富含胞嘧啶的脱氧寡核苷酸对免疫反应的负调节作用
发布时间：2018-11-17 12:20
【摘要】： 近年的研究表明,具有特定序列的单链脱氧寡核苷酸(ODN)具有免疫负调节作用,可能通过干预免疫系统或免疫细胞的异常活化,成为治疗自身免疫病、超敏反应和Toll样受体活化相关性疾病的药物。这类ODN被称为抑制性ODN,为人王合成的、长约几十个核苷酸的单链DNA分子。有研究表明,抑制性ODN可以抑制含CpG基序ODN(CpG ODN)的免疫刺激作用,也可能抑制LPS诱导的免疫反应等,且多为富含鸟嘌吟(G)的ODN。 根据哺乳动物线粒体DNA的序列特点以及对可能具有免疫负调节活性ODN的结构特性认识,我们设计了13条单链脱氧寡核苷酸,分别命名为MT00～12。然后,利用生物学活性方法对MT00～12是否能抑制免疫激活剂诱导免疫细胞产生抗病毒物质进行了筛选,发现富含胞嘧啶的MT01表现出较强的抑制活性。进一步研究显示:1)MT01不仅能抑制TLR9激动剂CpG ODN诱导的免疫反应,也能抑制灭活的DNA病毒、TLR7激动剂咪喹莫特或灭活的RNA病毒诱导的免疫反应,但对TLR4诱导的免疫反应则无抑制作用;2)MT01对SLE病人血清刺激的免疫反应也具有明显的抑制作用:3)MT01的结构,尤其富含胞嘧啶区域与其生物学活性直接相关,构效关系研究显示其免疫负调节活性可能是序列依赖性的:4)MT01在小鼠体内能明显抑制CpG ODN对乙肝表面抗原特异性抗体诱生的增强作用,但对乙肝表面抗原刺激抗体产生无抑制作用,说明MT01可能只对过强的免疫反应具有抑制作用;5)MT01可抑制小鼠B细胞活化,这提示其对抗原特异性抗体产生的抑制作用可能是通过抑制B细胞活化而实现的。 综上,一种富含胞嘧啶的单链脱氧寡核苷酸(MT01)具有选择性免疫负调节活性,可能具有治疗自身免疫病或TLR7/9活化相关性疾病的潜在应用价值。
[Abstract]:Recent studies have shown that single-stranded oligonucleotides (ODN) with specific sequences have negative immunomodulatory effects, which may be used to treat autoimmune diseases by interfering with the abnormal activation of immune system or immune cells. Drugs associated with hypersensitivity and Toll-like receptor activation-associated diseases. This type of ODN is known as a mono-stranded DNA molecule of about dozens of nucleotides synthesized by inhibitory ODN,. Some studies have shown that inhibitory ODN can inhibit the immunostimulatory effect of ODN (CpG ODN) containing CpG motif, and may also inhibit the immune response induced by LPS, and most of them are ODN. rich in CpG (G). According to the sequence characteristics of mammalian mitochondrial DNA and the recognition of the structural characteristics of ODN with possible immuno-negative regulatory activity, we designed 13 single-stranded oligodeoxynucleotides named MT00~12.. Then, the biological activity method was used to screen whether MT00~12 could inhibit the production of antiviral substances in immune cells induced by immunoactivator. It was found that MT01 rich in cytosine showed strong inhibitory activity. Further studies showed that: 1) MT01 could not only inhibit the immune response induced by TLR9 agonist CpG ODN, but also inhibit the immune response induced by inactivated DNA virus, TLR7 agonist Imiquimod or inactivated RNA virus. But the immune response induced by TLR4 was not inhibited. 2) MT01 also inhibited the immune response to serum stimulation in patients with SLE. 3) the structure of MT01, especially cytosine rich region, was directly related to its biological activity. The study of structure-activity relationship showed that its negative immunomodulatory activity might be sequence-dependent: 4) MT01 could significantly inhibit the enhancement of CpG ODN induced by HBsAg specific antibody in mice. However, there was no inhibitory effect on the antibody stimulated by hepatitis B surface antigen, indicating that MT01 may only inhibit the excessive immune response. 5) MT01 can inhibit the activation of B cells in mice, which suggests that the inhibition of antigen-specific antibodies may be achieved by inhibiting the activation of B cells. In conclusion, a cytosine rich single-strand deoxyoligodeoxynucleotide (MT01) has selective negative immunomodulatory activity, which may have potential application value in the treatment of autoimmune diseases or TLR7/9 activation-related diseases.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R392.11
[Abstract]:Recent studies have shown that single-stranded oligonucleotides (ODN) with specific sequences have negative immunomodulatory effects, which may be used to treat autoimmune diseases by interfering with the abnormal activation of immune system or immune cells. Drugs associated with hypersensitivity and Toll-like receptor activation-associated diseases. This type of ODN is known as a mono-stranded DNA molecule of about dozens of nucleotides synthesized by inhibitory ODN,. Some studies have shown that inhibitory ODN can inhibit the immunostimulatory effect of ODN (CpG ODN) containing CpG motif, and may also inhibit the immune response induced by LPS, and most of them are ODN. rich in CpG (G). According to the sequence characteristics of mammalian mitochondrial DNA and the recognition of the structural characteristics of ODN with possible immuno-negative regulatory activity, we designed 13 single-stranded oligodeoxynucleotides named MT00~12.. Then, the biological activity method was used to screen whether MT00~12 could inhibit the production of antiviral substances in immune cells induced by immunoactivator. It was found that MT01 rich in cytosine showed strong inhibitory activity. Further studies showed that: 1) MT01 could not only inhibit the immune response induced by TLR9 agonist CpG ODN, but also inhibit the immune response induced by inactivated DNA virus, TLR7 agonist Imiquimod or inactivated RNA virus. But the immune response induced by TLR4 was not inhibited. 2) MT01 also inhibited the immune response to serum stimulation in patients with SLE. 3) the structure of MT01, especially cytosine rich region, was directly related to its biological activity. The study of structure-activity relationship showed that its negative immunomodulatory activity might be sequence-dependent: 4) MT01 could significantly inhibit the enhancement of CpG ODN induced by HBsAg specific antibody in mice. However, there was no inhibitory effect on the antibody stimulated by hepatitis B surface antigen, indicating that MT01 may only inhibit the excessive immune response. 5) MT01 can inhibit the activation of B cells in mice, which suggests that the inhibition of antigen-specific antibodies may be achieved by inhibiting the activation of B cells. In conclusion, a cytosine rich single-strand deoxyoligodeoxynucleotide (MT01) has selective negative immunomodulatory activity, which may have potential application value in the treatment of autoimmune diseases or TLR7/9 activation-related diseases.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2009
【分类号】：R392.11
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