Harig S, Witzens M, Krackhardt A M, Trojan A, Barrett P, Broderick R, Zauls A J, Gribben J G
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Blood. 2001 Nov 15;98(10):2999-3005. doi: 10.1182/blood.v98.10.2999.
Cytotoxic T-lymphocyte (CTL) responses can be generated against peptides derived from the immunoglobulin (Ig) V region in some but not all patients. The main reason for this appears to be the low peptide-binding affinity of Ig-derived peptides to major histocompatibility complex (MHC) class I molecules and their resulting low immunogenicity. This might be improved by conservative amino acid modifications at the MHC-binding residues of the peptides (heteroclitic peptides). In this study, it was found that in 18 Ig-derived peptides, that heteroclitic peptides from the Ig gene with improved binding to human leukocyte antigen (HLA)-A0201 can be used to improve CTL responses. Amino acid substitution substantially increased predicted binding affinity, and there was a strong correlation between predicted and actual binding to HLA-A0201. CTLs generated against the heteroclitic peptide had not only enhanced cytotoxicity against the heteroclitic peptide but also increased killing of antigen-presenting cells pulsed with the native peptide. Surprisingly, no difference was observed in the frequency of T cells detected by MHC class I peptide tetramers after stimulation with the heteroclitic peptide compared with the native peptide. CTLs generated against heteroclitic peptides could kill patients' tumor cells, showing that Ig-derived peptides can be presented by the tumor cell and that the failure to mount an immune response (among other reasons) likely results from the low immunogenicity of the native Ig-derived peptide. These results suggest that heteroclitic Ig-derived peptides can enhance immunogenicity, thereby eliciting immune responses, and that they might be useful tools for enhancing immunotherapy approaches to treating B-cell malignant diseases.
在部分但并非所有患者中，可产生针对源自免疫球蛋白（Ig）V区的肽段的细胞毒性T淋巴细胞（CTL）应答。出现这种情况的主要原因似乎是Ig衍生肽与主要组织相容性复合体（MHC）I类分子的肽结合亲和力较低，导致其免疫原性较低。通过对肽段的MHC结合残基进行保守氨基酸修饰（异种肽），这一情况可能会得到改善。在本研究中，发现18种Ig衍生肽中，来自Ig基因的与人类白细胞抗原（HLA）-A0201结合能力增强的异种肽可用于改善CTL应答。氨基酸替换显著提高了预测的结合亲和力，并且预测与实际结合HLA-A0201之间存在很强的相关性。针对异种肽产生的CTL不仅增强了对异种肽的细胞毒性，还增加了对用天然肽脉冲处理的抗原呈递细胞的杀伤作用。令人惊讶的是，与天然肽相比，用异种肽刺激后，通过MHC I类肽四聚体检测到的T细胞频率没有差异。针对异种肽产生的CTL可以杀死患者的肿瘤细胞，表明Ig衍生肽可以由肿瘤细胞呈递，并且未能引发免疫应答（以及其他原因）可能是由于天然Ig衍生肽的免疫原性较低。这些结果表明，异种Ig衍生肽可以增强免疫原性，从而引发免疫应答，并且它们可能是增强治疗B细胞恶性疾病免疫治疗方法的有用工具。
