基于Al-MOFs复合佐剂的纳米疫苗SIT治疗过敏性哮喘的研究

Allergic disease is a common and frequently-occurring disease. Th2-skewed polarization is a major pathological feature of allergic diseases. Specific immunotherapy (SIT) which induces Th1 skewed immune response is a effective approach. But the allergen SIT is a long course of treatment and poor treatment compliance and severe side-effects may be caused by high concentration allergen. It is reported that R848 attached to a polymer scaffold or R848 compounded aluminum salts can induce more effective Th1 immune response and reduce allergen usage amount of SIT, but R848 can not adsorb effectively to aluminum adjuvant. . To solve this scientific problem, Al-MOFs nanomaterials of different morphology and size are synthesized, and then R848 is attached to its amino group through bridging agent. The stronger adjuvant activity is obtained because the release of R848 is slower and compounded aluminum salts to be used, after R848 is assemble and attached to Al-MOFs. For the first time, Al-MOFs nanomaterial is pioneeringly applied to adjuvant field. It is illustrated that Al-MOFs compound adjuvant improves the efficacy of dust mites vaccine through the mouse model of allergic asthma. Research on Al-MOFs compound adjuvant enhancing the immunogenicity of the vaccine is conducted on different levels of molecules, cells, tissues and body. This research provides a theoretical basis for the design of adjuvant and vaccines and brings a new idea and method for specific immunotherapy.

过敏性疾病是一种常见病和多发病，表现为Th2反应极化，过敏原特异性免疫治疗(SIT)能诱导机体产生Th1免疫反应，是有效的治疗手段，但SIT疗程长，依从性差，高浓度过敏原能引起副作用。据报道R848连接到聚合物支架或配合铝佐剂使用能诱导更有效的Th1免疫应答，减少SIT过敏原用量，但R848不能有效的吸附于铝佐剂。. 为解决这一科学难题，本研究合成一系列形貌和尺寸不同的纳米Al-MOFs，将小分子R848偶联到Al-MOFs的骨架中，偶联聚合后的激动剂释放缓慢，且配合铝佐剂共同作用，获得更高的佐剂活性。本项目首次将Al-MOFs纳米材料应用到佐剂领域，以小鼠过敏性哮喘模型为研究对象，阐明Al-MOFs复合佐剂对尘螨疫苗功效的影响，从分子、细胞、组织和机体不同层面研究Al-MOFs复合佐剂增强疫苗免疫原性的机制，为佐剂和疫苗的设计提供理论依据，为过敏性疾病的免疫治疗提供一种新思路和新方法。

过敏性哮喘是一种常见病和多发病，表现为Th2反应极化。过敏原特异性免疫治疗（SIT）能诱导机体产生Th1免疫反应，是有效的治疗手段，但SIT疗程长，依从性差，高浓度过敏原能引起副作用。合适的抗原和佐剂对于过敏原特异性免疫治疗SIT有重要意义，而广泛应用的铝佐剂引起Th2反应，不适合用于过敏性疾病的免疫治疗，铝佐剂与TLR配体共同作用是一种有吸引力的方法。因此本项目从材料设计出发，设计合成含有铝佐剂与TLR配体的复合佐剂纳米疫苗。首先我们合成了两种尘螨变应原，检测并对比分析其免疫原性，以Derp1为抗原我们合成了两种含有TLR配体的Al-MOFs复合佐剂纳米疫苗ARNPs（含有Al和R848）和ACNPs（含有Al和CpG），两种复合佐剂纳米疫苗都具有很好的生物相容性，抗原和佐剂负载能力，并且释放缓慢。其次我们研究了不同佐剂纳米疫苗的DCs摄取和DCs激活，证实含有Al和TLR配体的复合佐剂纳米疫苗比只含有TLR的纳米疫苗有更好的佐剂活性，能显著上调DCs细胞共刺激分子的分泌表达，含有Al和TLR配体的复合佐剂更适合疫苗的制备。最后根据项目计划，我们研究了ARNPs和ACNPs两种复合佐剂纳米疫苗对过敏性哮喘的治疗作用，含有Al和R848或CpG的复合佐剂纳米疫苗，均具有很好的治疗效果，相对于只含有TLR佐剂的疫苗，含有TLR配体的Al-MOFs复合佐剂纳米疫苗能更显著的降低小鼠气道高反应和气道炎症，促使Th2反应向Th1转变。研究成果将为特异性免疫治疗中佐剂和疫苗设计提供所论依据，具有潜在的生物医学应用价值，同时也为铝佐剂的生物医学的应用提供了更为广阔的空间。