Identification of HLA-DRB1*1501-Restricted T-cell epitopes from prostate-specific antigen
Identification of HLA-DRB1*1501-Restricted T-cell epitopes from prostate-specific antigen
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DOI：
10.1158/1078-0432.ccr-04-1927
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发表时间：
2005-04-15
影响因子：
11.5
通讯作者：
Alexander, RB
中科院分区：
文献类型：
--
作者：
Klyushnenkova, EN;Link, J;Alexander, RB
基于对前列腺组织的自身免疫诱导的前列腺癌免疫疗法的发展是非常有吸引力的，因为前列腺在生殖年龄之后不是重要器官。CD 4 T细胞在抗肿瘤免疫应答的发展中起重要作用，但尚未描述来源于前列腺分化抗原的天然加工的MHC II类限制性表位的鉴定。为了促进前列腺特异性抗原（PSA）衍生的VIHC II类限制性肽的搜索，我们用人PSA免疫HLA-DRB 1 * 1501转基因小鼠，并显示出对抗原的稳健的剂量依赖性免疫应答。筛选跨越整个PSA序列的重叠20-mer肽的文库，鉴定了两种20-mer肽，PSA（171-190）和PSA（221-240），其负责该反应性。用这些肽免疫DR 2b转基因小鼠诱导对肽和整个PSA的特异性应答。鉴定的肽用于刺激HLA-DRB 1 *1501+患者的CD 4 T细胞，这些患者患有罕见疾病肉芽肿性前列腺炎，并且似乎具有针对前列腺的预先存在的免疫应答。我们先前发现肉芽肿性前列腺炎与HLA-DRB 1 *1501相关，提示该病可能有自身免疫性病因。从这些患者以及一名前列腺癌患者的外周血中产生肽特异性CD 4 T细胞系。这些细胞系还识别HLA-DRB 1 *1501背景下的完整加工PSA。本研究将有助于了解循环自身反应性T细胞，器官特异性自身免疫和抗肿瘤免疫反应之间的相互作用。这些肽用于前列腺癌的免疫治疗的用途正在研究中。
The development of immunotherapy for prostate cancer based on the induction of autoimmunity to prostate tissue is very attractive because prostate is not a vital organ beyond the reproductive years. CD4 Tcells play an important role in the development of antitumor immune responses, yet the identification of naturally processed MHC Class II - restricted epitopes derived from prostate differentiation antigens has not been described. To facilitate the search for prostate-specific antigen (PSA) -derived VIHC class II -restricted peptides, we immunized mice transgenic for HLA-DRB1* 1501 with human PSA and showed a robust dose-dependent immune response to the antigen. Screening a library of overlapping 20-mer peptides that span the entire PSA sequence identified two 20-mer peptides, PSA(171-190) and PSA(221-240), which were responsible for this reactivity. Immunization of DR2b transgenic mice with these peptides induced specific responses to the peptide and whole PSA. Identified peptides were used to stimulate CD4 T cells from HLA-DRB1*1501+ patients with a rare condition, granulomatous prostatitis, and who seem to have a preexisting immune response directed against the prostate gland. We previously showed a linkage of granulomatous prostatitis to HLA-DRB1*1501, suggesting that this disease may have an autoimmune etiology. Peptide-specific CD4 T-cell lines were generated from the peripheral blood of these patients as well as one patient with prostate cancer, These lines also recognized whole, processed PSA in the context of HLA-DRB1*1501. This study will be instrumental in understanding the interaction between circulating self-reactiveT cells, organ-specific autoimmunity, and antitumor immune response. The use of these peptides for the immunotherapy of prostate cancer is under investigation.