Modulating adaptive immune responses to peptide self-assemblies.
Modulating adaptive immune responses to peptide self-assemblies.
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DOI：
10.1021/nn204530r
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发表时间：
2012-02-28
期刊：
影响因子：
17.1
通讯作者：
Collier JH
中科院分区：
文献类型：
--
作者：
Rudra JS;Sun T;Bird KC;Daniels MD;Gasiorowski JZ;Chong AS;Collier JH
自组装肽和肽衍生物在生物医学领域的应用，包括组织工程、伤口愈合、细胞递送、药物递送和疫苗等，已经引起了人们极大的兴趣。这类材料在免疫原性方面表现出显著的可变性，其中许多肽引起不可检测的抗体应答，但其他肽在没有任何补充佐剂的情况下引起非常强的应答。目前，用于避免强抗体反应或特异性诱导它们的策略还没有得到很好的开发，即使它们对于在组织工程和免疫疗法中使用这些材料都是至关重要的。在这里，我们研究了导致自组装肽OVA-Q11显著免疫原性的分子决定簇和免疫学机制，OVA-Q11先前已被证明在小鼠中引起强烈的抗体应答。我们发现，这些反应可以持续至少一年。使用过继转移实验和T细胞敲除模型，我们发现这些强抗体应答是T细胞依赖性的，这表明了避免或确保免疫原性的途径。事实上，通过删除T细胞识别的肽中的氨基酸区域，免疫原性可以显著降低。免疫原性也可以通过使自组装结构域中的关键残基突变而减弱，从而防止纤维化。第二种自组装肽KFE 8也是非免疫原性的，但OVA-KFE 8的纳米纤维引发了与OVA-Q11类似的强烈抗体应答，表明佐剂作用不依赖于特定的自组装肽序列。这些发现将促进自组装肽生物材料的设计，用于免疫原性不受欢迎的应用和免疫原性有利的应用。
Self-assembling peptides and peptide derivatives have received significant interest for several biomedical applications, including tissue engineering, wound healing, cell delivery, drug delivery, and vaccines. This class of materials has exhibited significant variability in immunogenicity, with many peptides eliciting no detectable antibody responses but others eliciting very strong responses without any supplemental adjuvants. Presently, strategies for either avoiding strong antibody responses or specifically inducing them are not well developed, even though they are critical for the use of these materials both within tissue engineering and within immunotherapies. Here, we investigated the molecular determinants and immunological mechanisms leading to the significant immunogenicity of the self-assembling peptide OVA-Q11, which has been shown previously to elicit strong antibody responses in mice. We show that these responses can last for at least a year. Using adoptive transfer experiments and T cell knockout models, we found that these strong antibody responses were T cell-dependent, suggesting a route for avoiding or ensuring immunogenicity. Indeed, by deleting amino acid regions in the peptide recognized by T cells, immunogenicity could be significantly diminished. Immunogenicity could also be attenuated by mutating key residues in the self-assembling domain, thus preventing fibrillization. A second self-assembling peptide, KFE8, was also non-immunogenic, but nanofibers of OVA-KFE8 elicited strong antibody responses similar to OVA-Q11, indicating that the adjuvant action was not dependent on the specific self-assembling peptide sequence. These findings will facilitate the design of self-assembled peptide biomaterials, both for applications where immunogenicity is undesirable and where it is advantageous.
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DOI：
10.1073/pnas.73.10.3671
发表时间：
1976-01-01
影响因子：
11.1
作者：
DINTZIS, HM;DINTZIS, RZ;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0701980104
发表时间：
2007-05-08
影响因子：
11.1
作者：
Haines-Butterick, Lisa;Rajagopal, Karthikan;Schneider, Joel P.
通讯作者：
Schneider, Joel P.
DOI：
10.1073/pnas.97.12.6728
发表时间：
2000-06-06
影响因子：
11.1
作者：
Holmes, TC;de Lacalle, S;Zhang, SG
通讯作者：
Zhang, SG