Incorporation of NKT cell-activating glycolipids enhances immunogenicity and vaccine efficacy of Mycobacterium bovis bacillus Calmette-Guerin.
Incorporation of NKT cell-activating glycolipids enhances immunogenicity and vaccine efficacy of Mycobacterium bovis bacillus Calmette-Guerin.
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DOI：
10.4049/jimmunol.0900858
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发表时间：
2009-08-01
期刊：
影响因子：
--
通讯作者：
Porcelli SA
中科院分区：
文献类型：
--
作者：
Venkataswamy MM;Baena A;Goldberg MF;Bricard G;Im JS;Chan J;Reddington F;Besra GS;Jacobs WR Jr;Porcelli SA
被称为卡介苗（BCG）的牛分枝杆菌减毒株已被广泛用作预防结核分枝杆菌疾病的疫苗，但成功的证据相对较少。最近的研究表明，BCG的失败可能是由于其保留了免疫逃避机制，延迟或阻止了强大的保护性细胞介导的免疫的启动。在这里，我们描述了一种方法，以提高卡介苗的免疫原性，通过纳入糖脂活化剂的CD 1d限制性自然杀伤T细胞（NKT细胞），一个保守的T细胞亚群，有可能增加许多类型的免疫反应。开发了一种将两种形式的NKT细胞激活剂α-半乳糖神经酰胺（αGalCer）稳定掺入活BCG生物体的方法，并评价了其对刺激T细胞应答和保护性抗分枝杆菌免疫的影响。我们发现，含有相对少量掺入的αGalCer的活BCG保留了强烈激活NKT细胞的能力。与未经修饰的BCG免疫相比，糖脂修饰的BCG刺激树突状细胞的成熟增加，并显着增强抗原特异性CD 8 + T细胞应答的启动。这些效应与用强毒M.结核这些结果支持分枝杆菌具有避免刺激CD 8 + T细胞应答的机制，并且这种应答显著有助于针对这些病原体的保护性免疫的观点。我们的发现提高了对BCG进行简单修饰的可能性，这种修饰可以产生更有效的结核病控制疫苗。
The attenuated strain of Mycobacterium bovis known as bacille Calmette-Guérin (BCG) has been widely used as a vaccine for prevention of disease by Mycobacterium tuberculosis, but with relatively little evidence of success. Recent studies suggest that the failure of BCG may be due to its retention of immune evasion mechanisms that delay or prevent the priming of robust protective cell-mediated immunity. Here we describe an approach to enhance the immunogenicity of BCG by incorporating glycolipid activators of CD1d–restricted Natural Killer T cells (NKT cells), a conserved T cell subset with the potential to augment many types of immune responses. A method was developed for stably incorporating two forms of the NKT cell activator α-galactosylceramide (αGalCer) into live BCG organisms, and the impact of this on stimulation of T cell responses and protective anti-mycobacterial immunity was evaluated. We found that live BCG containing relatively small amounts of incorporated αGalCer retained the ability to robustly activate NKT cells. Compared to immunization with unmodified BCG, the glycolipid-modified BCG stimulated increased maturation of dendritic cells and markedly augmented the priming of antigen-specific CD8+ T cells responses. These effects were correlated with improved protective effects of vaccination in mice challenged with virulent M. tuberculosis. These results support the view that mycobacteria possess mechanisms to avoid stimulation of CD8+ T cell responses, and that such responses contribute significantly to protective immunity against these pathogens. Our findings raise the possibility of a simple modification of BCG that could yield a more effective vaccine for control of tuberculosis.
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影响因子：
5.4
作者：
Dondji, Blaise;Deak, Eszter;McMahon-Pratt, Diane
通讯作者：
McMahon-Pratt, Diane
影响因子：
4.4
作者：
Forestier, Claire;Takaki, Toshiyuki;Porcelli, Steven A.
通讯作者：
Porcelli, Steven A.
影响因子：
120.7
作者：
Dye, C;Scheele, S;Raviglione, RC
通讯作者：
Raviglione, RC
影响因子：
15.9
作者：
Hinchey, Joseph;Lee, Sunhee;Porcelli, Steven A.
通讯作者：
Porcelli, Steven A.
DOI：
10.1084/jem.186.1.109
发表时间：
1997-07-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Exley M;Garcia J;Balk SP;Porcelli S
通讯作者：
Porcelli S