Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy.
Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy.
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DOI：
10.1038/ncomms5741
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发表时间：
2014-09-03
影响因子：
16.6
通讯作者：
Wraith, David C.
中科院分区：
文献类型：
--
作者：
Burton, Bronwen R.;Britton, Graham J.;Fang, Hai;Verhagen, Johan;Smithers, Ben;Sabatos-Peyton, Catherine A.;Carney, Laura J.;Gough, Julian;Strobel, Stephan;Wraith, David C.
抗原特异性免疫疗法通过恢复对目标抗原的免疫耐受而不损害免疫功能来对抗自身免疫或过敏。优化给药策略是有效调节致病性CD4+ t细胞活性的关键。在这里，我们报告剂量递增是必要的，安全，皮下递送高剂量的自身抗原需要有效的耐受性诱导和诱导无能，白细胞介素(IL)-10分泌调节性CD4+ T细胞。在不断增加剂量的免疫治疗的连续阶段，对CD4+ t细胞转录组的分析揭示了对转录本的逐渐抑制，这些转录本正调节炎症效应功能和抑制细胞周期途径。我们确定了转录因子c-Maf和NFIL3，以及负共刺激分子LAG-3、TIGIT、PD-1和TIM-3，它们表征了这种调节性CD4+ t细胞群，其表达与免疫调节性细胞因子IL-10相关。这些结果为t细胞定向免疫治疗的剂量递增提供了理论依据，并揭示了新的免疫和转录特征作为成功免疫治疗的替代标记。抗原特异性治疗的剂量递增被认为是安全有效的，但剂量变量对免疫系统的潜在影响尚不清楚。在这里，作者证明剂量增加导致抗原特异性淋巴细胞基因表达的顺序调节。
Antigen-specific immunotherapy combats autoimmunity or allergy by reinstating immunological tolerance to target antigens without compromising immune function. Optimization of dosing strategy is critical for effective modulation of pathogenic CD4+ T-cell activity. Here we report that dose escalation is imperative for safe, subcutaneous delivery of the high self-antigen doses required for effective tolerance induction and elicits anergic, interleukin (IL)-10-secreting regulatory CD4+ T cells. Analysis of the CD4+ T-cell transcriptome, at consecutive stages of escalating dose immunotherapy, reveals progressive suppression of transcripts positively regulating inflammatory effector function and repression of cell cycle pathways. We identify transcription factors, c-Maf and NFIL3, and negative co-stimulatory molecules, LAG-3, TIGIT, PD-1 and TIM-3, which characterize this regulatory CD4+ T-cell population and whose expression correlates with the immunoregulatory cytokine IL-10. These results provide a rationale for dose escalation in T-cell-directed immunotherapy and reveal novel immunological and transcriptional signatures as surrogate markers of successful immunotherapy. Dose escalation in antigen-specific therapies is recognized as safe and effective, but the underlying effects of dosing variables on the immune system are not understood. Here, the authors demonstrate that dose escalation causes sequential modulation of gene expression among antigen-specific lymphocytes.
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影响因子：
14.2
作者：
Burks, A. Wesley;Calderon, Moises A.;Akdis, Cezmi A.
通讯作者：
Akdis, Cezmi A.
影响因子：
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作者：
Kamanaka, Masahito;Kim, Sean T.;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
影响因子：
82.9
作者：
Gagliani, Nicola;Magnani, Chiara F.;Roncarolo, Maria-Grazia
通讯作者：
Roncarolo, Maria-Grazia
影响因子：
5.4
作者：
Anderson, Per O;Manzo, Barbara A;Sundstedt, Anette;Minaee, Sophie;Symonds, Alistair;Khalid, Sabah;Rodriguez-Cabezas, Maria E;Nicolson, Kirsty;Li, Suling;Wraith, David C;Wang, Ping
通讯作者：
Wang, Ping
DOI：
10.1056/nejmoa1200435
发表时间：
2012-07-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Burks AW;Jones SM;Wood RA;Fleischer DM;Sicherer SH;Lindblad RW;Stablein D;Henning AK;Vickery BP;Liu AH;Scurlock AM;Shreffler WG;Plaut M;Sampson HA;Consortium of Food Allergy Research (CoFAR)
通讯作者：
Consortium of Food Allergy Research (CoFAR)