CpG ODN对真菌性角膜炎病理改变的影响及免疫机制的实验研究
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摘要
目的
探讨CpG寡聚脱氧核苷酸(CpG ODN)对小鼠真菌性角膜炎病理改变的影响及可能的免疫作用机制。
方法
角膜基质注射法建立BALB/c白色念珠菌性及茄病镰刀菌性角膜炎模型,按照治疗方法不同分为以下五个实验组：不治疗组(A组)、感染同时结膜下注射CpG ODN组(B组)、感染同时结膜下注射non CpG ODN组(C组)、感染前48小时预先结膜下注射CpG ODN组(D组)及感染前48小时预先结膜下注射non CpG ODN组(E组)。观察记录小鼠角膜真菌感染后的角膜大体病变特点和临床病理损害评分,HE/PAS染色检查角膜病理改变及真菌生长情况,真菌培养计算角膜真菌载菌量,ELISA法检测白色念珠菌性角膜炎小鼠角膜、外周血清及体外培养脾细胞中IL-12、IFN-γ、IL-10、MCP-1及真菌特异性抗体IgG、IgM、IgA水平,免疫组化检测白色念珠菌感染后角膜组织中性粒细胞、巨噬细胞及淋巴细胞侵润情况。
结果
无论是白色念珠菌还是茄病镰刀菌FK,感染前48hr预先给予CpG ODN结膜下注射对角膜真菌感染的小鼠有明显的免疫保护作用,能明显减轻小鼠角膜组织的病理改变,与其他各组相比,显著降低了角膜临床病理损害评分(p<0.05),并可有效地减少角膜组织的真菌载菌量(p<0.05),有利于真菌病原体的清除以及角膜溃疡的愈合,病程明显缩短,并不加重角膜组织的炎症性病理损伤；而感染同时给予CpG ODN结膜下注射对真菌性角膜炎小鼠无明显的保护或治疗作用,角膜临床病理损害评分及角膜组织的真菌载菌量与其他各组无明显差异(p>0.05)。在白色念珠菌感染小鼠角膜后,CpG ODN预先注射组D组小鼠角膜感染后,其血清及角膜组织中IL-12、IFN-γ、IL-10及MCP-1的水平均有不同程度的升高,以IL-12水平的升高最为显著(p<0.05)；IL-12水平从感染第一天骤升后,至感染第14天均持续较高水平,始终显著高于A组、C组、D组及E组(p<0.05)；IL-10于感染1天骤升后略降低,至第14天接近于正常水平,其感染第一天水平低于D组(p>0.05),但仍明显高于A组、C组及E组(p<0.05)；IFN-γ于感染第一天后开始均逐渐升高。而CpG ODN感染同时注射的D组小鼠角膜感染后,其血清及角膜组织中的IL-12、IFN-γ在感染第一天也明显升高,CpG ODN感染同时注射组比不注射组小鼠角膜组织及血清中也可产生更多的Th1型细胞因子IL-12、IFN-γ(p<0.05),但IL-12水平显著低于B组(p<0.05)；与此同时其感染第一天Th2型细胞因子IL-10及趋化因子MCP-1水平的升高的程度也显著高于A组、C组、D组及E组(p<0.05)。总体上,CpG ODN注射组比不注射组小鼠角膜组织及血清中可产生更多的Th1型细胞因子IL-12、IFN-γ(p<0.05),并且感染早期D组小鼠角膜及血清比B组及其他各组表现了更为强烈的Th1型免疫偏移。同时,CpG ODN注射组比不注射组的小鼠脾细胞在体外培养时也可产生更多的Th1型细胞因子IL-12及IFN-γ(p<0.05)。各组小鼠角膜、血清及体外培养的脾细胞中特异性抗体IgG、IgM的IgA水平在感染早期均未见明显变化。免疫组化结果显示,CpG ODN注射组的小鼠在感染早期比不注射组的小鼠角膜内可见更多的中性粒细胞、巨噬细胞及淋巴细胞浸润。
结论
本实验结果显示,CpG ODN预先处理可以激活宿主的抗真菌免疫反应,对小鼠角膜真菌感染具有明显的免疫保护作用,其可能的免疫作用机制是CpGODN预先处理能促进小鼠全身及局部分泌Th1型细胞因子、促使免疫应答向Th1型转化,进而增强吞噬细胞对真菌的吞噬能力,实现真菌病原体的清除以及加速角膜溃疡的愈合。
Objective
To investigate the immune responses and the possible mechanism of CpG oligodeoxynucleotides (CpG ODN) in the treatment of fungal keratitis in mice.
Methods
Experimental murine fungal keratitis was induced by intrastromal injection of Candida albicans and Fusarium solani spores separately. According to the different methods of treatment, mice were divided into five groups as following, Group A:No treatment before or after fungal injection, Group B and Group C:CpG and non-CpG oligodeoxynucleotides separately was injected subconjunctivally after fungal injection instantly, Group D:CpG oligodeoxynucleotides was injected subconjunctivally 2 days before fungal injection, Group E:non-CpG oligodeoxynucleotides was injected subconjunctivally 2 days before fungal injection. Clinical scores and fungal load were measured regularly. Serum, cornea and proliferative spleen cells ex vivo, were colleted at different times in Candida albicans infected mice for measurement of interleukin (IL)-12、IFN-γ、IL-10、MCP-1 and Candida-specific-antibody IgG、IgM、and IgA. Immunohistochemistry was used to detect leukocyte, phagocyte, and lymphocyte infiltration in diseased corneas.
Results
In the corneas infected by both Candida albicans and Fusarium solani, CpG ODN pretreatment could significantly decreased the clinical scores and fungal load in the diseased corneas as compared with that in other groups (p<0.05). No significant difference was found in the clinical scores and fungal load among groups A、B、C and E (p>0.05). In the mice with cornea infected by Candida albicans and CpG pretreatment subconjunctivally, the levels of IL-12、IFN-γ、IL-10 and MCP-1 in both the serum and the cornea increased after infection in group D to some extents, in those the levels of IL-12 and IFN-y elevated most significantly (p<0.05). IL-12 level sharply increased at the first day after infection and persisted at a higher level to at least 14 days post-infection, which was significantly higher than that in any other groups (p<0.05). The level of IL-10 sharply increased at the first day and then reached to the normal level at 14 days post-infection, which was lower than that in group B (p>0.05), but much higher than that in group A、group C and group E on day 1 post infection (p<0.05). The levels of IFN-y increased at the fist day post-infection and elevated slightly later. While in group B, the levels of IL-12 and IFN-y in both the serum and the cornea sharply elevated as well when compared with that in mice without CpG ODN treatment (p<0.05). However, the IL-12 level in mice of group B was still significantly lower than that in group D (p<0.05). In addition, both IL-10 and MCP-1 in serum and cornea in mice of group B showed higher levels as compared with that in group A, group C, group D and group E on day 1 after infection (p<0.05). In total, the IL-12 and IFN-y in cornea and serum had increased significantly after infection in mice with-CpG ODN treatment when compared with that got no CpG ODN intervention (p<0.05). In the cornea and serum of CpG treatment groups (groups B and D), Thl cytokines of IL-12 and IFN-y elevated significantly than that in groups got no CpG ODN intervention (groups A, C and E) (p<0.05). The cytokines assay in the spleen cells ex vivo showed that the immune responses induced by pretreatment of CpG ODN were significantly biased toward the T-helper 1 type as well. No elevating of Candida-specific antibody was detected in the corneas, serum and spleen cells in any of the groups. The immunohistochemistry assay showed that more infiltration of immune cells, including leukocytes, macrophage, and lymphocytes, were found in the corneas of mice with subconjunctival injection of CpG ODN.
Conclusions
The present study suggested that CpG ODN pretreatment activated the host anti-fungal immune responses and showed more effectiveness to prevent the fungal keratitis. The immune responses against fungal keratitis in mice with CpG ODN pretreatment were mediated by significant T-helper 1 cytokines, which benefit for the clearance of fungal pathogens and healing up of corneal ulcers and thus contribute to a favourable perspective in the treatment of fungal keratitis.
探讨CpG寡聚脱氧核苷酸(CpG ODN)对小鼠真菌性角膜炎病理改变的影响及可能的免疫作用机制。
方法
角膜基质注射法建立BALB/c白色念珠菌性及茄病镰刀菌性角膜炎模型,按照治疗方法不同分为以下五个实验组：不治疗组(A组)、感染同时结膜下注射CpG ODN组(B组)、感染同时结膜下注射non CpG ODN组(C组)、感染前48小时预先结膜下注射CpG ODN组(D组)及感染前48小时预先结膜下注射non CpG ODN组(E组)。观察记录小鼠角膜真菌感染后的角膜大体病变特点和临床病理损害评分,HE/PAS染色检查角膜病理改变及真菌生长情况,真菌培养计算角膜真菌载菌量,ELISA法检测白色念珠菌性角膜炎小鼠角膜、外周血清及体外培养脾细胞中IL-12、IFN-γ、IL-10、MCP-1及真菌特异性抗体IgG、IgM、IgA水平,免疫组化检测白色念珠菌感染后角膜组织中性粒细胞、巨噬细胞及淋巴细胞侵润情况。
结果
无论是白色念珠菌还是茄病镰刀菌FK,感染前48hr预先给予CpG ODN结膜下注射对角膜真菌感染的小鼠有明显的免疫保护作用,能明显减轻小鼠角膜组织的病理改变,与其他各组相比,显著降低了角膜临床病理损害评分(p<0.05),并可有效地减少角膜组织的真菌载菌量(p<0.05),有利于真菌病原体的清除以及角膜溃疡的愈合,病程明显缩短,并不加重角膜组织的炎症性病理损伤；而感染同时给予CpG ODN结膜下注射对真菌性角膜炎小鼠无明显的保护或治疗作用,角膜临床病理损害评分及角膜组织的真菌载菌量与其他各组无明显差异(p>0.05)。在白色念珠菌感染小鼠角膜后,CpG ODN预先注射组D组小鼠角膜感染后,其血清及角膜组织中IL-12、IFN-γ、IL-10及MCP-1的水平均有不同程度的升高,以IL-12水平的升高最为显著(p<0.05)；IL-12水平从感染第一天骤升后,至感染第14天均持续较高水平,始终显著高于A组、C组、D组及E组(p<0.05)；IL-10于感染1天骤升后略降低,至第14天接近于正常水平,其感染第一天水平低于D组(p>0.05),但仍明显高于A组、C组及E组(p<0.05)；IFN-γ于感染第一天后开始均逐渐升高。而CpG ODN感染同时注射的D组小鼠角膜感染后,其血清及角膜组织中的IL-12、IFN-γ在感染第一天也明显升高,CpG ODN感染同时注射组比不注射组小鼠角膜组织及血清中也可产生更多的Th1型细胞因子IL-12、IFN-γ(p<0.05),但IL-12水平显著低于B组(p<0.05)；与此同时其感染第一天Th2型细胞因子IL-10及趋化因子MCP-1水平的升高的程度也显著高于A组、C组、D组及E组(p<0.05)。总体上,CpG ODN注射组比不注射组小鼠角膜组织及血清中可产生更多的Th1型细胞因子IL-12、IFN-γ(p<0.05),并且感染早期D组小鼠角膜及血清比B组及其他各组表现了更为强烈的Th1型免疫偏移。同时,CpG ODN注射组比不注射组的小鼠脾细胞在体外培养时也可产生更多的Th1型细胞因子IL-12及IFN-γ(p<0.05)。各组小鼠角膜、血清及体外培养的脾细胞中特异性抗体IgG、IgM的IgA水平在感染早期均未见明显变化。免疫组化结果显示,CpG ODN注射组的小鼠在感染早期比不注射组的小鼠角膜内可见更多的中性粒细胞、巨噬细胞及淋巴细胞浸润。
结论
本实验结果显示,CpG ODN预先处理可以激活宿主的抗真菌免疫反应,对小鼠角膜真菌感染具有明显的免疫保护作用,其可能的免疫作用机制是CpGODN预先处理能促进小鼠全身及局部分泌Th1型细胞因子、促使免疫应答向Th1型转化,进而增强吞噬细胞对真菌的吞噬能力,实现真菌病原体的清除以及加速角膜溃疡的愈合。
Objective
To investigate the immune responses and the possible mechanism of CpG oligodeoxynucleotides (CpG ODN) in the treatment of fungal keratitis in mice.
Methods
Experimental murine fungal keratitis was induced by intrastromal injection of Candida albicans and Fusarium solani spores separately. According to the different methods of treatment, mice were divided into five groups as following, Group A:No treatment before or after fungal injection, Group B and Group C:CpG and non-CpG oligodeoxynucleotides separately was injected subconjunctivally after fungal injection instantly, Group D:CpG oligodeoxynucleotides was injected subconjunctivally 2 days before fungal injection, Group E:non-CpG oligodeoxynucleotides was injected subconjunctivally 2 days before fungal injection. Clinical scores and fungal load were measured regularly. Serum, cornea and proliferative spleen cells ex vivo, were colleted at different times in Candida albicans infected mice for measurement of interleukin (IL)-12、IFN-γ、IL-10、MCP-1 and Candida-specific-antibody IgG、IgM、and IgA. Immunohistochemistry was used to detect leukocyte, phagocyte, and lymphocyte infiltration in diseased corneas.
Results
In the corneas infected by both Candida albicans and Fusarium solani, CpG ODN pretreatment could significantly decreased the clinical scores and fungal load in the diseased corneas as compared with that in other groups (p<0.05). No significant difference was found in the clinical scores and fungal load among groups A、B、C and E (p>0.05). In the mice with cornea infected by Candida albicans and CpG pretreatment subconjunctivally, the levels of IL-12、IFN-γ、IL-10 and MCP-1 in both the serum and the cornea increased after infection in group D to some extents, in those the levels of IL-12 and IFN-y elevated most significantly (p<0.05). IL-12 level sharply increased at the first day after infection and persisted at a higher level to at least 14 days post-infection, which was significantly higher than that in any other groups (p<0.05). The level of IL-10 sharply increased at the first day and then reached to the normal level at 14 days post-infection, which was lower than that in group B (p>0.05), but much higher than that in group A、group C and group E on day 1 post infection (p<0.05). The levels of IFN-y increased at the fist day post-infection and elevated slightly later. While in group B, the levels of IL-12 and IFN-y in both the serum and the cornea sharply elevated as well when compared with that in mice without CpG ODN treatment (p<0.05). However, the IL-12 level in mice of group B was still significantly lower than that in group D (p<0.05). In addition, both IL-10 and MCP-1 in serum and cornea in mice of group B showed higher levels as compared with that in group A, group C, group D and group E on day 1 after infection (p<0.05). In total, the IL-12 and IFN-y in cornea and serum had increased significantly after infection in mice with-CpG ODN treatment when compared with that got no CpG ODN intervention (p<0.05). In the cornea and serum of CpG treatment groups (groups B and D), Thl cytokines of IL-12 and IFN-y elevated significantly than that in groups got no CpG ODN intervention (groups A, C and E) (p<0.05). The cytokines assay in the spleen cells ex vivo showed that the immune responses induced by pretreatment of CpG ODN were significantly biased toward the T-helper 1 type as well. No elevating of Candida-specific antibody was detected in the corneas, serum and spleen cells in any of the groups. The immunohistochemistry assay showed that more infiltration of immune cells, including leukocytes, macrophage, and lymphocytes, were found in the corneas of mice with subconjunctival injection of CpG ODN.
Conclusions
The present study suggested that CpG ODN pretreatment activated the host anti-fungal immune responses and showed more effectiveness to prevent the fungal keratitis. The immune responses against fungal keratitis in mice with CpG ODN pretreatment were mediated by significant T-helper 1 cytokines, which benefit for the clearance of fungal pathogens and healing up of corneal ulcers and thus contribute to a favourable perspective in the treatment of fungal keratitis.
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