Covalent Conjugation of Peptide Antigen to Mesoporous Silica Rods to Enhance Cellular Responses
Covalent Conjugation of Peptide Antigen to Mesoporous Silica Rods to Enhance Cellular Responses
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DOI：
10.1021/acs.bioconjchem.7b00656
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发表时间：
2018-03-01
影响因子：
4.7
通讯作者：
Mooney, David J.
中科院分区：
文献类型：
--
作者：
Dellacherie, Maxence O.;Li, Aileen W.;Mooney, David J.
短肽是细胞免疫识别的最小形式的抗原，因此被认为是用于疫苗接种的安全且高度特异性的抗原来源。然而，成功的肽免疫疗法受到肽抗原在体内的短半衰期以及它们的弱免疫原性的限制。我们最近报道了一种基于树突状细胞募集介孔二氧化硅棒（MSR）支架的疫苗策略，以增强T细胞对亚单位抗原的应答。在这项研究中，我们研究了共价结合肽抗原的MSR，以增加其保留在支架中的效果。与被动吸附相比，使用稳定的硫醚和可还原的二硫键，肽缀合大大增加了肽负载。在体外，骨髓来源的树突状细胞（BMDCs）可以呈递与MSR缀合的卵清蛋白（OVA）衍生肽，并诱导抗原特异性T细胞增殖。稳定的结合降低了体外呈递，而可还原的结合保持了与可溶性肽一样高的呈递水平。与可溶性肽相比，在体外，OT-II T细胞的扩增不受吸附或与MSR的稳定缀合的影响，但与MSR的可逆缀合增强。与标准推注或简单的吸附方法相比，两种缀合方案都增加了肽在体内MSR支架中的停留时间。当皮下注射负载GM-CSF和CpG-ODN的MSR支架时，募集的树突状细胞可以原位呈递抗原，并且稳定的结合增加了呈递能力。总的来说，这种简单的缀合方法可以作为一种通用平台，有效地将肽抗原掺入MSR疫苗中并增强细胞应答。
Short peptides are the minimal modality of antigen recognized by cellular immunity and are therefore considered a safe and highly specific source of antigen for vaccination. Nevertheless, successful peptide immunotherapy is limited by the short half-life of peptide antigens in vivo as well as their weak immunogenicity. We recently reported a vaccine strategy based on dendritic cell-recruiting Mesoporous Silica Rod (MSR) scaffolds to enhance T-cell responses against subunit antigen. In this study, we investigated the effect of covalently conjugating peptide antigens to MSRs to increase their retention in the scaffolds. Using both stable thioether and reducible disulfide linkages, peptide conjugation greatly increased peptide loading compared to passive adsorption. In vitro, Bone Marrow derived Dendritic Cells (BMDCs) could present Ovalbumin (OVA)-derived peptides conjugated to MSRs and induce antigen-specific T-cell proliferation. Stable conjugation decreased presentation in vitro while reducible conjugation maintained levels of presentation as high as soluble peptide. Compared to soluble peptide, in vitro, expansion of OT-II T-cells was not affected by adsorption or stable conjugation to MSRs but was enhanced with reversible conjugation to MSRs. Both conjugation schemes increased peptide residence time in MSR scaffolds in vivo compared to standard bolus injections or a simple adsorption method. When MSR scaffolds loaded with GM-CSF and CpG-ODN were injected subcutaneously, recruited dendritic cells could present antigen in situ with the stable conjugation increasing presentation capacity. Overall, this simple conjugation approach could serve as a versatile platform to efficiently incorporate peptide antigens in MSR vaccines and potentiate cellular responses.