T-CELL RECEPTOR ANTAGONIST PEPTIDES ARE HIGHLY EFFECTIVE INHIBITORS OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS
T-CELL RECEPTOR ANTAGONIST PEPTIDES ARE HIGHLY EFFECTIVE INHIBITORS OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS
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DOI：
10.1002/eji.1830240424
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发表时间：
1994-04-01
影响因子：
5.4
通讯作者：
ISHIOKA, GY
中科院分区：
文献类型：
--
作者：
FRANCO, A;SOUTHWOOD, S;ISHIOKA, GY
已经检查了使用T细胞受体（TcR）拮抗剂肽抑制自身免疫性疾病的可行性。首先，分析了I-A（S）限制性致脑炎决定簇蛋白脂质蛋白（PLP）139-151的精细抗原结构。发现残基145和148是I-A（S）锚残基，并且残基144似乎在T细胞活化中特别关键。发现残基142、143、146和147对于所研究的一些但不是全部T细胞的活化至关重要。接下来，测试良好的I-A（S）结合非抗原性类似物的TcR拮抗作用。因此，鉴定了几种可用作TcR拮抗剂的单取代类似物。此外，当将两种这样的类似物组合时，所得的TcR拮抗剂库在体外抑制大多数PLP 139-151特异性T细胞克隆。当检查该TcR拮抗剂库在体内抑制EAE诱导的功效时，发现类似物库是疾病诱导的显著有效的抑制剂。TcR拮抗剂池比我们最好的主要组织相容性复合物阻断剂的效力高约10倍，并且当以等摩尔量注射致脑炎PLP 139-151决定簇时仍然能够显著抑制。
The feasibility of using T cell receptor (TcR) antagonist peptides to inhibit autoimmune disease has been examined. First, the fine antigenic structure of the I-A(S)-restricted encephalitogenic determinant proteolipid protein (PLP) 139-151 has been analyzed. It was found that residues 145 and 148 were I-A(S) anchor residues, and residue 144 appeared to be especially critical in T cell activation. Residues 142, 143, 146, and 147 were found to be crucial for activation of some, but not all, of the T cells studied. Next, good I-A(S)-binding nonantigenic analogs were tested for TcR antagonism. Accordingly, several single substitution analogs were identified which could act as TcR antagonists. Moreover, when two such analogs were combined, the resulting TcR antagonist pool inhibited most of the PLP 139-151-specific T cell clones in vitro. When the efficacy of this TcR antagonist pool in inhibiting EAE induction in vivo was examined, it was found that the analog pool was a remarkably potent inhibitor of disease induction. The TcR antagonist pool was approximately 10-fold more potent than our best major histocompatibility complex blocker and was still capable of significant inhibition when injected in equimolar amounts with the encephalitogenic PLP 139-151 determinant.