Elamanchili Praveen, Lutsiak Christine M E, Hamdy Samar, Diwan Manish, Samuel John
Faculty of Pharmacy and Pharmaceutical Sciences, 3118, Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2N8.
J Immunother. 2007 May-Jun;30(4):378-95. doi: 10.1097/CJI.0b013e31802cf3e3.
A clinically relevant delivery system that can efficiently target and deliver antigens and adjuvant to dendritic cells (DCs) is under active investigation. Immunization with antigens and immunomodulators encapsulated in poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles elicits potent cellular immune responses; but understanding how this mode of delivery affects DCs and priming of naive T cells needs further investigation. In the current study, we assessed the extent of maturation of DCs after treatment with monophosphoryl lipid A (MPLA) encapsulated in PLGA nanoparticles and the generation of primary T-cell immune responses elicited by DCs loaded with antigens using this approach. Results indicated that DCs up-regulated the expression of surface maturation markers and demonstrated an enhanced allostimulatory capacity after treatment with MPLA containing PLGA nanoparticles. Treatment of DCs with MPLA containing nanoparticles released high amounts of proinflammatory and TH1 (T helper 1) polarizing cytokines and chemokines greater than that achieved by MPLA in solution. The delivery of ovalbumin in PLGA nanoparticles to DCs induced potent in vitro and in vivo antigen-specific primary TH1 immune responses that were furthermore enhanced with codelivery of MPLA along with the antigen in the nanoparticle formulation. Delivery of MUC1 lipopeptide (BLP25, a cancer vaccine candidate) and MPLA in PLGA nanoparticles to human DCs induced proliferation of MUC1 reactive T cells in vitro demonstrating the break in tolerance to self-antigen MUC1. These results demonstrated that targeting antigens along with toll-like receptor ligands in PLGA nanoparticles to DCs is a promising approach for generating potent TH1 polarizing immune responses that can potentially override self-tolerance mechanisms and become beneficial in the immunotherapy of cancer and infectious diseases.
一种能够有效靶向并将抗原和佐剂递送至树突状细胞（DC）的临床相关递送系统正在积极研究中。用包裹在聚（D，L-乳酸-乙醇酸）（PLGA）纳米颗粒中的抗原和免疫调节剂进行免疫可引发强大的细胞免疫反应；但了解这种递送方式如何影响DC以及初始T细胞的致敏还需要进一步研究。在本研究中，我们评估了用包裹在PLGA纳米颗粒中的单磷酰脂质A（MPLA）处理后DC的成熟程度，以及使用这种方法负载抗原的DC引发的原发性T细胞免疫反应的产生情况。结果表明，在用含MPLA的PLGA纳米颗粒处理后，DC上调了表面成熟标志物的表达，并表现出增强的同种异体刺激能力。用含纳米颗粒的MPLA处理DC释放出大量促炎和TH1（辅助性T细胞1）极化细胞因子和趋化因子，其释放量高于溶液中的MPLA。将卵清蛋白包裹在PLGA纳米颗粒中递送至DC可诱导强大的体外和体内抗原特异性原发性TH1免疫反应，并且在纳米颗粒制剂中与抗原共递送MPLA时，该免疫反应会进一步增强。将MUC1脂肽（BLP25，一种癌症疫苗候选物）和MPLA包裹在PLGA纳米颗粒中递送至人DC可在体外诱导MUC1反应性T细胞增殖，表明对自身抗原MUC1的耐受性被打破。这些结果表明，将抗原与Toll样受体配体一起包裹在PLGA纳米颗粒中靶向DC是一种有前景的方法，可产生强大的TH1极化免疫反应，这可能会突破自身耐受机制，并在癌症和传染病的免疫治疗中发挥有益作用。
