Structural features of peptide analogs of human histocompatibility leukocyte antigen class I epitopes that are more potent and immunogenic than wild-type peptide.
Structural features of peptide analogs of human histocompatibility leukocyte antigen class I epitopes that are more potent and immunogenic than wild-type peptide.
复制标题
DOI：
10.1084/jem.194.6.833
复制
发表时间：
2001-09-17
期刊：
影响因子：
--
通讯作者：
Sette A
中科院分区：
文献类型：
--
作者：
Tangri S;Ishioka GY;Huang X;Sidney J;Southwood S;Fikes J;Sette A
某些肽类似物在主要组织相容性复合体锚定点以外的残基上进行取代，并且令人惊讶地比野生型肽（异斜类似物）具有更高的抗原性。迄今为止，尚不清楚野生型表位可以多频繁地被修饰以获得异相活性。在这项研究中，我们分析了两种不同的人类组织相容性白细胞抗原 (HLA)-A2.1 限制性表位的大量类似物，发现异附着类似物与更高强度的反应和对抗原的敏感性增加（高达 107 倍）相关，并且对应于肽中部奇数位置（位置 3、5 或 7）的保守或半保守取代。这些发现通过在小鼠和人类系统中使用四个额外表位进行额外的免疫原性研究得到了验证。当 p53.261 表位的预测类似物被证明可诱导细胞毒性 T 淋巴细胞 (CTL) 识别体内低浓度肽（高亲合力）并在体外表现出抗肿瘤识别时，异斜类似物的生物学相关性就得到了强调。最后，用两种异附着类似物对人外周血单核细胞进行体外免疫，导致募集更多数量的 CTL，这与抗原敏感性增加相关。总之，在所研究的六个案例中的每一个中都鉴定了异斜类似物，并定义了允许鉴定此类类似物的结构特征。异簇表位引发的强CTL免疫表明它们在针对耐受性或弱免疫原性肿瘤相关抗原和病毒抗原的疫苗接种中具有重要价值。
Certain peptide analogs that carry substitutions at residues other than the main major histocompatibility complex anchors and are surprisingly much more antigenic than wild-type peptide (heteroclitic analogs). To date, it was unknown how frequently wild-type epitopes could be modified to obtain heteroclitic activity. In this study, we analyzed a large panel of analogs of two different human histocompatibility leukocyte antigen (HLA)-A2.1–restricted epitopes and found that heteroclitic analogs were associated with higher magnitude responses and increased (up to 107-fold) sensitivity to antigen, and corresponded to conservative or semiconservative substitutions at odd-numbered positions in the middle of the peptide (positions 3, 5, or 7). These findings were validated by performing additional immunogenicity studies in murine and human systems with four additional epitopes. The biological relevance of heteroclitic analogs was underlined when predicted analogs of the p53.261 epitope was shown to induce cytotoxic T lymphocytes (CTLs) that recognize low concentrations of peptide (high avidity) in vivo and demonstrate in vitro antitumor recognition. Finally, in vitro immunization of human peripheral blood mononuclear cells with two heteroclitic analogs resulted in recruitment of more numerous CTLs which were associated with increased antigen sensitivity. In conclusion, heteroclitic analogs were identified in each of the six cases studied and structural features were defined which allow identification of such analogs. The strong CTL immunity elicited by heteroclitic epitopes suggest that they could be of significant value in vaccination against tolerant or weakly immunogenic tumor-associated and viral antigens.
登录
查看更多内容
影响因子：
5.4
作者：
GAVIN, MA;DERE, B;BEVAN, MJ
通讯作者：
BEVAN, MJ
DOI：
10.1084/jem.184.1.121
发表时间：
1996-07-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Blake J;Johnston JV;Hellström KE;Marquardt H;Chen L
通讯作者：
Chen L
影响因子：
2.2
作者：
McKinney, DM;Skvoretz, R;Sette, A
通讯作者：
Sette, A
影响因子：
4.4
作者：
Nicholson, LB;Anderson, AC;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
15.3
作者：
Celluzzi, CM;Mayordomo, JI;Storkus, WJ;Lotze, MT;Falo, LD
通讯作者：
Falo, LD