OVA免疫耐受因子制备及其免疫活性研究
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摘要
免疫耐受现象普遍存在,有生理性和病理性两种表现形式。病理性免疫耐受的发生与外周免疫耐受的形成、维持及打破密切相关。1995年,CD4+CD25+调节性T细胞的发现使外周免疫耐受的研究取得了突破性的进展,大量证据证实CD4+CD25+ T细胞在外周免疫耐受形成和维持中发挥关键性作用。CD4+CD25+ T细胞主要是通过细胞接触以及分泌抑制性细胞因子如TGF-β、IL-10来介导外周免疫耐受的形成与维持。CD4+CD25+ T细胞表面的众多分子被证实参与CD4+CD25+ T细胞抑制功能的调节,但这些分子并不能单独介导外周耐受的形成。是否存在一些分子能够不依赖于细胞、独立地传递免疫耐受信息,从而使受体建立并维持抗原特异性的外周免疫耐受,至今未见报道。深入探讨这类分子的存在、来源等,不仅对阐明其形成的分子机理,丰富免疫耐受理论有着重要的学术意义,研究的结果也对临床免疫耐受相关疾病的治疗有着重要的应用价值。
本研究以卵清蛋白(ovalbumin,OVA)和4周龄BALB/c小鼠为材料,采用尾静脉注射、淋巴细胞分离技术、分子筛离心分离方法、淋巴细胞增殖试验、流式细胞术、ELISA、迟发型超敏反应(delayed type hypersensitivity,DTH)等技术,首先建立OVA外周免疫耐受小鼠模型,对其进行鉴定;分离此模型小鼠脾淋巴细胞,裂解获得不同组分,并鉴定出能够使4周龄正常BALB/c建立OVA外周免疫耐受的组分,命名为OVA免疫耐受因子(OVA immune tolerant factor,OVA ITF);分离OVA外周免疫耐受小鼠的脾淋巴细胞中的各T细胞亚群,按照OVA ITF制备方法制备各亚群的组分,对其转移OVA免疫耐受特性进行研究。获得如下研究结果:
1.成功建立了OVA外周免疫耐受BALB/c小鼠模型,该小鼠OVA特异性T细胞增殖明显受到抑制,CD4+CD25+ T细胞在CD4亚群中的比例显著升高。
2.体外试验显示,免疫耐受小鼠脾淋巴细胞裂解物中小于3ku的组分(OVA ITF)能显著抑制静息态OVA特异性T细胞克隆的增殖,抑制率达到60%;同时,该因子对活化态淋巴细胞增殖的抑制率高达70%。而添加分子量大于5ku和3-5ku间的组分,对淋巴细胞增殖的抑制表现为抗原非特异性。
3.转移OVA免疫耐受小鼠脾淋巴细胞裂解物各组分,只有分子量小于3ku的组分(OVA ITF)能够抗原特异性地抑制受体鼠OVA淋巴细胞克隆的活化;而分子量大于5ku和3-5ku间的组分并无此效应。
4.转移试验中,只有CD4+CD25+T细胞的ITFCD4+CD25+能够显著性抑制OVA特异性DTH反应、抑制OVA特异性T细胞的增殖,而ITFCD4-和ITFCD4+CD25-无此效应。
5.在ITFCD4+CD25+建立的OVA免疫耐受小鼠上,脾淋巴细胞中CD4+CD25+ T细胞在CD4亚群的比例显著升高,同时脾淋巴细胞分泌高水平的TGF-β1。
6.转移ITFCD4+CD25+和CD4+CD25+ T细胞后,受体小鼠脾淋巴细胞中CD4+CD25+ T细胞的比例以及抑制性细胞因子的分泌水平存在差异。
研究结果表明,从OVA耐受鼠脾淋巴细胞的CD4+CD25+ T细胞亚群中发现了一种新型的低分子量(3ku)的活性成分,即OVA ITF。它能够在分子水平介导正常BALB/c小鼠建立OVA外周免疫耐受,这种分子只能由OVA外周免疫耐受小鼠的CD4+CD25+T细胞产生。
The controls of immune tolerance depend on two regulatory mechanisms which were called central tolerance and peripheral tolerance. To understand the mechanisms of peripheral tolerance will yield practical clues that translate to clinical therapy of autoimmune diseases, graft-rejection, and cancers which escape the CTL killing by forming specific tolerance to peripheral tumor antigen in host. Since 1995, CD4+CD25+ T cell subpopulation was found and accumulating researches have demonstrated that CD4+CD25+ regulatory T cells play a critical role on the establishment and maintenance of peripheral tolerance. The mechanism of Treg-mediated peripheral tolerance is dependent on cell-cell contact and/or suppressor cytokines such as IL-10 and TGF-β. During the formation process of peripheral tolerance, several molecules are related to the regulatory of suppressor activity of CD4+CD25+ T cells; however, they are not the candidate molecules which are responsible for the establishment of peripheral tolerance independently. It is unknown whether some molecules which can induce peripheral tolerance exist. Thus, to investigate the existence, origin and chemical nature of such molecules will not only provide direct molecular evidence to the mechanisms of Treg-medited peripheral tolerance, but also might introduce a novel pathway for clinical therapy present.
In this study, we used OVA and BALB/c mice as experimental materials to induce immune tolerance model. Then, we prepared three fractions with different molecular weights from splenic lymphocytes of OVA tolerant mice and transferred them into na?ve BALB/c mice to analyze whether any of them could establish peripheral tolerance in recipient mice. Furthermore, to clarify the origin of OVA ITF, we prepared factors smaller than 3ku from CD4+CD25+ T cells, and CD4+CD25- T cells, as well as CD4-T cells from OVA tolerant mice, and transfer them into na?ve mice, respectively. Then, antigen-specific DTH reaction and lymphocyte proliferation, cytokine secretion, the percentage of CD4+CD25+ T cells were assayed, finding the results as following:
1. After a low dose of OVA were injected into na?ve mice, a significantly lower in proliferation responses of OVA-specific lymphocytes was found and the percentage of CD4+CD25+ T cells within CD4 subset increased dramatically. These results demonstrate that OVA-specific tolerance has been set up in BALB/c mice.
2. In vitro, adding to OVA ITF suppressed remarkably the proliferation of na?ve OVA-specific lymphocytes and the inhibit effect reached 60%; the inhibit effect to activated OVA-specific lymphocytes was more than 70%, whereas the factors which either larger than 5ku or between 3ku to 5ku suppressed lymphocyte proliferation in an antigen-nonspecific manner.
3. Adoptive transfer of factors with different molecular weight from splenic lymphocyte lysate of OVA tolerant mice, OVA ITF significantly suppressed the proliferation of OVA-specific lymphocytes, however, the same effects could not be observed on the factors which either larger than 5ku or between 3ku to 5ku.
4. Mice received either ITFCD4+CD25+ or CD4+CD25+ T cells induced successfully OVA-specific tolerance with a significant reduction of the DTH reaction and the responses of OVA-specific T cell proliferation, while mice transferred with ITFCD4- and ITFCD4+CD25- showed no obvious suppressive effects on the same analysis.
5. Mice transferred with ITFCD4+CD25+ establish OVA-specific tolerance in recipient mice, performing in a sharp increase in the percentage of CD4+CD25+ T cells within CD4 subset and a high level of TGF-β1.
6. The effects on peripheral tolerance mediated by ITFCD4+CD25+ were nearly the same as that of CD4+CD25+ T cells of OVA tolerant mice, although the time needed to establish immune tolerance and induction of the level of IL-10 for ITFCD4+CD25+ and CD4+CD25+ T cells were different.
In conclusion, we have demonstrated that a smaller than 3ku factor (OVA ITF) extracted from CD4+CD25+ T cells in OVA tolerant mice is able to transfer OVA-specific tolerance to na?ve mice. It indicates that OVA ITF might play a crucial role for CD4+CD25+ T cells on exerting their immunoregulatory function, which will provide evidence to further clarify the molecular mechanisms of peripheral tolerance mediated by CD4+CD25+ T cells.
本研究以卵清蛋白(ovalbumin,OVA)和4周龄BALB/c小鼠为材料,采用尾静脉注射、淋巴细胞分离技术、分子筛离心分离方法、淋巴细胞增殖试验、流式细胞术、ELISA、迟发型超敏反应(delayed type hypersensitivity,DTH)等技术,首先建立OVA外周免疫耐受小鼠模型,对其进行鉴定;分离此模型小鼠脾淋巴细胞,裂解获得不同组分,并鉴定出能够使4周龄正常BALB/c建立OVA外周免疫耐受的组分,命名为OVA免疫耐受因子(OVA immune tolerant factor,OVA ITF);分离OVA外周免疫耐受小鼠的脾淋巴细胞中的各T细胞亚群,按照OVA ITF制备方法制备各亚群的组分,对其转移OVA免疫耐受特性进行研究。获得如下研究结果:
1.成功建立了OVA外周免疫耐受BALB/c小鼠模型,该小鼠OVA特异性T细胞增殖明显受到抑制,CD4+CD25+ T细胞在CD4亚群中的比例显著升高。
2.体外试验显示,免疫耐受小鼠脾淋巴细胞裂解物中小于3ku的组分(OVA ITF)能显著抑制静息态OVA特异性T细胞克隆的增殖,抑制率达到60%;同时,该因子对活化态淋巴细胞增殖的抑制率高达70%。而添加分子量大于5ku和3-5ku间的组分,对淋巴细胞增殖的抑制表现为抗原非特异性。
3.转移OVA免疫耐受小鼠脾淋巴细胞裂解物各组分,只有分子量小于3ku的组分(OVA ITF)能够抗原特异性地抑制受体鼠OVA淋巴细胞克隆的活化;而分子量大于5ku和3-5ku间的组分并无此效应。
4.转移试验中,只有CD4+CD25+T细胞的ITFCD4+CD25+能够显著性抑制OVA特异性DTH反应、抑制OVA特异性T细胞的增殖,而ITFCD4-和ITFCD4+CD25-无此效应。
5.在ITFCD4+CD25+建立的OVA免疫耐受小鼠上,脾淋巴细胞中CD4+CD25+ T细胞在CD4亚群的比例显著升高,同时脾淋巴细胞分泌高水平的TGF-β1。
6.转移ITFCD4+CD25+和CD4+CD25+ T细胞后,受体小鼠脾淋巴细胞中CD4+CD25+ T细胞的比例以及抑制性细胞因子的分泌水平存在差异。
研究结果表明,从OVA耐受鼠脾淋巴细胞的CD4+CD25+ T细胞亚群中发现了一种新型的低分子量(3ku)的活性成分,即OVA ITF。它能够在分子水平介导正常BALB/c小鼠建立OVA外周免疫耐受,这种分子只能由OVA外周免疫耐受小鼠的CD4+CD25+T细胞产生。
The controls of immune tolerance depend on two regulatory mechanisms which were called central tolerance and peripheral tolerance. To understand the mechanisms of peripheral tolerance will yield practical clues that translate to clinical therapy of autoimmune diseases, graft-rejection, and cancers which escape the CTL killing by forming specific tolerance to peripheral tumor antigen in host. Since 1995, CD4+CD25+ T cell subpopulation was found and accumulating researches have demonstrated that CD4+CD25+ regulatory T cells play a critical role on the establishment and maintenance of peripheral tolerance. The mechanism of Treg-mediated peripheral tolerance is dependent on cell-cell contact and/or suppressor cytokines such as IL-10 and TGF-β. During the formation process of peripheral tolerance, several molecules are related to the regulatory of suppressor activity of CD4+CD25+ T cells; however, they are not the candidate molecules which are responsible for the establishment of peripheral tolerance independently. It is unknown whether some molecules which can induce peripheral tolerance exist. Thus, to investigate the existence, origin and chemical nature of such molecules will not only provide direct molecular evidence to the mechanisms of Treg-medited peripheral tolerance, but also might introduce a novel pathway for clinical therapy present.
In this study, we used OVA and BALB/c mice as experimental materials to induce immune tolerance model. Then, we prepared three fractions with different molecular weights from splenic lymphocytes of OVA tolerant mice and transferred them into na?ve BALB/c mice to analyze whether any of them could establish peripheral tolerance in recipient mice. Furthermore, to clarify the origin of OVA ITF, we prepared factors smaller than 3ku from CD4+CD25+ T cells, and CD4+CD25- T cells, as well as CD4-T cells from OVA tolerant mice, and transfer them into na?ve mice, respectively. Then, antigen-specific DTH reaction and lymphocyte proliferation, cytokine secretion, the percentage of CD4+CD25+ T cells were assayed, finding the results as following:
1. After a low dose of OVA were injected into na?ve mice, a significantly lower in proliferation responses of OVA-specific lymphocytes was found and the percentage of CD4+CD25+ T cells within CD4 subset increased dramatically. These results demonstrate that OVA-specific tolerance has been set up in BALB/c mice.
2. In vitro, adding to OVA ITF suppressed remarkably the proliferation of na?ve OVA-specific lymphocytes and the inhibit effect reached 60%; the inhibit effect to activated OVA-specific lymphocytes was more than 70%, whereas the factors which either larger than 5ku or between 3ku to 5ku suppressed lymphocyte proliferation in an antigen-nonspecific manner.
3. Adoptive transfer of factors with different molecular weight from splenic lymphocyte lysate of OVA tolerant mice, OVA ITF significantly suppressed the proliferation of OVA-specific lymphocytes, however, the same effects could not be observed on the factors which either larger than 5ku or between 3ku to 5ku.
4. Mice received either ITFCD4+CD25+ or CD4+CD25+ T cells induced successfully OVA-specific tolerance with a significant reduction of the DTH reaction and the responses of OVA-specific T cell proliferation, while mice transferred with ITFCD4- and ITFCD4+CD25- showed no obvious suppressive effects on the same analysis.
5. Mice transferred with ITFCD4+CD25+ establish OVA-specific tolerance in recipient mice, performing in a sharp increase in the percentage of CD4+CD25+ T cells within CD4 subset and a high level of TGF-β1.
6. The effects on peripheral tolerance mediated by ITFCD4+CD25+ were nearly the same as that of CD4+CD25+ T cells of OVA tolerant mice, although the time needed to establish immune tolerance and induction of the level of IL-10 for ITFCD4+CD25+ and CD4+CD25+ T cells were different.
In conclusion, we have demonstrated that a smaller than 3ku factor (OVA ITF) extracted from CD4+CD25+ T cells in OVA tolerant mice is able to transfer OVA-specific tolerance to na?ve mice. It indicates that OVA ITF might play a crucial role for CD4+CD25+ T cells on exerting their immunoregulatory function, which will provide evidence to further clarify the molecular mechanisms of peripheral tolerance mediated by CD4+CD25+ T cells.
引文
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