动物黏膜免疫佐剂研究新进展

黏膜佐剂可提高疫苗的免疫原性,延长抗原与黏膜及免疫活性细胞的作用时间,减少黏膜免疫耐受,增强疫苗免疫效果。本文主要综述了细菌脂肽、polyI:C和单磷酰类脂A等Toll样受体配体佐剂,芽胞、脂质体和纳米乳等黏膜传递系统以及其他新型黏膜佐剂的研究新进展,展望了黏膜佐剂在免疫学上的应用前景。     

黏膜疫苗抗原运输方式及佐剂研究进展

黏膜免疫是机体防御感染的第一道防线,诱导有效的黏膜免疫应答对病原由黏膜感染途径引发的疾病预防具有重要的意义。目前,在黏膜疫苗的研究中存在某些关键性问题,最重要的是黏膜抗原不能有效地被运输至黏膜诱发部位,致使黏膜免疫系统不能被有效刺激,而不能产生高效的免疫应答。因此,选择安全而有效的黏膜佐剂及选择有效的抗原运输系统是发展黏膜疫苗的必须条件。论文就近几年来黏膜疫苗佐剂及抗原运输方式进行综述。     

CpG ODN联合重组乳酸乳球菌鼻内免疫BALB/c小鼠的佐剂效应

本试验初次建立了CpG ODN联合重组乳酸乳球菌滴鼻免疫BALB/c小鼠模型。结果得出CpG ODN佐剂协同重组菌抗原组血清中抗PRRSV特异性抗体IgG和呼吸道黏膜抗体s-Ig A均高于单独重组菌组(P>0.05)和单独佐剂组(P<0.01),佐剂CpG ODN协同重组菌抗原组的Th1型细胞因子IL-2、IFN-γ及黏膜淋巴因子IL-5的活性高于单独抗原组(P>0.05)及单独佐剂组(P<0.01)。试验结果说明CpG ODN作为佐剂与重组菌鼻腔免疫小鼠后,可以提高重组菌诱导的黏膜免疫反应和Th1细胞参与的系统免疫反应,为研究安全有效的重组菌黏膜疫苗奠定了基础。     

大肠杆菌不耐热肠毒素突变体作为佐剂的研究进展

黏膜免疫是防止病原菌侵入黏膜表面引起疾病的最有效的途径,通过黏膜免疫不仅能产生全身免疫反应,还能产生局部的黏膜免疫反应,该免疫途径无痛苦且易操作,同时减少疾病传播的风险.但大多数抗原的黏膜免疫原性都很差,通过口服或滴鼻免疫可溶性蛋白通常引起特异性免疫耐受,这些使得在黏膜免疫中使用恰当的佐剂成为必须. 不耐热肠毒素（Heat— labile enterotoxin,LT）是由肠毒素大肠杆菌（enterotoxigenic Escherichia col i,ETEC）分泌的一种外毒素,既有较强的免疫原性又有较强的黏膜佐剂效应.但由于强的毒性,限制了它的广泛应用,因此通过构建各种突变体使之具备优良的佐剂活性且没有显著的毒性是当前研究的主要目标.本文主要从突变体的酶活性、毒性以及佐剂活性进行综述,为黏膜疫苗的研制打下一定基础.     

细胞因子类佐剂在黏膜免疫中的作用

黏膜免疫和黏膜疫苗佐剂的研究是近年来免疫学研究的一个重要方面.由于细胞因子在免疫应答的产生和调节中具有重要作用,可作为免疫佐剂增强疫苗的免疫效果,所以,细胞因子在黏膜佐剂研究中引起了人们广泛的兴趣与关注.文章主要简述黏膜免疫应答的调节及细胞因子类佐剂在黏膜免疫的研究与应用.     

益生菌对肠道黏膜免疫的影响

益生菌作为一类以活菌为主的新型菌制剂,能在肠道内定殖,维护肠道菌群平衡,并刺激肠黏膜免疫组织,对肠道黏膜免疫有重要的影响。益生菌可直接作用于宿主的免疫系统,刺激胸腺、脾脏和法氏囊等免疫器官的发育,促进巨噬细胞活力或发挥佐剂作用,活化肠黏膜内相关淋巴组织,使免疫球蛋白A分泌增加,使免疫球蛋白A生物合成增加,提高消化道黏膜免疫功能。     

细胞因子类佐剂在黏膜免疫中的作用

黏膜免疫和黏膜疫苗佐剂的研究是近年来免疫学研究的一个重要方面。由于细胞因子在免疫应答的产生和调节中具有重要作用，可作为免疫佐剂增强疫苗的免疫效果，所以，细胞因子在黏膜佐剂研究中引起了人们广泛的兴趣与关注。文章主要简述黏膜免疫应答的调节及细胞因子类佐剂在黏膜免疫的研究与应用。     

新型疫苗佐剂研究进展

佐剂是增强和调节疫苗抗原免疫反应的免疫刺激物,与抗原一起使用能产生更强的免疫反应。佐剂能激活机体的天然免疫系统,当佐剂和抗原同时或预先注射到机体内,可改变抗原的形态并延长抗原在体内的滞留时间,促进单核吞噬细胞对抗原的递呈能力及刺激淋巴细胞增殖分化,从而增强机体对抗原的免疫应答或改变免疫应答类型。佐剂的发展史长达一百多年,目前使用最广泛的疫苗佐剂是铝佐剂,传统的灭活疫苗在很大程度上依靠以铝盐为主的复合物作为主要佐剂。但近年来,随着基因工程技术和生物技术的飞速发展,重组疫苗、基因工程载体疫苗、核酸疫苗等新型疫苗逐步被开发出来,这些新型疫苗与传统疫苗相比往往存在免疫应答能力差等问题,早期的抗原不纯导致传统的铝盐佐剂已无法满足需要。为解决新型疫苗免疫原性差的问题,科研人员致力于开发广谱且高效的新型疫苗佐剂用来增强新型疫苗的作用。新型疫苗佐剂种类繁多,功能各不相同且机制较为复杂,可分为新型油乳佐剂、脂质体佐剂、CpG寡核苷酸佐剂、细胞因子佐剂、纳米佐剂、多糖佐剂及复合系统类佐剂等。笔者对疫苗佐剂的发展史、作用机制及新型疫苗佐剂的分类进行分析和评述,以期为新型疫苗佐剂的研制及开发提供参考。     

壳聚糖及其衍生物作为疫苗佐剂研究进展

近年来,随着新型基因工程疫苗的快速发展,其在疫病防控中发挥越来越重要的作用。与传统疫苗相比,新型疫苗特异性好、安全性高,但同时也存在免疫原性弱,难以诱导机体产生有效的免疫应答等不足。如何利用安全有效的免疫佐剂来增强新型疫苗免疫效果已成为当前亟待解决的突出问题。壳聚糖是来源于甲壳质的天然高分子化合物,具有良好的黏膜吸附性、生物相容性、安全性和可改造性,与传统免疫佐剂相比,它不仅能够协助疫苗激活机体的体液免疫,更能有效激活机体的细胞免疫,尤其是其可增强疫苗诱导的黏膜免疫效应。论文就近年来有关壳聚糖及其衍生物的理化特性、作为疫苗佐剂的优势及机制等进行综述,以期为壳聚糖及其衍生物佐剂作用机理研究与临床应用提供参考。     

大肠埃希菌不耐热肠毒素作为黏膜免疫佐剂的研究进展

免疫佐剂是一类通过刺激机体免疫系统而非特异性地增强机体对抗原免疫应答的活性物质,也是近年来研究的热点.免疫佐剂种类众多,利用细菌及其代谢产物作为黏膜免疫佐剂具有很好的发展前景,研究较多的是霍乱毒素(CT)和大肠埃希菌不耐热肠毒素(LT),从研究效果看,LT比CT更为理想.但是LT和CT一样本身具有毒性,这是其作为黏膜佐剂的主要缺点.目前,国内外研究工作者对其突变体做了大量研究,以期找到具有黏膜佐剂活性但低毒或无毒的大肠埃希菌不耐热肠毒素突变体.文章对大肠埃希菌不耐热肠毒素分子及其突变体的研究做一综述.     

黏膜免疫佐剂的筛选——Ⅰ．组织学与免疫组织化学研究

动物体内存在黏膜免疫系统,黏膜结合淋巴组织是黏膜免疫应答的组织基础.机体的淋巴组织50%以上存在于黏膜免疫系统.黏膜免疫系统具有重要而独特的功能,是病原体入侵的最大门户,接触大量种类繁多的抗原,被认为是执行局部特异性免疫功能的主要场所.因此,黏膜疫苗的研制和应用具有巨大的前景.选择合适的黏膜免疫载体,以最有效的促进黏膜免疫应答的途径投送抗原,加强黏膜免疫的效力,减少病毒性疾病的发生以及为细菌性疾病的防治,开辟一条非抗生素的新途径.     

Advances in mucosal vaccination

Pathogens that enter the body via mucosal surfaces face unique defense mechanisms that combine the innate barrier provided by the mucus layer with an adaptive response typified by the production and transepithelial secretion of pathogen-specific IgA. Both the measurement and induction of mucosal responses pose significant challenges for experimental and practical application and may need to be adapted to the species under study. In particular, for livestock, immunization procedures developed in small rodent models are not always effective in large animals or compatible with management practices. This paper reviews the latest advances in our understanding of the processes that lead to secretory IgA responses and how this relates to the development of mucosal immunization procedures and adjuvants for veterinary vaccines. In addition, it highlights the complex interactions that can take place between the pathogen and the host's immune response, with specific reference to Chlamydia/Chlamydophila infections in sheep.     

Analysis of the mucosal microenvironment: factors determining successful responses to mucosal vaccines

The predominance of IgA antibodies in mucosal sites reflects a combination of high rate IgA isotype switching among precursor cells in induction sites, their selective localisation in mucosal effector tissues and vigorous proliferation of these cells after extravasation. Each of these steps leading to IgA expression at the mucosa is under cytokine control. This paper will address the role of cytokines in induction and expression of IgA responses, the contribution of various precursor cell subsets and their differential responses to cytokine signals and strategies for manipulating cytokine expression. With respect to IgA antibody production in the gut whereas IL-4 and TGF-beta have been implicated in isotype switching of precursor cells to IgA commitment, their subsequent localisation, proliferation and effector activity expression is dependent on IL-5 and IL-6 expression locally. Most IgA plasma cells in the intestine derive from cells of the B2 lineage in the Peyer's patch, but a subpopulation of cells derived from the peritoneal cavity (B1 cells) also contribute to the IgA plasma cell population in the intestinal lamina propria. Whereas IgA+ cells of the B2 lineage are IL-6 dependent but IL-5 independent, B1-derived IgA+ cells are IL-5 dependent and IL-6 independent. On the other hand, cell mediated immune responses in the gut are highly dependent on IFN-gamma production by both Th1 CD4 cells and CD8 cells and in enteric Salmonella infection IFN-gamma production is essential but antibody has little effect on this process.Therapeutic interventions based on the information emerging from these studies will lead to improved vaccination responses and correction of immunodeficiencies especially in young animals.     

The postnatal development of the mucosal immune system and mucosal tolerance in domestic animals

The mucosal immune system is exposed to a range of antigens associated with pathogens, to which it must mount active immune responses. However, it is also exposed to a large number of harmless antigens associated with food and with commensal microbial flora, to which expression of active, inflammatory immune responses to these antigens is undesirable. The mucosal immune system must contain machinery capable of evaluating the antigens to which it is exposed and mounting appropriate effector or regulatory responses. Since the immune system is likely to have evolved initially in mucosal tissues, the requirement to prevent damaging allergic responses must be at least as old as the adaptive immune system, and studies of the mechanisms should include a range of non-mammalian species. Despite the importance for rational design of vaccines and for control of allergic reactions, the mechanisms involved are still largely unclear. It is not clear that the classical experimental protocol of "oral tolerance" is, in fact, measuring a biologically important phenomenon, nor is it clear whether tolerance is regulated in the evolutionarily recent organised lymphoid tissue (the lymph nodes) or the more ancient, diffuse architecture in the intestine. The capacity of the immune system to discriminate between "dangerous" and "harmless" antigens appears to develop with age and exposure to microbial flora. Thus, the ability of an individual or a group of animals to correctly regulate mucosal immune responses will depend on age, genetics and on their microbial environment and history. Attempts to manipulate the mucosal immune system towards active immune responses by oral vaccines, or towards oral tolerance, are likely to be confounded by environmentally-induced variability between individuals and between groups of animals.     

动物粘膜免疫及其细胞因子

粘膜免疫系统是机体抵抗病原微生物的第一道防线,广泛分布在呼吸道、消化道、泌尿生殖道及一些外分泌腺体的淋巴组织,是执行局部特异性免疫功能的主要场所,粘膜免疫的重要功能和独特性质日益受到重视。本文主要就其抗原逞递、淋巴细胞归巢、SIgA的功能及吸入耐受、细胞因子等方面的研究概况进行综述。     

Protollin黏膜免疫佐剂的研制

在人和动物的机体内存在着完整的黏膜免疫系统.黏膜免疫要取得好的免疫效果,关键是免疫佐剂的使用.比较理想的黏膜佐剂应高效、安全,能激活黏膜免疫系统[1].     

肠道粘膜免疫研究进展

肠道粘膜不仅是机体消化、吸收营养物质的场所，而且还具有重要的免疫功能。分泌型免疫球蛋白A、上皮内淋巴细胞、微皱褶细胞和细胞因子，共同组成肠道粘膜免疫系统，以阻止食物大分子和外来微生物抗原的侵入，保护肠道的结构和正常生理功能。     

Use of mucosal grafts and temporary tube implants for treatment of teat sinus mucosal injuries

A mucosal lesion was created in the center of each test sinus of 6 mature, healthy, nonlactating Holstein cows by resecting a circumferential band of mucosa. Each lesion was then treated by implantation of strip grafts of autogenous oral mucosa, temporary silastic tube implant, or a combination of strip grafts and temporary silastic tube implant. All teats were evaluated for patency 6 weeks after treatment, and tube implants were removed through a second thelotomy incision. All teats were reevaluated for gross and radiographic patency 12 weeks after treatment, and teats were collected for histologic evaluation of lesions. All 4 teats treated with grafts only were obstructed at 6 and 12 weeks after treatment. Incomplete coverage of the lesion with mucosa was observed in all 4 teats. The major source of obstruction was proliferation of epithelium and keratin into the lumen. All 8 teats treated with temporary silastic tube implants alone were patent at 6 weeks after treatment, but were obstructed at 12 weeks after treatment. Foci of mucosa at the lesion site were detected in only 2 of the 8 teats. Obstruction resulted from proliferation of granulation tissue into the lumen. All 12 teats treated with grafts and a temporary tube implant were patent at 6 weeks after treatment and 11 of 12 were patent at 12 weeks after treatment, although marked luminal narrowing was evident in 9 of 11 teats. Partial to complete coverage of the lesion with mucosa was seen in all teats. Proliferative granulation tissue, epithelium, and keratin contributed to luminal narrowing in 10 of 11 patent teats. Bacteriologic culture of quarters from 6 of the 11 teats patent at the final evaluation yielded pathogens.