本文選題：噬菌體展示 + IL-2Rα��； 參考：《吉林大學(xué)》2007年博士論文

【摘要】： 免疫抑制劑在器官移植排斥反應(yīng)的預(yù)防和治療中起到了關(guān)鍵作用,人們認(rèn)為最佳的免疫抑制劑至少應(yīng)達(dá)到三個(gè)目標(biāo):選擇性、協(xié)同性和特異性。但是,當(dāng)前臨床應(yīng)用的免疫抑制劑只是部分地滿足這些目標(biāo)。為研制新型的肽類免疫抑制劑,我們以抗人IL-2Rα單克隆抗體5G1為靶分子,對(duì)噬菌體環(huán)七肽庫(kù)進(jìn)行了5輪篩選,經(jīng)鑒定獲得了5個(gè)與靶分子具有高親和力的噬菌體陽(yáng)性克隆,通過(guò)對(duì)其DNA序列進(jìn)行分析,得到IL-2Rα模擬表位肽的氨基酸保守序列: Lys-X-{X}-Lys-Gly。應(yīng)用化學(xué)合成法制備環(huán)七肽CP,其氨基酸序列為:Cys-Asn-Ala-Leu- Lys-Arg-Lys-Gly-Cys,相對(duì)分子量為990.2。經(jīng)檢測(cè)證實(shí)CP對(duì)正常小鼠脾細(xì)胞沒(méi)有毒性。計(jì)算機(jī)模擬證實(shí)CP與人IL-2的功能活性部位可形成穩(wěn)定、良好的結(jié)合。經(jīng)淋巴細(xì)胞周期測(cè)定、淋巴細(xì)胞增殖反應(yīng)、遲發(fā)型超敏反應(yīng)和局部移植物抗宿主反應(yīng)等多項(xiàng)體內(nèi)外的實(shí)驗(yàn)證實(shí):環(huán)七肽CP具有較強(qiáng)的免疫抑制活性,其與環(huán)孢菌素A聯(lián)用抑制效應(yīng)明顯增強(qiáng),顯示二者具有協(xié)同效應(yīng)。環(huán)七肽CP可有效地抑制小鼠異基因皮膚移植排斥反應(yīng),誘導(dǎo)出宿主對(duì)皮膚移植物的耐受;實(shí)驗(yàn)證實(shí)克隆不應(yīng)答、減少宿主體內(nèi)CD4+ T淋巴細(xì)胞的數(shù)目和抑制其功能、Th1型細(xì)胞因子偏移的糾正等機(jī)制參與了移植耐受的形成。以上的實(shí)驗(yàn)結(jié)果表明:環(huán)七肽CP以IL-2Rα模擬肽的方式發(fā)揮生物學(xué)效應(yīng),本研究為將其研制成一種高效、低毒、特異性強(qiáng)的小分子肽類免疫抑制劑奠定了基礎(chǔ)。
[Abstract]:Immunosuppressants play a key role in the prevention and treatment of organ transplantation rejection. It is considered that the best immunosuppressant should achieve at least three goals: selectivity, synergy and specificity. However, the current clinical use of immunosuppressants only partially meets these goals. In order to develop a novel peptide immunosuppressant, we used 5G1 monoclonal antibody against human IL-2R 偽 as target molecule to screen phage cyclopeptide library for five rounds. Five phage positive clones with high affinity to target molecule were obtained. The amino acid conserved sequence of IL-2R 偽 mimic epitope peptide was obtained by analyzing its DNA sequence: Lys-X- {X} -Lys-Gly. The cyclic heptapeptide CPS was prepared by chemical synthesis. Its amino acid sequence was: 1 Cys-Asn-Ala-Leu-Lys-Arg-Lys-Gly-Cys-Gly-Cys. the relative molecular weight was 990.2. CP is not toxic to spleen cells of normal mice. It was proved by computer simulation that the functional active sites of CP and IL-2 could form stable and good binding. Lymphocyte cycle assay, lymphocyte proliferation, delayed type hypersensitivity and local graft versus host reaction in vivo and in vitro confirmed that cyclopeptide CP had strong immunosuppressive activity. The inhibitory effect of cyclosporine A combined with cyclosporine A was significantly enhanced, indicating that the two had synergistic effect. Cyclopeptide CP can effectively inhibit allogeneic skin graft rejection in mice and induce host tolerance to skin grafts. The mechanism of decreasing the number of CD4 T lymphocytes and inhibiting the correction of Th1 type cytokine shift in host is involved in the formation of transplantation tolerance. The above results show that cyclic heptapeptide CP exerts biological effect on IL-2R 偽 mimic peptide. This study has laid a foundation for the development of a small molecular peptide immunosuppressant with high efficiency, low toxicity and strong specificity.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2007
【分類號(hào)】：R392.33

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