新型CpG ODN的抗病毒作用及其作为病毒疫苗佐剂的实验研究
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摘要
含有非甲基化CpG基序的寡聚脱氧核苷酸(CpG ODN),能刺激哺乳动物免疫细胞,诱导Th1途径的免疫应答。A型CpG ODN能刺激人浆细胞样树突状细胞产生大量IFN-α,强烈激活NK细胞;B型CpG ODN能刺激B细胞增殖,分泌细胞因子;C型CpG ODN兼有A型和B型的作用。CpG ODN被广泛用于治疗感染性疾病、癌症、过敏性疾病,以及疫苗佐剂的研究,并已取得了肯定的结果。
我们对本室设计的C型CpG ODN BW001诱导产生抗病毒作用的机理进行了探讨,BW001能刺激人PBMC表达IFN-β、IFN-ω、IFN-γ以及至少10种IFN-α亚型的mRNA。进一步研究发现,BW001能诱生抗柯萨奇病毒B3的作用。我们还对本室设计的不同类型CpG ODN作为乙肝疫苗佐剂的作用进行了研究,结果A型、B型和C型CpG ODN均能显著促进特异性抗体的产生,且IgG类型以IgG2a为主,刺激了Th1途径的免疫应答。上述研究为研制我国自主知识产权的防治病毒感染性疾病的新药提供了实验基础。
Synthesized un-methylated CpG-containing oligodeoxynucleotides (CpG ODNs) can activate mammalian cells through pattern recognition receptor TLR9 signal pathway, stimulating lymphocytes, dendritic cells and monocytes to proliferate, maturate and secrete many kinds of cytokines, chemokines and/or immunoglobulin (Ig). There are three types of stimulatory CpG ODN, type-A, type-B and type-C, basing on their structures and their activities in stimulating human peripheral blood mononuclear cells (PBMCs) in vitro. Type-A CpG ODN can stimulate human plasmacytoid dendritic cells (pDCs) to produce large amounts of IFN-α, and strong activate natural killer (NK) cells. Structurally, type-A CpG ODN has phosphodiester-backbone palindrome sequence containing CpG motif and phosphorothioate-modified-backbone poly-G at the 3′and 5′ends. Type-B CpG ODN can stimulate B cell proliferation and secretion of large amounts of Ig, IL-6 and IL-10, and stimulate the maturation of pDC. Type-B CpG ODN has full phosphorothioate-modified backbone containing one or more CpG motif(s), and has no poly-G. Type-C CpG ODN has immune properties intermediate between the A and B classes. The structure of type-C CpG ODN is similar to that of type-A CpG ODN except its full phosphorothioate-modified backbone. The recognition of CpG motifs is different in variant species. The CpG motifs that strong activate human cells usually can not stimulate the cells of other species effectively.
Synthetic CpG ODNs have been demonstrated to have many immunostimulatory activities in mouse and in human, which can enhance the innate and adaptive immune reactions and promote the Th1 response. Therefore, CpG ODN has been researched extensively in the treatments of infectious diseases, tumor and allergic diseases, and in the usage as vaccine adjuvant. Moreover, encouraging results have been obtained in mouse models and different phage of clinical trails.
Viral infectious diseases are threatening human health all the time. The morbidity of AIDS is increasing yearly; the chronic infection of HBV or HCV seriously affects the patients’life quality; and the explosion of SARS and avian influenza in resent years took away many lives. There is no very effective method to treat viral infectious disease at present. Usually, recombinant IFN and nucleoside analogue are standard therapeutics to inhibit viral replication, combined with supportive treatment. But the side effects of the drugs are relative sever, especially for patients needing long time therapy, which are not tolerant. What’s more, repeated administrating of recombinant IFN will induce the production of neutralizing antibodies, which will influence the long time treatment. These limitations will impact the therapeutic effect, especially for the chronic viral infectious patients. Therefore, to develop more effective antiviral reagents is followed with interest by many researchers. Not only the antiviral drugs, but also the viral vaccines are in consideration, including exploitation of novel vaccines and improvement of vaccine adjuvant.
To develop new medications for prevention and treatment of viral infectious diseases, our laboratory designed and screened large amounts of CpG ODNs and obtained many CpG ODNs with effects in inducing antiviral activity and (or) stimulating B cell proliferation. Basing on these studies, we approached the antiviral mechanisms of a type-C CpG ODN BW001 with conspicuous antiviral activity, and further studied its anti-Coxsackie virus B3 (CVB3) activity. Moreover, we investigated the effects of type-A, type-B and type-C CpG ODNs as adjuvant for hepatitis B virus (HBV) vaccine. The contents of this paper are focused on the following parts:
1 Screening of different types of CpG ODNs
First, we screened some of the CpG ODNs designed by our laboratory. The vesicular stomatitis virus (VSV) protection assay was used for the screening of type-A CpG ODN. Human PBMCs were stimulated with different CpG ODNs, and the cell culture supernatants were collected for detecting their antiviral activity. Simultaneously, the 3H-TdR incorporation assay was used for the screening of type-B CpG ODNs. Human PBMCs were stimulated with different CpG ODNs, and the 3H-TdR was added for estimating the cell proliferation. Through these two processes, we obtained type-A CpG ODN PB9, BW004, PB3, BW103 and 110;type-B CpG ODN BW206, 678, BW015, 658, 640 and 607;and type-C CpG ODN BW001, BW005, 647, 111, 109, 656, C9 and 664.
2 The mechanisms of CpG ODN BW001 inducing antiviral activity
2.1 Expression of mRNAs of multiple types of IFNs from human PBMC stimulated by BW001
According to other studies of our laboratory, CpG ODN BW001 is one of the CpG ODNs that induce conspicuous antiviral activities; therefore we further investigated the mechanisms of its antiviral activity. RT-PCR was used to detect the mRNAs of multiple types of IFNs expressed by BW001-stimulated human PBMCs. The total RNAs of the PBMCs was isolated after BW001 stimulating, and reverse-transcribed into cDNAs, followed by amplified with primers for IFN-α, IFN-β, IFN-ωand IFN-γrespectively. The result showed that BW001 could stimulate human PBMC to express the mRNAs of IFN-α, IFN-β, IFN-ωand IFN-γ, indicating that BW001-induced antiviral activity is associated with the expression of these IFNs.
2.2 High level of IFN-αproduced from human PBMC stimulated by BW001
Since IFN-αis the most important cytokine in human antiviral responses, we further tested the level of IFN-αsecreted from PBMCs of different donors stimulated by BW001. IFN-αquantization ELISA kit was used to detect the IFN-αin the cell culture supernatants of PBMC stimulated by BW001. As a result, the PBMCs from all 6 donors stimulated by BW001 secreted high level of IFN-α, and the stimulatory effect of BW001 was depend on its CpG sequence.
2.3 Expression of mRNAs of various IFN-αsubtypes from human PBMC stimulated by BW001
There are at least 13 members in human IFN-αfamily, and the antiviral activities of these subtypes are different. Since the mRNA sequences of these IFN-αsubtypes have high homology, we designed consensus primers for amplifying the cDNAs of these subtypes through RT-PCR. Then the PCR products were ligated into clone plasmids, followed by sequenced to identify which IFN-αsubtype it represented. The data indicated that at least 10 kinds of mRNAs of IFN-αsubtypes could be induced with different proportion, including IFN-α1 and (or) IFN-α13, IFN-α2, IFN-α7, IFN-α5, IFN-α16, IFN-α21, IFN-α8, IFN-α4, IFN-α10 and IFN-α17,suggesting that BW001-induced antiviral activity is associated with the expression of most subtypes of IFN-α.
3 Anti-CVB3 activity of human PBMC induced by CpG ODN BW001
The previous work of our laboratory showed that BW001 could induce human PBMC to produce anti-VSV and anti-SARS-CoV activity. To further investigate whether BW001 could stimulated PBMC to produce antiviral activity against a wider spectrum of viruses, we tested the anti-CVB3 activity induced by BW001. Hela cells were treated with the cell culture supernatant of PBMC stimulated by BW001, followed by attacked with 10×TCID50 of CVB3. The result showed that BW001 stimulated supernatant could significantly protect Hela cells from CVB3 infection, indicating BW001-induced antiviral activity may resist extensive viral attacking.
4 Screening of CpG ODNs with effects in stimulating mice cells
To study the effects of CpG ODNs as vaccine adjuvant in animal model, we further screened the CpG ODNs we designed with effects in stimulating mice cells. The VSV protection assay was used for the screening of CpG ODNs that could stimulate mice splenocytes to produce antiviral activity. Mice splenocytes were stimulated with different CpG ODNs, and the cell culture supernatants were collected for detecting their antiviral activity. Simultaneously, the 3H-TdR incorporation assay was used for the screening of CpG ODNs that could stimulate mice splenocytes proliferation. Mice splenocytes were stimulated with different CpG ODNs, and the 3H-TdR was added for estimating the cell proliferation. Through these two processes, we obtained the CpG ODNs with effects in stimulating mice cells, including type-A CpG ODN BW004, BW103 and PB9;type-B CpG ODN BW015 and BW206, 656, 109, 647, 678, 640 and 664;and type-C CpG ODN BW005.
5 The effects of different types of CpG ODNs as adjuvant for HBV vaccine
Since type-B CpG ODN can strong stimulate B cell to proliferate, differentiate and secrete Ig, many researchers use type-B CpG ODN for studies about vaccine adjuvant. In this study, we use different types of CpG ODNs as adjuvant for HBV vaccine, investigating their effects. The CpG ODNs we used included BW103 and BW004 (type-A), BW015 and BW206 (type-B), and BW005 (type-C). The BALB/c mice were immunized by HBV vaccine (containing Al(OH)3) only or combined with different CpG ODNs, and their blood was collected at variant time point for detecting of antigen specific antibodies using ELISA kit. Compared with using HBV vaccine only, the levels of antigen specific antibodies were significantly enhanced in the sera of mice immunized by HBV vaccine combined with CpG ODNs. All types of CpG ODNs could enhance the antibody levels, and the high levels of antibody emerged earlier and lasted longer. Since IgG2a is the characteristic molecule of Th1-pathway immune response, we further tested the IgG2a in the sera of mice. The result showed that type-A, type-B and type-C CpG ODN as adjuvant for HBV vaccine could all stimulate the production of IgG2a, indicating they induced the Th1-pathway immune response.
To sum up, the type-C CpG ODN BW001 designed by our laboratory could stimulate human PBMC to express the mRNAs of IFN-α, IFN-β, IFN-ω, IFN-γand at least 10 kinds of IFN-αsubtypes, which contributed to the antiviral activity. Moreover, BW001 could stimulate human PBMC to produce anti-VSV and anti-CVB3 activities. Combined with other works of our laboratory about BW001 in inducing anti-SARS-CoV activity, we presumed that BW001-induced antiviral activity may resist extensive viral attacking. In addition, CpG ODNs BW103 and BW004 (type-A), BW015 and BW206 (type-B), and BW005 (type-C), designed by our laboratory used as adjuvant for HBV vaccine could significantly enhance the production of antigen specific antibodies and induce the production of IgG2a, stimulating the Th1-pathway immune response. Therefore, these CpG ODNs have the potential to be developed into novel medications for the prevention and treatment of viral infectious diseases.
我们对本室设计的C型CpG ODN BW001诱导产生抗病毒作用的机理进行了探讨,BW001能刺激人PBMC表达IFN-β、IFN-ω、IFN-γ以及至少10种IFN-α亚型的mRNA。进一步研究发现,BW001能诱生抗柯萨奇病毒B3的作用。我们还对本室设计的不同类型CpG ODN作为乙肝疫苗佐剂的作用进行了研究,结果A型、B型和C型CpG ODN均能显著促进特异性抗体的产生,且IgG类型以IgG2a为主,刺激了Th1途径的免疫应答。上述研究为研制我国自主知识产权的防治病毒感染性疾病的新药提供了实验基础。
Synthesized un-methylated CpG-containing oligodeoxynucleotides (CpG ODNs) can activate mammalian cells through pattern recognition receptor TLR9 signal pathway, stimulating lymphocytes, dendritic cells and monocytes to proliferate, maturate and secrete many kinds of cytokines, chemokines and/or immunoglobulin (Ig). There are three types of stimulatory CpG ODN, type-A, type-B and type-C, basing on their structures and their activities in stimulating human peripheral blood mononuclear cells (PBMCs) in vitro. Type-A CpG ODN can stimulate human plasmacytoid dendritic cells (pDCs) to produce large amounts of IFN-α, and strong activate natural killer (NK) cells. Structurally, type-A CpG ODN has phosphodiester-backbone palindrome sequence containing CpG motif and phosphorothioate-modified-backbone poly-G at the 3′and 5′ends. Type-B CpG ODN can stimulate B cell proliferation and secretion of large amounts of Ig, IL-6 and IL-10, and stimulate the maturation of pDC. Type-B CpG ODN has full phosphorothioate-modified backbone containing one or more CpG motif(s), and has no poly-G. Type-C CpG ODN has immune properties intermediate between the A and B classes. The structure of type-C CpG ODN is similar to that of type-A CpG ODN except its full phosphorothioate-modified backbone. The recognition of CpG motifs is different in variant species. The CpG motifs that strong activate human cells usually can not stimulate the cells of other species effectively.
Synthetic CpG ODNs have been demonstrated to have many immunostimulatory activities in mouse and in human, which can enhance the innate and adaptive immune reactions and promote the Th1 response. Therefore, CpG ODN has been researched extensively in the treatments of infectious diseases, tumor and allergic diseases, and in the usage as vaccine adjuvant. Moreover, encouraging results have been obtained in mouse models and different phage of clinical trails.
Viral infectious diseases are threatening human health all the time. The morbidity of AIDS is increasing yearly; the chronic infection of HBV or HCV seriously affects the patients’life quality; and the explosion of SARS and avian influenza in resent years took away many lives. There is no very effective method to treat viral infectious disease at present. Usually, recombinant IFN and nucleoside analogue are standard therapeutics to inhibit viral replication, combined with supportive treatment. But the side effects of the drugs are relative sever, especially for patients needing long time therapy, which are not tolerant. What’s more, repeated administrating of recombinant IFN will induce the production of neutralizing antibodies, which will influence the long time treatment. These limitations will impact the therapeutic effect, especially for the chronic viral infectious patients. Therefore, to develop more effective antiviral reagents is followed with interest by many researchers. Not only the antiviral drugs, but also the viral vaccines are in consideration, including exploitation of novel vaccines and improvement of vaccine adjuvant.
To develop new medications for prevention and treatment of viral infectious diseases, our laboratory designed and screened large amounts of CpG ODNs and obtained many CpG ODNs with effects in inducing antiviral activity and (or) stimulating B cell proliferation. Basing on these studies, we approached the antiviral mechanisms of a type-C CpG ODN BW001 with conspicuous antiviral activity, and further studied its anti-Coxsackie virus B3 (CVB3) activity. Moreover, we investigated the effects of type-A, type-B and type-C CpG ODNs as adjuvant for hepatitis B virus (HBV) vaccine. The contents of this paper are focused on the following parts:
1 Screening of different types of CpG ODNs
First, we screened some of the CpG ODNs designed by our laboratory. The vesicular stomatitis virus (VSV) protection assay was used for the screening of type-A CpG ODN. Human PBMCs were stimulated with different CpG ODNs, and the cell culture supernatants were collected for detecting their antiviral activity. Simultaneously, the 3H-TdR incorporation assay was used for the screening of type-B CpG ODNs. Human PBMCs were stimulated with different CpG ODNs, and the 3H-TdR was added for estimating the cell proliferation. Through these two processes, we obtained type-A CpG ODN PB9, BW004, PB3, BW103 and 110;type-B CpG ODN BW206, 678, BW015, 658, 640 and 607;and type-C CpG ODN BW001, BW005, 647, 111, 109, 656, C9 and 664.
2 The mechanisms of CpG ODN BW001 inducing antiviral activity
2.1 Expression of mRNAs of multiple types of IFNs from human PBMC stimulated by BW001
According to other studies of our laboratory, CpG ODN BW001 is one of the CpG ODNs that induce conspicuous antiviral activities; therefore we further investigated the mechanisms of its antiviral activity. RT-PCR was used to detect the mRNAs of multiple types of IFNs expressed by BW001-stimulated human PBMCs. The total RNAs of the PBMCs was isolated after BW001 stimulating, and reverse-transcribed into cDNAs, followed by amplified with primers for IFN-α, IFN-β, IFN-ωand IFN-γrespectively. The result showed that BW001 could stimulate human PBMC to express the mRNAs of IFN-α, IFN-β, IFN-ωand IFN-γ, indicating that BW001-induced antiviral activity is associated with the expression of these IFNs.
2.2 High level of IFN-αproduced from human PBMC stimulated by BW001
Since IFN-αis the most important cytokine in human antiviral responses, we further tested the level of IFN-αsecreted from PBMCs of different donors stimulated by BW001. IFN-αquantization ELISA kit was used to detect the IFN-αin the cell culture supernatants of PBMC stimulated by BW001. As a result, the PBMCs from all 6 donors stimulated by BW001 secreted high level of IFN-α, and the stimulatory effect of BW001 was depend on its CpG sequence.
2.3 Expression of mRNAs of various IFN-αsubtypes from human PBMC stimulated by BW001
There are at least 13 members in human IFN-αfamily, and the antiviral activities of these subtypes are different. Since the mRNA sequences of these IFN-αsubtypes have high homology, we designed consensus primers for amplifying the cDNAs of these subtypes through RT-PCR. Then the PCR products were ligated into clone plasmids, followed by sequenced to identify which IFN-αsubtype it represented. The data indicated that at least 10 kinds of mRNAs of IFN-αsubtypes could be induced with different proportion, including IFN-α1 and (or) IFN-α13, IFN-α2, IFN-α7, IFN-α5, IFN-α16, IFN-α21, IFN-α8, IFN-α4, IFN-α10 and IFN-α17,suggesting that BW001-induced antiviral activity is associated with the expression of most subtypes of IFN-α.
3 Anti-CVB3 activity of human PBMC induced by CpG ODN BW001
The previous work of our laboratory showed that BW001 could induce human PBMC to produce anti-VSV and anti-SARS-CoV activity. To further investigate whether BW001 could stimulated PBMC to produce antiviral activity against a wider spectrum of viruses, we tested the anti-CVB3 activity induced by BW001. Hela cells were treated with the cell culture supernatant of PBMC stimulated by BW001, followed by attacked with 10×TCID50 of CVB3. The result showed that BW001 stimulated supernatant could significantly protect Hela cells from CVB3 infection, indicating BW001-induced antiviral activity may resist extensive viral attacking.
4 Screening of CpG ODNs with effects in stimulating mice cells
To study the effects of CpG ODNs as vaccine adjuvant in animal model, we further screened the CpG ODNs we designed with effects in stimulating mice cells. The VSV protection assay was used for the screening of CpG ODNs that could stimulate mice splenocytes to produce antiviral activity. Mice splenocytes were stimulated with different CpG ODNs, and the cell culture supernatants were collected for detecting their antiviral activity. Simultaneously, the 3H-TdR incorporation assay was used for the screening of CpG ODNs that could stimulate mice splenocytes proliferation. Mice splenocytes were stimulated with different CpG ODNs, and the 3H-TdR was added for estimating the cell proliferation. Through these two processes, we obtained the CpG ODNs with effects in stimulating mice cells, including type-A CpG ODN BW004, BW103 and PB9;type-B CpG ODN BW015 and BW206, 656, 109, 647, 678, 640 and 664;and type-C CpG ODN BW005.
5 The effects of different types of CpG ODNs as adjuvant for HBV vaccine
Since type-B CpG ODN can strong stimulate B cell to proliferate, differentiate and secrete Ig, many researchers use type-B CpG ODN for studies about vaccine adjuvant. In this study, we use different types of CpG ODNs as adjuvant for HBV vaccine, investigating their effects. The CpG ODNs we used included BW103 and BW004 (type-A), BW015 and BW206 (type-B), and BW005 (type-C). The BALB/c mice were immunized by HBV vaccine (containing Al(OH)3) only or combined with different CpG ODNs, and their blood was collected at variant time point for detecting of antigen specific antibodies using ELISA kit. Compared with using HBV vaccine only, the levels of antigen specific antibodies were significantly enhanced in the sera of mice immunized by HBV vaccine combined with CpG ODNs. All types of CpG ODNs could enhance the antibody levels, and the high levels of antibody emerged earlier and lasted longer. Since IgG2a is the characteristic molecule of Th1-pathway immune response, we further tested the IgG2a in the sera of mice. The result showed that type-A, type-B and type-C CpG ODN as adjuvant for HBV vaccine could all stimulate the production of IgG2a, indicating they induced the Th1-pathway immune response.
To sum up, the type-C CpG ODN BW001 designed by our laboratory could stimulate human PBMC to express the mRNAs of IFN-α, IFN-β, IFN-ω, IFN-γand at least 10 kinds of IFN-αsubtypes, which contributed to the antiviral activity. Moreover, BW001 could stimulate human PBMC to produce anti-VSV and anti-CVB3 activities. Combined with other works of our laboratory about BW001 in inducing anti-SARS-CoV activity, we presumed that BW001-induced antiviral activity may resist extensive viral attacking. In addition, CpG ODNs BW103 and BW004 (type-A), BW015 and BW206 (type-B), and BW005 (type-C), designed by our laboratory used as adjuvant for HBV vaccine could significantly enhance the production of antigen specific antibodies and induce the production of IgG2a, stimulating the Th1-pathway immune response. Therefore, these CpG ODNs have the potential to be developed into novel medications for the prevention and treatment of viral infectious diseases.
引文
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