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Limited Transplantation of Antigen-Expressing Hematopoietic Stem Cells Induces Long-Lasting Cytotoxic T Cell Responses

机译：表达抗原的造血干细胞的有限移植诱导持久的细胞毒性T细胞反应。

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Harnessing the ability of cytotoxic T lymphocytes (CTLs) to recognize and eradicate tumor or pathogen-infected cells is a critical goal of modern immune-based therapies. Although multiple immunization strategies efficiently induce high levels of antigen-specific CTLs, the initial increase is typically followed by a rapid contraction phase resulting in a sharp decline in the frequency of functional CTLs. We describe a novel approach to immunotherapy based on a transplantation of low numbers of antigen-expressing hematopoietic stem cells (HSCs) following nonmyeloablative or partially myeloablative conditioning. Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model. Recipient animals display high levels of antigen-specific CTLs four months following transplantation in contrast to dendritic cell-immunized animals in which the response typically declines at 4–6 weeks post-immunization. Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting. Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo. In conclusion, the data presented here supports potential application of immunization by limited transplantation of antigen-expressing HSCs for the prevention and treatment of cancer and therapeutic immunization of chronic infectious diseases such as HIV-1/AIDS.
机译：利用细胞毒性T淋巴细胞（CTL）识别和根除肿瘤或病原体感染的细胞的能力是现代基于免疫疗法的关键目标。尽管多种免疫策略有效地诱导了高水平的抗原特异性CTL，但通常在初始增加之后是快速收缩期，导致功能性CTL频率急剧下降。我们描述了一种基于非清髓性或部分清髓性调理条件的少量表达抗原的造血干细胞（HSC）移植的免疫疗法新方法。有限数量的分化的转基因造血细胞对抗原的连续呈递导致在小鼠模型中诱导并长期维持全功能效应T细胞应答。与树突状细胞免疫的动物相比，接受移植的动物在移植后四个月显示出高水平的抗原特异性CTL，而树突状细胞免疫的动物通常在免疫后4-6周反应下降。大多数HSC诱导的抗原特异性CD8 + T细胞表现出中央记忆表型，在体内有效杀死靶细胞，并在预防性环境中保护受体抵抗肿瘤的生长。此外，我们确认先前发表的观察结果，在清髓性调理后高水平表达抗原的HSC植入会导致体内的耐受性和特异性细胞毒活性的缺乏。总之，此处提供的数据支持通过有限度移植表达抗原的HSC来预防和治疗癌症以及治疗慢性感染性疾病（如HIV-1 / AIDS）的免疫接种方法的潜在应用。

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