Selection of a novel anti-nicotine vaccine: influence of antigen design on antibody function in mice.
Selection of a novel anti-nicotine vaccine: influence of antigen design on antibody function in mice.
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DOI：
10.1371/journal.pone.0076557
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
McCluskie MJ
中科院分区：
文献类型：
--
作者：
Pryde DC;Jones LH;Gervais DP;Stead DR;Blakemore DC;Selby MD;Brown AD;Coe JW;Badland M;Beal DM;Glen R;Wharton Y;Miller GJ;White P;Zhang N;Benoit M;Robertson K;Merson JR;Davis HL;McCluskie MJ
抗尼古丁疫苗可能通过诱导抗尼古丁抗体(Ab)来帮助戒烟，从而减少尼古丁进入大脑，从而产生相关的奖励。AB函数取决于抗体的数量(效价)和质量(亲和力)。以往临床试验中检测的抗尼古丁疫苗，尽管抗体效价高，但效果不佳，如果诱导出低亲和力的抗体，可能是由于功能不充分所致。在本研究中，我们设计并合成了一系列新的尼古丁样半抗原，它们都以白喉类毒素(DT)为载体，但在连接物与尼古丁的结合部位、连接物的性质以及用于连接半抗原的手柄上有所不同。以CpG(TLR9激动剂)和氢氧化铝(Al(OH)3)为佐剂，在小鼠模型中对所得到的半抗原结合物进行评估，从而使用放射性标记尼古丁攻击模型来评估抗体效价、亲和力和功能。一系列在长度、刚性和极性上不同的附加连接体与单个半抗原一起使用来产生附加的DT-连接物，这也在小鼠身上进行了测试。用不同的半抗原制备的结合物可产生不同效价的抗尼古丁抗体。有几个半抗原的抗体效价也很高，但其中的抗体亲和力和功能差异很大。接头对抗体效价、亲和力和功能也有影响。这些结果表明，尼古丁结合抗原在小鼠体内诱导的免疫应答很大程度上受半抗原设计的影响，包括连接到尼古丁上的连接物的位置、所使用的连接物的性质以及用于将半抗原连接到DT上的手柄。抗体效价和亲和力对抗体功能均有影响，但亲和力对抗原差异更为敏感。
Anti-nicotine vaccines may aid smoking cessation via the induction of anti-nicotine antibodies (Ab) which reduce nicotine entering the brain, and hence the associated reward. Ab function depends on both the quantity (titer) and the quality (affinity) of the Ab. Anti-nicotine vaccines tested previously in clinical studies had poor efficacy despite high Ab titer, and this may be due to inadequate function if Ab of low affinity were induced. In this study, we designed and synthesized a series of novel nicotine-like haptens which were all linked to diphtheria toxoid (DT) as carrier, but which differed in the site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. The resulting hapten conjugates were evaluated in a mouse model, using CpG (a TLR9 agonist) and aluminum hydroxide (Al(OH)3) as adjuvants, whereby Ab titers, affinity and function were evaluated using a radiolabeled nicotine challenge model. A series of additional linkers varying in length, rigidity and polarity were used with a single hapten to generate additional DT-conjugates, which were also tested in mice. Conjugates made with different haptens resulted in various titers of anti-nicotine Ab. Several haptens gave similarly high Ab titers, but among these, Ab affinity and hence function varied considerably. Linker also influenced Ab titer, affinity and function. These results demonstrate that immune responses induced in mice by nicotine-conjugate antigens are greatly influenced by hapten design including site of attachment of linker to nicotine, the nature of linker used, and the handle used to attach the hapten to DT. While both Ab titer and affinity contributed to function, affinity was more sensitive to antigen differences.
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影响因子：
7.3
作者：
Carroll FI;Abraham P;Gong PK;Pidaparthi RR;Blough BE;Che Y;Hampton A;Gunnell M;Lay JO Jr;Peterson EC;Owens SM
通讯作者：
Owens SM
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影响因子：
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作者：
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通讯作者：
Hartwig, John F.