Human dendritic cells transfected with RNA encoding prostate-specific antigen stimulate prostate-specific CTL responses in vitro
Human dendritic cells transfected with RNA encoding prostate-specific antigen stimulate prostate-specific CTL responses in vitro
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DOI：
10.4049/jimmunol.164.10.5508
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发表时间：
2000-05-15
影响因子：
4.4
通讯作者：
Vieweg, J
中科院分区：
文献类型：
--
作者：
Heiser, A;Dahm, P;Vieweg, J
尽管对自身Ags的免疫耐受是防止正常组织损伤的重要机制，但越来越多的证据表明，对肿瘤Ags（通常代表正常外周表达蛋白）的耐受不是绝对的，可以有效地逆转。前列腺特异性抗原（PSA）是一种由正常和恶性前列腺上皮表达的自身抗原，因此提供了一个独特的机会来检查自身抗原作为特异性CTL靶点的能力。在这项研究中，我们研究了转染了编码PSA的mRNA的自体树突状细胞（DC）在体外刺激CTL对抗PSA Ags的效果，RNA形式的Ag具有编码许多HLA等位基因的多个表位的优势，从而允许在许多癌症患者中诱导CTL反应，而不依赖于他们的HLA库。在这项研究中，我们发现转染PSA mrna的DC能够在体外刺激针对PSA Ags的初级CTL反应。PSA特异性CTL不与与PSA具有显著同源性的蛋白钾化管Ags发生交叉反应，表明有害的自身免疫毒性可能不是这种方法的重大问题，从男性或女性健康志愿者或癌症患者中产生的PSA rna转染DC在体外刺激PSA特异性CTL方面同样有效。这意味着，无论是对PSA抗原的天然耐受性，还是肿瘤介导的T细胞能量，都可能是CTL生成对抗自身Ag PSA的主要障碍。这项研究为在主动或过继免疫方案中使用PSA rna转染的DC提供了临床前理论依据。
Although immunological tolerance to self Ags represents an important mechanism to prevent normal tissue injury, there is growing evidence that tolerance to tumor Ags, which often represent normal peripherally expressed proteins, is not absolute and can be effectively reverted. Prostate-specific Ag (PSA) is a self Ag expressed by both normal and malignant prostatic epithelium, and therefore offers a unique opportunity to examine the ability of self Ags to serve as specific CTL targets. In this study, we investigated the efficacy of autologous dendritic cells (DC) transfected with mRNA encoding PSA to stimulate CTL against PSA Ags in vitro, Ag in form of RNA carries the advantage to encode multiple epitopes for many HLA alleles, thus permitting induction of CTL responses among many cancer patients independent of their HLA repertoire. In this study, we show that PSA mRNA-transfected DC were capable of stimulating primary CTL responses against PSA Ags in vitro. The PSA-specific CTL did not cross-react with kallikrein Ags, a protein, which shares significant homology with PSA, suggesting that harmful autoimmune toxicity may not represent a significant problem with this approach, PSA RNA-transfected DC generated from male or female healthy volunteers or from cancer patients were equally effective in stimulating PSA-specific CTL in vitro, implying that neither natural tolerance to PSA Ags nor tumor-mediated T cell anergy may represent major barriers for CTL generation against the self Ag PSA, This study provides a preclinical rationale for using PSA RNA-transfected DC in active or adoptive immunization protocols.