDR3反应性T细胞进行过继转移实验，得出了这一结论。特别值得注意的是，T细胞克隆型的单链构象多态(SSCP)分析表明，CDR3反应性克隆在幼年SJL/J小鼠体内扩增并存在于CD25^+T细胞中。这意味着与TCR CDR3多肽反应的单个T细胞克隆处于持续激活和扩张状态。因此，自发性T细胞和调节性T细胞之间的抗原是非特异性的。这一结果可能会导致开发一种新的TCR疫苗。事实上，CDR3多肽形式的改变可能会导致调节性克隆的失活，导致EAE的下调。这样的疫苗应该具有实用价值，因为它可以有效地治疗不同的疾病，即使在发生表位扩散后也能成功治疗疾病。我们现在的重点是为CDR3反应性调节性T细胞寻找合适的配体。

Autoimmune encephalitogenic T cells tend to express limited sequence motifs in the CDR3 regions of T cell receptor alpha - and beta -chains (Int. Immunol. 6 : 947, 1994). We have recently reported that a peptide sequence from alpha -chain CDR3 of an encephalitogenic clone 4b. 14a would enhance the severity of experi-mental autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), adjuvant arthritis or autoimmune diabetes, regardless of the antigen/MHC specificities (J.Neurosci. Res. 45 : 706-713, 1996). Here we clarify that the observed augmentation of autoimmune encephalomyelitis is probably mediated by a regulatory T cell clone reactive to the CDR3 peptide. We reached the conclusion by generat-ing T cell hybridomas reactive to the peptide and performing adoptive transfer experiments with CDR3 reactive T cells. Of particular note, the single strand conformation polymorphism (SSCP) analysis for T cell clonorype revealed that CDR3 reactive clone is in vivo expanded and present among the CD25^+T cells in naive SJL/J mice. This implies that a single T cell clone reactive to a TCR CDR3 peptide is in a state of persistent activation and expansion. Thus antigen nonspecific between autopathogenic T cells and the regulatory T cells. The result could lead to the development of a new TCR vaccine. In fact, and altered form of the CDR3 peptide may induce inactivation of the regulatory clone, leading to the down-regulation of EAE.Such a vaccine should be of practical value, since it could be effective for different diseases and manage to treat disease even after occurrence of epitope-spreading. We are now focusing on the identifica-tion of an appropriate ligand for the CDR3 reactive regulatory T cells.