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【Nature Medicine——编译】CD40受体激活树突细胞肿
Published online: 23 January 2005; | doi:10.1038/nm1183
Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccines in vivo
Modest clinical outcomes of dendritic-cell (DC) vaccine trials call for the refinement of DC vaccine design. Although many potential antigens have been identified, development of methods to enhance antigen presentation by DCs has lagged. We have engineered a potent, drug-inducible CD40 (iCD40) receptor that permits temporally controlled, lymphoid-localized, DC-specific activation. iCD40 is comprised of a membrane-localized cytoplasmic domain of CD40 fused to drug-binding domains. This allows it to respond to a lipid-permeable, high-affinity dimerizer drug while circumventing ectodomain-dependent negative-feedback mechanisms. These modifications permit prolonged activation of iCD40-expressing DCs in vivo, resulting in more potent CD8+ T-cell effector responses, including the eradication of previously established solid tumors, relative to activation of DCs ex vivo (P < 0.01), typical of most clinical DC protocols. In addition, iCD40-mediated DC activation exceeded that achieved by stimulating the full-length, endogenous CD40 receptor both in vitro and in vivo. Because iCD40 is insulated from the extracellular environment and can be activated within the context of an immunological synapse, iCD40-expressing DCs have a prolonged lifespan and should lead to more potent vaccines, perhaps even in immune-compromised patients.
树突细胞疫苗实验的适度的临床结果冀希望于精巧的树突细胞疫苗的设计。尽管许多潜在的抗原已经被确定，然而通过树突细胞提高抗原表达的方法的发展仍然止步不前。我们设计了一种有效的、药物可诱导的CD40（iCD40）受体，这种受体允许时序控制的、淋巴样局限的、树突细胞特殊的激活作用。iCD40包含CD40融合到药物结合区域的膜局限的胞浆区。这种结构允许了它对于脂质可渗透的、高亲和力的dimerizer药物的应答，当环绕外区功能依赖的阴性反馈机制时。这种修饰允许了在体内表达iCD40的树突细胞的延长激活，导致了更加有效的CD8+ T细胞效应子的反应，包括以前建立的实体瘤的根除，与体外树突细胞的激活相比，典型的临床树突细胞的记录。另外，iCD40介导的树突细胞的激活超过了通过刺激全长的、内源性的CD40受体而完成的，无论是在体内还是在体外。因为iCD40与细胞外的环境是绝缘的，并且能够在免疫突触内被活化，iCD40表达的树突细胞具有较长的寿命，能够导致更加有效的疫苗，或许在缺乏免疫抵抗力的病人中。 全文下载:
http://www.dxy.cn/bbs/user/download/2783955/1.pdf [标签:content1][标签:content2]
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作者:admin@医学,生命科学 2011-05-08 17:14
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