分子佐剂通过粘膜免疫途径增强草原兔尾鼠卵透明带3DNA疫苗抗生育效果的研究
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摘要
草原兔尾鼠(Lagurus lagurus)属啮齿目仓鼠科田鼠亚科兔尾鼠属,是新疆荒漠草场的一种野生害鼠,对新疆荒漠草场造成巨大的损害,严重威胁着新疆畜牧业的发展。化学毒杀、诱捕、射杀等传统方法时效短、物种专一性差,对环境造成破坏,不能有效控制害鼠的种群数量。采用免疫不育技术降低有害动物的生育率是一种更人道的、物种专一性更强的防治有害动物的方法。
免疫不育疫苗主要以精子或卵子蛋白以及在受精和胚胎早期发育过程中发挥重要作用的蛋白或激素为抗原。肌肉和皮下接种等免疫不育疫苗传统接种方式很难在野外施用以控制有害动物种群数量,而口服饵料等粘膜免疫方式可以对有害动物进行大量接种,是切实可行的方法。鼠卵透明带3(Zona pellucida 3)主要由3种糖蛋白(ZP1、ZP2、ZP3)组成, ZP3作为精子的初级受体,诱发顶体反应,其抗体可以阻止精卵结合,在生殖过程中起重要作用,因此成为免疫不育疫苗的理想靶抗原。
DNA疫苗既能激发体液免疫,又能诱导细胞免疫,且具有制备简单、易于贮存运输等诸多优点,已被广泛地应用于免疫不育疫苗的研究中。由于DNA疫苗存在免疫原性不强,免疫效果不佳等原因,因此需要通过添加佐剂,改变发送途径,优化载体等方式来提高DNA不育疫苗的抗生育效果。
为了筛选出能有效提高LZP3DNA不育疫苗抗生育效果的分子佐剂,本研究选用小鼠白细胞介素31、白细胞介素15、白细胞介素33和非细胞因子FAI3作为分子佐剂,通过粘膜免疫途径,增强草原兔尾鼠LZP3DNA不育疫苗抗生育效果。并进一步探讨细胞因子和非细胞因子FAI3作为佐剂对草原兔尾鼠卵透明带DNA不育疫苗的免疫调节作用。
白细胞介素31主要由活化的Th2细胞生成,在T细胞介导的免疫反应中起重要作用,它参与了炎症和变性皮肤疾病。在遗传过敏性皮炎和接触性过敏性皮炎患者中,IL-31表达水平的增高与IL-4和IL-13具有一定的相关性。细胞因子白细胞介素33(interleukin 33,IL-33)是IL-1家族的新成员。IL-33通过IL-1受体ST2发挥其生物学功能,活化NF-kB和MAP激酶,在体外促进TH2细胞产生TH2相关细胞因子。人IL-33的表达仅限于支气管、小气道的上皮细胞、成纤维细胞以及平滑肌细胞,这暗示IL-33有可能参与了黏膜免疫。DC细胞通过ST2直接对IL-33产生应答,被IL-33活化的DC细胞触发了一种非典型的Th2型免疫反应,生成IL-5和IL-13。IL-33与DC细胞的相互作用可能代表了一种引发Th2型免疫反应的新途径。白细胞介素15是一个促炎症细胞因子,通过诱导淋巴细胞的活化、增殖,细胞因子的释放来增强体液和细胞免疫反应。IL-15充当佐剂时,能提高抗体滴度,促进DC细胞成熟。
FAI(Fbrinogen/ albumin/ IgG,纤维蛋白原/白蛋白/免疫球蛋白G受体)是来自C群链球菌的一种多配基结合蛋白,它能同时结合纤维蛋白原、白蛋白和免疫球蛋白G。位于415bp-702bp处的fai3基因片段具有粘膜佐剂活性。
首先克隆获得了小鼠细胞因子白细胞介素33基因、白细胞介素31基因和白细胞介素31突变体。成功构建了pcD- mIL-15、pcD- mIL31、pcD- muIL31、pcD- mIL33和pcD- fai3五种重组质粒,这五种质粒均能在真核细胞中表达相应的佐剂分子。用壳聚糖chitosan作为发送载体,chitosan同时或单独包裹DNA疫苗pcD-Lzp3和重组质粒pcD-mIL-15、pcD-mIL31、pcD-muIL31、pcD-mIL33和pcD- fai3形成不同的chitosan-DNA复合物。在第0, 14, 28和42d,分别用不同的chitosan-DNA复合物通过滴鼻免疫途径免疫ICR小鼠。间接ELISA检测血清中抗LZP3特异性IgG、IgG1和IgG2a抗体,以及阴道洗液和粪便中的特异性IgA抗体。
结果显示:滴鼻共免疫chi-(pcD-Lzp3+pcD-mIL-31)或chi-(pcD-Lzp3+pcD-muIL-31)都能诱导机体产生较高水平的血清IgG,降低了雌鼠的平均窝仔数。这两个共免疫组都产生较强的淋巴细胞增殖活性,激发Th1型免疫反应。共免疫chi-(pcD-Lzp3+pcD- muIL-31)不育小鼠的卵巢形态异常;在chi-(pcD-Lzp3+ pcD-mIL-31)组,不育小鼠卵巢中卵泡数量明显减少。
Chi-(pcD-Lzp3+pcD-mIL-15)产生较强的淋巴细胞增殖活性。chi-(pcD-Lzp3+pcD-mIL-15)共免疫组小鼠的卵巢组织具有各级形态发育正常的卵泡,无卵巢炎的发生。滴鼻共免疫chi-(pcD-Lzp3+pcD-mIL-33)诱导产生了最高水平的血清IgG和粘膜sIgA,生育率和平均窝仔数显著降低。Chi-(pcD-Lzp3+pcD-mIL-33)共免疫组不育小鼠的卵巢组织出现了卵泡萎缩、卵母细胞丢失等异常现象。这些研究结果表明, mIL-33作为分子佐剂与DNA不育疫苗pcD-Lzp3滴鼻共免疫小鼠,能显著提高DNA不育疫苗抗生育效果,并能够诱导机体产生较强的系统体液免疫反应和粘膜免疫反应。
Chi-(pcD-Lzp3+pcD-fai3)滴鼻共免疫也诱导机体生成了抗Lzp3特异性血清IgG和黏膜sIgA,生育率和平均窝仔数显著降低。共免疫组小鼠的卵巢组织具有各级形态发育正常的卵泡,无卵巢炎的发生。结果显示,fai3作为分子佐剂与DNA不育疫苗pcD-Lzp3滴鼻共免疫小鼠增强了体液免疫反应和黏膜免疫反应,提高了DNA不育疫苗的抗生育效果。在chi-(pcD-Lzp3+pcD-fai3)和chi-(pcD-Lzp3+pcD-mIL-33)共免疫组,免疫接种后不育小鼠的抗体水平显著高于生育小鼠,小鼠不育与抗体水平之间具有明显的相关性。
口服免疫是不育疫苗发送的有效途径。本研究进一步探讨了小鼠白细胞介素15和FAI3作为口服粘膜佐剂增强Lzp3 DNA不育疫苗抗生育效果的可行性。将上述chitosan-DNA复合物加入鼠粮中,制成饵料,免疫ICR小鼠。结果显示,口服共免疫chi-(pcD-Lzp3+pcD-fai3)都诱导产生了较高水平的血清IgG和肠粘膜sIgA,生育率和平均窝仔数都有所下降。Chi-(pcD-Lzp3+pcD-mIL-15)免疫组产生了较强的淋巴细胞增殖活性。对卵巢切片进行组织学检测,结果显示,两个共免疫组小鼠的卵巢组织正常。
综上所述,小鼠细胞因子白细胞介素33作为分子佐剂与草原兔尾鼠DNA不育疫苗pcD-Lzp3滴鼻共免疫小鼠,增强了机体的系统体液免疫反应和粘膜免疫反应,提高了DNA不育疫苗的抗生育率。白细胞介素31、白细胞介素15与草原兔尾鼠DNA不育疫苗pcD-Lzp3滴鼻共免疫小鼠,所产生的抗体水平和抗生育率均低于chi-(pcD-Lzp3+pcD-mIL-33)共免疫组。这些结果说明小鼠细胞因子白细胞介素33与白细胞介素31、白细胞介素15相比较,具有更强的分子佐剂功效。非细胞因子FAI3作为分子佐剂与DNA不育疫苗pcD-Lzp3,通过滴鼻和口服两种黏膜免疫途径共免疫小鼠,不仅增强了体液免疫反应,还激发了机体的粘膜免疫反应。因此,mIL-33和FAI3都可以作为分子佐剂,与DNA不育疫苗pcD-Lzp3共免疫,能够显著提高DNA不育疫苗pcD-Lzp3的抗生育效果。
Lagurus lagurus is a wild pest mouse distributed in desert pasture of northern region in Xingjiang. It destroys the pasture and results in the environmental damages for both ecologically and economically, and severely demolishes the stock raising of Xinjiang. Conventional control ways which rely on poisoning, trapping and shooting can be ineffective in the long term, often lead to losses in non-target species, and cause severely environmental problems. Immunocontraception can block or prevent oocyte fertilization through immunological interference, and it is a more humane, species-specific and effective control method. DNA vaccine is conventionally delivered by muscular or subcutaneous injection, while this is not feasible for the overpopulation control of the widely distributed pest animals. Delivering bait will be feasible ways that control the population of pest mouse through mass vaccination.
In mice, the oocyte is enveloped by an extracellular matrix termed zona pellucida (ZP), which is composed of three distinct glycoproteins-ZP1, ZP2 and ZP3. ZP3 acts as the primary sperm receptor, which can recognize and combine with sperm and induce acrosome reaction. ZP3 elicits antibodies that can inhibit sperm–oocyte binding and reduce fertility, it has been considered as a promising target antigen in immunocontraceptive vaccines.
Because DNA vaccine has several advantages such as inducing humour immune response and cell immune response at the same time, simple preparation and cheap cost, it is also used to study the immunocontraceptive vaccine. But, the immunogenicity of DNA vaccine is not high, and its immune effect need be improved. So it is necessary to enhance the immune effect of DNA contraceptive vaccine through some methods such as adding adjuvant, change delivery route and optimizing plasmid vectors.
To screen an molecule adjuvant that can improve the antifertility effect of DNA immunocontraceptive vaccine. We investigated the feasibility of mouse cytokine IL-31, IL-15, IL-33 and non-cytokine FAI3 as different molecular adjuvant, to enhance systemic and mucosal immune responses and improve antifertility effect of contraceptive DNA vaccine pcD-Lzp3 following the co-immunization. We have expored the immune effect that these three mouse cytokines and non-cytokine regulate the antifertility effects of DNA vaccine pcD-Lzp3.
Cytokine IL-31 is a new cytokine that is mainly produced by activated CD4+ T helper type 2 (Th2) cells. IL-31 is important in T cell-mediated immune responses; it is involved in inflammation and degenerative skin diseases. In allergic contact dermatitis, IL-31 expression was enhanced and correlated with IL-4 and IL-13. IL-33 is a new member of IL-1-family cytokines. IL-33 mediates its biological effects via IL-1 receptor ST2, activates NFkB and MAP kinases, and drives production of TH2-associated cytokines from in vitro polarized TH2 cells. The expression pattern of human IL-33 appears restricted to epithelial cells from bronchus and small airways, fibroblasts, and smooth muscle cells, suggesting its potential involvement in mucosal immunity. DCs respond directly to IL-33 through the receptor ST2, IL-33-actived DCs trigger an atypical Th2-type response that produce IL-5 and IL-13, The IL-33 and DC interaction may represent a new pathway to initiate Th2-type immune response. IL-15 is a proinflammatory cytokine that enhance humoral and cellular immune responses by inducing proliferation, activation, and cytokine release from lymphocytes. IL-15 has been shown to promote DC maturation, and increased antibody titers when used as adjuvant. However, FAI is a fibrinogen–albumin–IgG receptor from group C streptococci, it is a novel multiple-ligand-binding protein that can bind to fibrinogen, albumin and IgG. The third gene fragment of FAI(415bp-702bp)- fai3 has the activity of mucosal adjuvant.
At first, mouse IL-33 gene, IL-31 gene and IL-31 mutant gene were amplified by RT-PCR from testis and spleens of Balb/c mice. The recombinant plasmids pcD-mIL-15, pcD-mIL31,pcD-muIL31,pcD-mIL33 and pcD-fai3 were constructed successfully, and were expressed instantaneously in eukaryotic cell. The recombinant plasmids pcD-mIL-15, pcD-mIL31, pcD-muIL31, pcD-mIL33 and pcD-fai3 were encapsulated separately with chitosan to generate the different chitosan-DNA complexes. ICR mice were immunized with these chitosan-DNA complexes by intranasal route or oral route on day 0, 14, 28 and 42, respectively. Indirect ELISA was employed to determine the anti-LZP3 specific IgG, IgG1 and IgG2a antibody in sera, and the anti-LZP3 specific IgA in vaginal secretion and the feces.
The results showed that the high levels of serum IgG and the low mean litter size were induced in the mice of intranasally co-immunized with chi-(pcD-Lzp3+pcD- muIL-31) or chi-(pcD-Lzp3+pcD-mIL-31). The lymphocyte proliferation results showed that the strong cell immune response was induced in the mice of these two co-immunized groups , and the high IgG2a levels suggested that Th1 immune respone was actived. Histological examinations on the ovaries from the infertile female mice of chi-(pcD-Lzp3+pcD-muIL-31) exhibited abnormal histological structure. In the co-immunized group of chi-(pcD-Lzp3+ pcD-mIL-31), the follicles were lacked in the ovaries of infertile mice, and the number of follicles were decreased markedly.
The mice of intranasally co-immunized with chi-(pcD-Lzp3+pcD-mIL-33) induced the highest levels of serum IgG , vaginal secreted IgA , fecal IgA and the lowest mean litter size. The lymphocyte proliferation results showed that the strongest cell immune response was induced in the mice of co-immunized with chi-(pcD-Lzp3+pcD-mIL-15). Histological examinations on the ovaries from the female mice of chi-(pcD-Lzp3+pcD-mIL-15) exhibited normal histological structure and normal follicles in different stage of development, without pathological changes specifically. The ovaries from the infertile female mice of chi-(pcD-Lzp3+pcD-mIL-33) showed the atretic follicle and the loss of oocyte . Our work demonstrated that the intranasal delivery of the molecular adjuvant mIL-33 with chi-pcD-Lzp3 could significantly enhance the antifertility effect of the Lzp3 DNA vaccine for contraception by enhancing both the systemic and mucosal immune responses.
The mice of co-immunized group of chi-(pcD-Lzp3+pcD-fai3) produced the higher levels of serum IgG and fecal secreted IgA , and the low birth rate. Histological examinations on the ovaries from the female mice of chi-(pcD-Lzp3+pcD-fai3) exhibited normal histological structure and normal follicles in different stage of development, without pathological changes specifically. The level of IgG antibody in the infertile mice was significantly higher than in the fertile mice in the co-immunized group of chi-(pcD-Lzp3+pcD-mIL-33),chi-(pcD-Lzp3+pcD-fai3) , thus, there was a direct relationship between the levels of total IgG antibody and the infertility rate of mice among these groups.
Delivering bait is a feasible, potentially effective way, it will be used as the delivering method of DNA vaccine pcD-Lzp3 in the future. We investigate the feasibility of fai3 and mIL-15 as mucosal adjuvant by oral route, to improve antifertility effect of DNA vaccine pcD-Lzp3. The above-mentioned chitosan-DNA complexes were add to mouse food, and made the food as the bait. Then, these baits were feed ICR mice on day 0, 14, 28 and 42, respectively.
The ELISA results showed that the higher level of serum IgG and secreted IgA in feces, the lower mean litter size and birth rate were induced in the mice of co-immunized with chi-(pcD-Lzp3+pcD-fai3) through oral route. The level of serum IgG in the mice of chi-(pcD-Lzp3+pcD-mIL-15) was lower than that of chi-(pcD-Lzp3+pcD-fai3) co-immunized group, but the mice of this group induced the strong lymphocyte cell proliferation. Histological examinations also show the ovaries of immunized mice with the normal histological structure.
In conclusion, mouse cytokine-mIL-33 as the molecular adjuvant co-immunized with pcD-Lzp3 through intranal route, could improve the antifertility effect of the Lzp3 DNA contraceptive vaccine by enhancing both the systemic and mucosal immune responses. Mouse cytokine mIL-31 and mIL-15 as the molecular adjuvant co-immunized with pcD-Lzp3, respectively, produced the lower level of IgG and antifertility effect than that of the co-immunized with chi-(pcD-Lzp3+pcD-mIL-33) . These results suggested that cytokine mIL-33 would have more better efficacy of molecular adjuvant than cytokine mIL-31 and mIL-15.
Non-cytokine FAI3 as the molecular adjuvant co-immunized with pcD-Lzp3 intranally or orally, not only enhanced the systemic immune response, but also stimulated the mucosal immune response,and also can reduce the birth rate of mice. Thus, both mIL-33and FAI3 could act as molecular adjuvant, to improve the antifertility effect of DNA vaccine pcD-Lzp3 .
免疫不育疫苗主要以精子或卵子蛋白以及在受精和胚胎早期发育过程中发挥重要作用的蛋白或激素为抗原。肌肉和皮下接种等免疫不育疫苗传统接种方式很难在野外施用以控制有害动物种群数量,而口服饵料等粘膜免疫方式可以对有害动物进行大量接种,是切实可行的方法。鼠卵透明带3(Zona pellucida 3)主要由3种糖蛋白(ZP1、ZP2、ZP3)组成, ZP3作为精子的初级受体,诱发顶体反应,其抗体可以阻止精卵结合,在生殖过程中起重要作用,因此成为免疫不育疫苗的理想靶抗原。
DNA疫苗既能激发体液免疫,又能诱导细胞免疫,且具有制备简单、易于贮存运输等诸多优点,已被广泛地应用于免疫不育疫苗的研究中。由于DNA疫苗存在免疫原性不强,免疫效果不佳等原因,因此需要通过添加佐剂,改变发送途径,优化载体等方式来提高DNA不育疫苗的抗生育效果。
为了筛选出能有效提高LZP3DNA不育疫苗抗生育效果的分子佐剂,本研究选用小鼠白细胞介素31、白细胞介素15、白细胞介素33和非细胞因子FAI3作为分子佐剂,通过粘膜免疫途径,增强草原兔尾鼠LZP3DNA不育疫苗抗生育效果。并进一步探讨细胞因子和非细胞因子FAI3作为佐剂对草原兔尾鼠卵透明带DNA不育疫苗的免疫调节作用。
白细胞介素31主要由活化的Th2细胞生成,在T细胞介导的免疫反应中起重要作用,它参与了炎症和变性皮肤疾病。在遗传过敏性皮炎和接触性过敏性皮炎患者中,IL-31表达水平的增高与IL-4和IL-13具有一定的相关性。细胞因子白细胞介素33(interleukin 33,IL-33)是IL-1家族的新成员。IL-33通过IL-1受体ST2发挥其生物学功能,活化NF-kB和MAP激酶,在体外促进TH2细胞产生TH2相关细胞因子。人IL-33的表达仅限于支气管、小气道的上皮细胞、成纤维细胞以及平滑肌细胞,这暗示IL-33有可能参与了黏膜免疫。DC细胞通过ST2直接对IL-33产生应答,被IL-33活化的DC细胞触发了一种非典型的Th2型免疫反应,生成IL-5和IL-13。IL-33与DC细胞的相互作用可能代表了一种引发Th2型免疫反应的新途径。白细胞介素15是一个促炎症细胞因子,通过诱导淋巴细胞的活化、增殖,细胞因子的释放来增强体液和细胞免疫反应。IL-15充当佐剂时,能提高抗体滴度,促进DC细胞成熟。
FAI(Fbrinogen/ albumin/ IgG,纤维蛋白原/白蛋白/免疫球蛋白G受体)是来自C群链球菌的一种多配基结合蛋白,它能同时结合纤维蛋白原、白蛋白和免疫球蛋白G。位于415bp-702bp处的fai3基因片段具有粘膜佐剂活性。
首先克隆获得了小鼠细胞因子白细胞介素33基因、白细胞介素31基因和白细胞介素31突变体。成功构建了pcD- mIL-15、pcD- mIL31、pcD- muIL31、pcD- mIL33和pcD- fai3五种重组质粒,这五种质粒均能在真核细胞中表达相应的佐剂分子。用壳聚糖chitosan作为发送载体,chitosan同时或单独包裹DNA疫苗pcD-Lzp3和重组质粒pcD-mIL-15、pcD-mIL31、pcD-muIL31、pcD-mIL33和pcD- fai3形成不同的chitosan-DNA复合物。在第0, 14, 28和42d,分别用不同的chitosan-DNA复合物通过滴鼻免疫途径免疫ICR小鼠。间接ELISA检测血清中抗LZP3特异性IgG、IgG1和IgG2a抗体,以及阴道洗液和粪便中的特异性IgA抗体。
结果显示:滴鼻共免疫chi-(pcD-Lzp3+pcD-mIL-31)或chi-(pcD-Lzp3+pcD-muIL-31)都能诱导机体产生较高水平的血清IgG,降低了雌鼠的平均窝仔数。这两个共免疫组都产生较强的淋巴细胞增殖活性,激发Th1型免疫反应。共免疫chi-(pcD-Lzp3+pcD- muIL-31)不育小鼠的卵巢形态异常;在chi-(pcD-Lzp3+ pcD-mIL-31)组,不育小鼠卵巢中卵泡数量明显减少。
Chi-(pcD-Lzp3+pcD-mIL-15)产生较强的淋巴细胞增殖活性。chi-(pcD-Lzp3+pcD-mIL-15)共免疫组小鼠的卵巢组织具有各级形态发育正常的卵泡,无卵巢炎的发生。滴鼻共免疫chi-(pcD-Lzp3+pcD-mIL-33)诱导产生了最高水平的血清IgG和粘膜sIgA,生育率和平均窝仔数显著降低。Chi-(pcD-Lzp3+pcD-mIL-33)共免疫组不育小鼠的卵巢组织出现了卵泡萎缩、卵母细胞丢失等异常现象。这些研究结果表明, mIL-33作为分子佐剂与DNA不育疫苗pcD-Lzp3滴鼻共免疫小鼠,能显著提高DNA不育疫苗抗生育效果,并能够诱导机体产生较强的系统体液免疫反应和粘膜免疫反应。
Chi-(pcD-Lzp3+pcD-fai3)滴鼻共免疫也诱导机体生成了抗Lzp3特异性血清IgG和黏膜sIgA,生育率和平均窝仔数显著降低。共免疫组小鼠的卵巢组织具有各级形态发育正常的卵泡,无卵巢炎的发生。结果显示,fai3作为分子佐剂与DNA不育疫苗pcD-Lzp3滴鼻共免疫小鼠增强了体液免疫反应和黏膜免疫反应,提高了DNA不育疫苗的抗生育效果。在chi-(pcD-Lzp3+pcD-fai3)和chi-(pcD-Lzp3+pcD-mIL-33)共免疫组,免疫接种后不育小鼠的抗体水平显著高于生育小鼠,小鼠不育与抗体水平之间具有明显的相关性。
口服免疫是不育疫苗发送的有效途径。本研究进一步探讨了小鼠白细胞介素15和FAI3作为口服粘膜佐剂增强Lzp3 DNA不育疫苗抗生育效果的可行性。将上述chitosan-DNA复合物加入鼠粮中,制成饵料,免疫ICR小鼠。结果显示,口服共免疫chi-(pcD-Lzp3+pcD-fai3)都诱导产生了较高水平的血清IgG和肠粘膜sIgA,生育率和平均窝仔数都有所下降。Chi-(pcD-Lzp3+pcD-mIL-15)免疫组产生了较强的淋巴细胞增殖活性。对卵巢切片进行组织学检测,结果显示,两个共免疫组小鼠的卵巢组织正常。
综上所述,小鼠细胞因子白细胞介素33作为分子佐剂与草原兔尾鼠DNA不育疫苗pcD-Lzp3滴鼻共免疫小鼠,增强了机体的系统体液免疫反应和粘膜免疫反应,提高了DNA不育疫苗的抗生育率。白细胞介素31、白细胞介素15与草原兔尾鼠DNA不育疫苗pcD-Lzp3滴鼻共免疫小鼠,所产生的抗体水平和抗生育率均低于chi-(pcD-Lzp3+pcD-mIL-33)共免疫组。这些结果说明小鼠细胞因子白细胞介素33与白细胞介素31、白细胞介素15相比较,具有更强的分子佐剂功效。非细胞因子FAI3作为分子佐剂与DNA不育疫苗pcD-Lzp3,通过滴鼻和口服两种黏膜免疫途径共免疫小鼠,不仅增强了体液免疫反应,还激发了机体的粘膜免疫反应。因此,mIL-33和FAI3都可以作为分子佐剂,与DNA不育疫苗pcD-Lzp3共免疫,能够显著提高DNA不育疫苗pcD-Lzp3的抗生育效果。
Lagurus lagurus is a wild pest mouse distributed in desert pasture of northern region in Xingjiang. It destroys the pasture and results in the environmental damages for both ecologically and economically, and severely demolishes the stock raising of Xinjiang. Conventional control ways which rely on poisoning, trapping and shooting can be ineffective in the long term, often lead to losses in non-target species, and cause severely environmental problems. Immunocontraception can block or prevent oocyte fertilization through immunological interference, and it is a more humane, species-specific and effective control method. DNA vaccine is conventionally delivered by muscular or subcutaneous injection, while this is not feasible for the overpopulation control of the widely distributed pest animals. Delivering bait will be feasible ways that control the population of pest mouse through mass vaccination.
In mice, the oocyte is enveloped by an extracellular matrix termed zona pellucida (ZP), which is composed of three distinct glycoproteins-ZP1, ZP2 and ZP3. ZP3 acts as the primary sperm receptor, which can recognize and combine with sperm and induce acrosome reaction. ZP3 elicits antibodies that can inhibit sperm–oocyte binding and reduce fertility, it has been considered as a promising target antigen in immunocontraceptive vaccines.
Because DNA vaccine has several advantages such as inducing humour immune response and cell immune response at the same time, simple preparation and cheap cost, it is also used to study the immunocontraceptive vaccine. But, the immunogenicity of DNA vaccine is not high, and its immune effect need be improved. So it is necessary to enhance the immune effect of DNA contraceptive vaccine through some methods such as adding adjuvant, change delivery route and optimizing plasmid vectors.
To screen an molecule adjuvant that can improve the antifertility effect of DNA immunocontraceptive vaccine. We investigated the feasibility of mouse cytokine IL-31, IL-15, IL-33 and non-cytokine FAI3 as different molecular adjuvant, to enhance systemic and mucosal immune responses and improve antifertility effect of contraceptive DNA vaccine pcD-Lzp3 following the co-immunization. We have expored the immune effect that these three mouse cytokines and non-cytokine regulate the antifertility effects of DNA vaccine pcD-Lzp3.
Cytokine IL-31 is a new cytokine that is mainly produced by activated CD4+ T helper type 2 (Th2) cells. IL-31 is important in T cell-mediated immune responses; it is involved in inflammation and degenerative skin diseases. In allergic contact dermatitis, IL-31 expression was enhanced and correlated with IL-4 and IL-13. IL-33 is a new member of IL-1-family cytokines. IL-33 mediates its biological effects via IL-1 receptor ST2, activates NFkB and MAP kinases, and drives production of TH2-associated cytokines from in vitro polarized TH2 cells. The expression pattern of human IL-33 appears restricted to epithelial cells from bronchus and small airways, fibroblasts, and smooth muscle cells, suggesting its potential involvement in mucosal immunity. DCs respond directly to IL-33 through the receptor ST2, IL-33-actived DCs trigger an atypical Th2-type response that produce IL-5 and IL-13, The IL-33 and DC interaction may represent a new pathway to initiate Th2-type immune response. IL-15 is a proinflammatory cytokine that enhance humoral and cellular immune responses by inducing proliferation, activation, and cytokine release from lymphocytes. IL-15 has been shown to promote DC maturation, and increased antibody titers when used as adjuvant. However, FAI is a fibrinogen–albumin–IgG receptor from group C streptococci, it is a novel multiple-ligand-binding protein that can bind to fibrinogen, albumin and IgG. The third gene fragment of FAI(415bp-702bp)- fai3 has the activity of mucosal adjuvant.
At first, mouse IL-33 gene, IL-31 gene and IL-31 mutant gene were amplified by RT-PCR from testis and spleens of Balb/c mice. The recombinant plasmids pcD-mIL-15, pcD-mIL31,pcD-muIL31,pcD-mIL33 and pcD-fai3 were constructed successfully, and were expressed instantaneously in eukaryotic cell. The recombinant plasmids pcD-mIL-15, pcD-mIL31, pcD-muIL31, pcD-mIL33 and pcD-fai3 were encapsulated separately with chitosan to generate the different chitosan-DNA complexes. ICR mice were immunized with these chitosan-DNA complexes by intranasal route or oral route on day 0, 14, 28 and 42, respectively. Indirect ELISA was employed to determine the anti-LZP3 specific IgG, IgG1 and IgG2a antibody in sera, and the anti-LZP3 specific IgA in vaginal secretion and the feces.
The results showed that the high levels of serum IgG and the low mean litter size were induced in the mice of intranasally co-immunized with chi-(pcD-Lzp3+pcD- muIL-31) or chi-(pcD-Lzp3+pcD-mIL-31). The lymphocyte proliferation results showed that the strong cell immune response was induced in the mice of these two co-immunized groups , and the high IgG2a levels suggested that Th1 immune respone was actived. Histological examinations on the ovaries from the infertile female mice of chi-(pcD-Lzp3+pcD-muIL-31) exhibited abnormal histological structure. In the co-immunized group of chi-(pcD-Lzp3+ pcD-mIL-31), the follicles were lacked in the ovaries of infertile mice, and the number of follicles were decreased markedly.
The mice of intranasally co-immunized with chi-(pcD-Lzp3+pcD-mIL-33) induced the highest levels of serum IgG , vaginal secreted IgA , fecal IgA and the lowest mean litter size. The lymphocyte proliferation results showed that the strongest cell immune response was induced in the mice of co-immunized with chi-(pcD-Lzp3+pcD-mIL-15). Histological examinations on the ovaries from the female mice of chi-(pcD-Lzp3+pcD-mIL-15) exhibited normal histological structure and normal follicles in different stage of development, without pathological changes specifically. The ovaries from the infertile female mice of chi-(pcD-Lzp3+pcD-mIL-33) showed the atretic follicle and the loss of oocyte . Our work demonstrated that the intranasal delivery of the molecular adjuvant mIL-33 with chi-pcD-Lzp3 could significantly enhance the antifertility effect of the Lzp3 DNA vaccine for contraception by enhancing both the systemic and mucosal immune responses.
The mice of co-immunized group of chi-(pcD-Lzp3+pcD-fai3) produced the higher levels of serum IgG and fecal secreted IgA , and the low birth rate. Histological examinations on the ovaries from the female mice of chi-(pcD-Lzp3+pcD-fai3) exhibited normal histological structure and normal follicles in different stage of development, without pathological changes specifically. The level of IgG antibody in the infertile mice was significantly higher than in the fertile mice in the co-immunized group of chi-(pcD-Lzp3+pcD-mIL-33),chi-(pcD-Lzp3+pcD-fai3) , thus, there was a direct relationship between the levels of total IgG antibody and the infertility rate of mice among these groups.
Delivering bait is a feasible, potentially effective way, it will be used as the delivering method of DNA vaccine pcD-Lzp3 in the future. We investigate the feasibility of fai3 and mIL-15 as mucosal adjuvant by oral route, to improve antifertility effect of DNA vaccine pcD-Lzp3. The above-mentioned chitosan-DNA complexes were add to mouse food, and made the food as the bait. Then, these baits were feed ICR mice on day 0, 14, 28 and 42, respectively.
The ELISA results showed that the higher level of serum IgG and secreted IgA in feces, the lower mean litter size and birth rate were induced in the mice of co-immunized with chi-(pcD-Lzp3+pcD-fai3) through oral route. The level of serum IgG in the mice of chi-(pcD-Lzp3+pcD-mIL-15) was lower than that of chi-(pcD-Lzp3+pcD-fai3) co-immunized group, but the mice of this group induced the strong lymphocyte cell proliferation. Histological examinations also show the ovaries of immunized mice with the normal histological structure.
In conclusion, mouse cytokine-mIL-33 as the molecular adjuvant co-immunized with pcD-Lzp3 through intranal route, could improve the antifertility effect of the Lzp3 DNA contraceptive vaccine by enhancing both the systemic and mucosal immune responses. Mouse cytokine mIL-31 and mIL-15 as the molecular adjuvant co-immunized with pcD-Lzp3, respectively, produced the lower level of IgG and antifertility effect than that of the co-immunized with chi-(pcD-Lzp3+pcD-mIL-33) . These results suggested that cytokine mIL-33 would have more better efficacy of molecular adjuvant than cytokine mIL-31 and mIL-15.
Non-cytokine FAI3 as the molecular adjuvant co-immunized with pcD-Lzp3 intranally or orally, not only enhanced the systemic immune response, but also stimulated the mucosal immune response,and also can reduce the birth rate of mice. Thus, both mIL-33and FAI3 could act as molecular adjuvant, to improve the antifertility effect of DNA vaccine pcD-Lzp3 .
引文
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[1] Gupta SK, Srivastava N, Choudhury S, Rath A, Sivapurapu N, Gahlay GK, Batra D. Update on zona pellucida glycoproteins based contraceptive vaccine[J]. Journal of Reproductive Immunology. 2004,62(1-2):79–89.
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[1] Choudhury S, Kakkar V, Suman P,Chakrabarti K, Vrati S, Satish K, Gupta SK. Immunogenicity of zona pellucida glycoprotein-3 and spermatozoa YLP12 peptides presented on Johnson grass mosaic virus-like particles[J].Vaccine . 2009, 27(22):2948-2953.
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[1] Choudhury S, Kakkar V, Suman P,Chakrabarti K, Vrati S, Satish K, Gupta SK.Immunogenicity of zona pellucida glycoprotein-3 and spermatozoa YLP12 peptides presented on Johnson grass mosaic virus-like particles[J]. Vaccine .2009, 27 (22): 2948-2953.
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