Lymph Node-Targeting Nanovaccine through Antigen-CpG Self-Assembly Potentiates Cytotoxic T Cell Activation

Journal of Immunology Research, Jun 2018

Therapeutic vaccines that arouse the cytotoxic T cell immune response to reject infected cells have been investigated extensively for treating disease. Due to the large amounts of resident antigen-presenting cells (APCs) and T cells in lymph nodes, great efforts have been made to explore the strategy of targeting lymph nodes directly with nanovaccines to activate T cells. However, these nanovaccines still have several problems, such as a low loading efficiency and compromised activity of antigens and adjuvants derived from traditional complicated preparation. There are also safety concerns about materials synthesized without FDA approval. Herein, we construct an assembled nanoparticle composed of an antigen (ovalbumin, OVA) and adjuvant (CpG) to ensure its safety and high loading efficiency. The activity of both components was well preserved due to the mild self-assembly process. The small size, narrow distribution, negative charge, and good stability of the nanoparticle endow these nanovaccines with superior capacity for lymph node targeting. Correspondingly, the accumulation at lymph nodes can be improved by 10-fold. Subsequently, due to the sufficient APC internalization and maturation in lymph nodes, ~60% of T cells are stimulated to proliferate and over 70% of target cells are specifically killed. Based on the effective and quick cellular immune response, the assembled nanoparticles exhibit great potential as therapeutic vaccines.

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Lymph Node-Targeting Nanovaccine through Antigen-CpG Self-Assembly Potentiates Cytotoxic T Cell Activation

Lymph Node-Targeting Nanovaccine through Antigen-CpG Self-Assembly Potentiates Cytotoxic T Cell Activation Xiaobo Xi,1,2 Lijun Zhang,1,2 Guihong Lu,3 Xiaoyong Gao,1 Wei Wei,1,2 and Guanghui Ma1,2,4 1State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China 2University of Chinese Academy of Sciences, Beijing 100049, China 3School of Life Science, Beijing Institute of Technology, Beijing 100081, China 4Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing 211816, China Correspondence should be addressed to Wei Wei; nc.ca.epi@iewiew and Guanghui Ma; nc.ca.epi@amhg Received 7 March 2018; Accepted 2 May 2018; Published 19 June 2018 Academic Editor: Channakeshava S Umeshappa Copyright © 2018 Xiaobo Xi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Therapeutic vaccines that arouse the cytotoxic T cell immune response to reject infected cells have been investigated extensively for treating disease. Due to the large amounts of resident antigen-presenting cells (APCs) and T cells in lymph nodes, great efforts have been made to explore the strategy of targeting lymph nodes directly with nanovaccines to activate T cells. However, these nanovaccines still have several problems, such as a low loading efficiency and compromised activity of antigens and adjuvants derived from traditional complicated preparation. There are also safety concerns about materials synthesized without FDA approval. Herein, we construct an assembled nanoparticle composed of an antigen (ovalbumin, OVA) and adjuvant (CpG) to ensure its safety and high loading efficiency. The activity of both components was well preserved due to the mild self-assembly process. The small size, narrow distribution, negative charge, and good stability of the nanoparticle endow these nanovaccines with superior capacity for lymph node targeting. Correspondingly, the accumulation at lymph nodes can be improved by 10-fold. Subsequently, due to the sufficient APC internalization and maturation in lymph nodes, ~60% of T cells are stimulated to proliferate and over 70% of target cells are specifically killed. Based on the effective and quick cellular immune response, the assembled nanoparticles exhibit great potential as therapeutic vaccines. 1. Introduction Traditional prophylactic vaccines, which act via humoral immunity, fail to combat infected or neoplastic cells [1, 2]. Much effort has been devoted to develop cellular immunity-mediated therapeutic vaccines [3]. During the cellular immune response, cytotoxic T cells play a central role in eliminating target cells [4, 5]. To activate cytotoxic T cells, antigens should be captured and presented via the major histocompatibility complex- (MHC-) I [6]. However, antigen alone with rapid clearance shows little effect on the cellular response [7]. Therefore, strategies for efficient antigen internalization and subsequent MHC-I presentation are urgently needed for therapeutic vaccines. Inspired by the aluminum adjuvant widely used in prophylactic vaccines, researchers have developed various systems to serve as the antigen depot at the vaccination site [8, 9]. Along with the sustained release of antigen within several days in the retention systems, a flow of antigen-presenting cells (APCs) can be recruited for uptake and maturation, and these then home to lymph nodes to activate T cells. During this process, many factors are responsible for the generated immune responses, such as number and type of recruited APCs, uptake amount of antigen, and APC maturation and subsequent trafficking to lymph nodes [10–12]. As a large number of APCs and T cells reside in lymph nodes, directly delivering antigen into lymph nodes is being considered as an alternative and even preferred strategy [13, 14]. Correspondingly, many nanodelivery systems are being developed, including polymer and inorganic nanoparticles, liposomes, dendrimers, and micelles [15, 16]. In addition to antigen, adjuvants such as CpG oligodeoxynucleotides (CpG ODN) and flagellin can be codelivered to the lymph nodes, which will significantly improve the MHC-I presentation for cytotoxic T cell activation [13, 17]. Although promising, these nanovaccines still have several problems. In most cases, antigen and adjuvant are loaded via encapsulation or conjugation [18, 19]. The harsh process that this involves, such as homogenization and use of an organic solvent, can compromise their activity and loading efficiency [20, 21]. Moreover, most synthesized materials utilized as the framework of nanovaccines have yet been approved by the United States Food and Drug Administration (FDA) [22]. Their biosafety remains a critical issue to resolve before their clinical use. Therefore, developing a facile appr (...truncated)


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Xiaobo Xi, Lijun Zhang, Guihong Lu, Xiaoyong Gao, Wei Wei, Guanghui Ma. Lymph Node-Targeting Nanovaccine through Antigen-CpG Self-Assembly Potentiates Cytotoxic T Cell Activation, Journal of Immunology Research, 2018, 2018, DOI: 10.1155/2018/3714960