Protection and polyfunctional T cells induced by Ag85B-TB10.4/IC31 against Mycobacterium tuberculosis is highly dependent on the antigen dose.
Protection and polyfunctional T cells induced by Ag85B-TB10.4/IC31 against Mycobacterium tuberculosis is highly dependent on the antigen dose.
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DOI：
10.1371/journal.pone.0005930
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发表时间：
2009-06-16
期刊：
影响因子：
3.7
通讯作者：
Dietrich J
中科院分区：
文献类型：
--
作者：
Aagaard C;Hoang TT;Izzo A;Billeskov R;Troudt J;Arnett K;Keyser A;Elvang T;Andersen P;Dietrich J
此前，我们已经证明，Ag85B-TB10.4是一种高效的结核病疫苗，当以阳离子脂质体为基础的Th1诱导佐剂递送时。另一种诱导Th1的佐剂是IC31®，它在临床前和临床试验中都显示出非常有希望的特性。在这项研究中，我们研究了佐剂IC31®中提供的Ag85B-TB10.4诱导抗结核分枝杆菌感染的能力的潜力。此外，我们还检测了抗原剂量是否会影响诱导的T细胞的表型。我们发现，Ag85B-Tb10.4和IC31®联合免疫可产生大量共表达IL-2、干扰素-γ和肿瘤坏死因子-α的多功能CD4T细胞。在小鼠结核病模型中，这与对结核分枝杆菌后续攻击的保护有关。重要的是，我们的结果还表明，疫苗诱导的T细胞反应和保护效果都高度依赖于抗原剂量。因此，尽管5微克和15微克的抗原剂量对结核分枝杆菌没有显著的保护作用，但将其剂量降低到0.5微克则选择性地增加了多功能T细胞的数量，并诱导了对结核分枝杆菌感染的强大保护。在豚鼠结核分枝杆菌气雾剂感染模型上也观察了抗原剂量的影响。在这个模型中，抗原剂量增加2.5倍，就会将对结核分枝杆菌感染的保护力降低到未接种疫苗的动物中观察到的水平。抗原剂量的微小变化会极大地影响特定T细胞亚群的诱导，因此在测试新疫苗时，剂量是一个关键因素。然而，佐剂IC31®在最佳剂量的Ag85B-TB10.4的作用下，对结核分枝杆菌有很强的保护作用。这种疫苗现已进入临床试验。
Previously we have shown that Ag85B-TB10.4 is a highly efficient vaccine against tuberculosis when delivered in a Th1 inducing adjuvant based on cationic liposomes. Another Th1 inducing adjuvant, which has shown a very promising profile in both preclinical and clinical trials, is IC31®. In this study, we examined the potential of Ag85B-TB10.4 delivered in the adjuvant IC31® for the ability to induce protection against infection with Mycobacterium tuberculosis. In addition, we examined if the antigen dose could influence the phenotype of the induced T cells. We found that vaccination with the combination of Ag85B-TB10.4 and IC31® resulted in high numbers of polyfunctional CD4 T cells co-expressing IL-2, IFN-γ and TNF-α. This correlated with protection against subsequent challenge with M.tb in the mouse TB model. Importantly, our results also showed that both the vaccine induced T cell response, and the protective efficacy, was highly dependent on the antigen dose. Thus, whereas antigen doses of 5 and 15 µg did not induce significant protection against M.tb, reducing the dose to 0.5 µg selectively increased the number of polyfunctional T cells and induced a strong protection against infection with M.tb. The influence of antigen dose was also observed in the guinea pig model of aerosol infection with M.tb. In this model a 2.5 fold increase in the antigen dose reduced the protection against infection with M.tb to the level observed in non-vaccinated animals. Small changes in the antigen dose can greatly influence the induction of specific T cell subpopulations and the dose is therefore a crucial factor when testing new vaccines. However, the adjuvant IC31® can, with the optimal dose of Ag85B-TB10.4, induce strong protection against Mycobacterium tuberculosis. This vaccine has now entered clinical trials.
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影响因子：
3.1
作者：
Brandt, L;Cunha, JF;Andersen, P
通讯作者：
Andersen, P
影响因子：
4.4
作者：
Dietrich, Jes;Andersen, Claire;Andersen, Peter
通讯作者：
Andersen, Peter
影响因子：
9.4
作者：
Brock, I;Weldingh, K;Andersen, P
通讯作者：
Andersen, P
影响因子：
3.4
作者：
Christensen, Dennis;Foged, Camilla;Agger, Else Marie
通讯作者：
Agger, Else Marie
DOI：
10.1164/ajrccm.163.4.2009100
发表时间：
2001-03-01
影响因子：
24.7
作者：
Lalvani, A;Pathan, AA;Hill, AVS
通讯作者：
Hill, AVS