Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation
Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation
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DOI：
10.1182/blood-2005-08-3503
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发表时间：
2006-03-15
期刊：
影响因子：
20.3
通讯作者：
Riddell, SR
中科院分区：
文献类型：
--
作者：
Berger, C;Flowers, ME;Riddell, SR
引入一种诱导自杀基因，如单纯疱疹病毒胸苷激酶（HSV-TK），可能允许在同种异体造血细胞移植（HCT）后利用供体T细胞的抗肿瘤活性，而不会出现移植物抗宿主病。然而，单纯疱疹病毒- tk是外来的，对基因修饰T细胞的免疫反应可能导致它们过早被消除。我们发现，HCT受体输注HSV-TK修饰的供体T细胞后，快速诱导CID8（+）和CD4(+) T细胞对HSV-TK的反应，并与转移细胞的消失相吻合。使用重叠的HSV-TK肽板的细胞因子流式细胞术可以快速检测和定量血液中HSV-TK特异性T细胞，并鉴定出多个免疫原性表位。反复输注修饰的T细胞增强了诱导的hsv - tk特异性T细胞，这些T细胞作为记忆细胞持续存在。这些研究证明了非免疫原性自杀基因的必要性，并确定了一种检测CD4（+）和CD8(+) t细胞对转基因产品反应的策略，这种策略应该普遍适用于监测基因治疗试验中的患者。基因修饰的T细胞能引发强大而持久的免疫反应，这意味着这种方法可能用于疫苗接种，以引发T细胞对病毒或肿瘤抗原的反应。
The introduction of an inducible suicide gene such as the herpes simplex virus thymidine kinase (HSV-TK) might allow exploitation of the antitumor activity of donor T cells after allogeneic hematopoietic cell transplantation (HCT) without graft versus host disease. However, HSV-TK is foreign, and immune responses to gene-modified T cells could lead to their premature elimination. We show that after the infusion of HSV-TK-modified donor T cells to HCT recipients, CID8(+) and CD4(+) T-cell responses to HSV-TK are rapidly induced and coincide with the disappearance of transferred cells. Cytokine flow cytometry using an overlapping panel of HSV-TK peptides allowed rapid detection and cluantitation of HSV-TK-specific T cells in the blood and identified multiple immunogenic epitopes. Repeated infusion of modified T cells boosted the induced HSV-TK-specific T cells, which persisted as memory cells. These studies demonstrate the need for nonimmunogenic suicide genes and identify a strategy for detection of CD4(+) and CD8(+) T-cell responses to transgene products that should be generally applicable to monitoring patients on gene therapy trials. The potency of gene-modified T cells to elicit robust and durable immune responses imply this approach might be used for vaccination to elicit T-cell responses to viral or tumor antigens.