Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccines in vivo
| العنوان: | Re-engineered CD40 receptor enables potent pharmacological activation of dendritic-cell cancer vaccines in vivo |
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| المؤلفون: | Rana A. K. Singh, M. H. Huls, David M. Spencer, Brent A. Hanks, Jianghong Jiang, Weitao Song, Kevin M. Slawin, Michael A. Barry |
| المصدر: | Nature Medicine. 11:130-137 |
| بيانات النشر: | Springer Science and Business Media LLC, 2005. |
| سنة النشر: | 2005 |
| مصطلحات موضوعية: | Male, Recombinant Fusion Proteins, Antigen presentation, Context (language use), Biology, Lymphocyte Activation, Protein Engineering, Cancer Vaccines, General Biochemistry, Genetics and Molecular Biology, Immunological synapse, Jurkat Cells, Mice, In vivo, Animals, Humans, CD40 Antigens, Receptor, Cells, Cultured, NF-kappa B, Dendritic Cells, General Medicine, Dendritic cell, Protein Structure, Tertiary, Cell biology, Mice, Inbred C57BL, Immunology, Ex vivo, CD8, Signal Transduction |
| الوصف: | 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. |
| تدمد: | 1546-170X 1078-8956 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::496b120326e8b5f90d147fe351db4fc2Test https://doi.org/10.1038/nm1183Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....496b120326e8b5f90d147fe351db4fc2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1546170X 10788956 |
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