Chondrex膠原抗體誘導(dǎo)小鼠關(guān)節(jié)炎模型

膠原誘導(dǎo)性關(guān)節(jié)炎小鼠(CIA)作為人類類風(fēng)濕關(guān)節(jié)炎模型應(yīng)用廣泛,但CIA引起的關(guān)節(jié)炎起病比較緩慢，造模周期較長(zhǎng)，一般為6-8周(1-12)。Chondrex公司已開發(fā)出單一種單克隆抗體合劑誘導(dǎo)的小鼠關(guān)節(jié)炎模型（CAIA），明顯縮短了造模周期。與CIA相比，CAIA模型具有以下優(yōu)點(diǎn): (1)可在大多數(shù)小鼠上誘發(fā)關(guān)節(jié)炎，包括CIA不敏感的小鼠；(2)CAIA造模周期短，加速篩選和評(píng)估類風(fēng)濕性關(guān)節(jié)炎治療藥物；（3）應(yīng)用于轉(zhuǎn)基因小鼠來研究基因?qū)﹃P(guān)節(jié)炎發(fā)病的影響；（4）用于研究與人類類風(fēng)濕性關(guān)節(jié)炎相關(guān)的各種炎癥介質(zhì)和因素在疾病中的作用，例如細(xì)菌和病毒毒素（13-17）。

CAIA without LPS

膠原抗體誘導(dǎo)的關(guān)節(jié)炎（不加LPS）

CIA是由于自身抗體形成的免疫復(fù)合物通過激活補(bǔ)體而誘發(fā)關(guān)節(jié)炎癥，因此研究表明多克隆膠原蛋白抗體(8-19) 或單克隆膠原蛋白抗體合劑能誘發(fā)關(guān)節(jié)炎(20-21)。根據(jù)MHC類型，這些自身反應(yīng)性抗體可以識(shí)別位于小鼠II型膠原蛋白的CB11或者CB8片段中的特定抗原定簇（關(guān)節(jié)炎抗原表位）（22-23）。

Chondrex公司生產(chǎn)的能誘發(fā)小鼠關(guān)節(jié)炎的抗體合劑含有 ： A2-10 (IgG2a), F10-21 (IgG2a), D8-6 (IgG2a), D1-2G(IgG2b), and D2-112 (IgG2b). 其中兩個(gè)單克隆抗體（F10-21和D8-6）識(shí)別在LysC-2(291-374)的83個(gè)氨基酸肽段，該肽段有LysC內(nèi)切酶作用產(chǎn)生。 另外三個(gè)單克隆抗體（A2-10,D1-2G和D2-112） 能夠識(shí)別二型膠原蛋白CB11片段（124-402）中LysC-1(124-290)的167各氨基酸肽段（13）。這些抗原表位氨基酸序列在各種物種中具有高度保守性，包括雞，小鼠，大鼠，牛，豬，猴子和人 （20-21）。

CAIA with LPS

膠原抗體誘導(dǎo)的關(guān)節(jié)炎（加LPS）

研究表明，聯(lián)合注射低于致炎劑量的單克隆抗體合劑和大腸桿菌多脂（LPS）可誘發(fā)嚴(yán)重的小鼠關(guān)節(jié)炎（13）。通過胃腸道吸收的細(xì)菌毒素（如LPS）與低致炎水平的二型膠原自身抗體對(duì)引發(fā)關(guān)節(jié)炎有發(fā)協(xié)同作用（24）。這種模型相比于傳統(tǒng)CIA 模型有多重優(yōu)勢(shì)。第一，起病時(shí)間短，發(fā)病率高達(dá)100%。第二，可在大多數(shù)小鼠上誘導(dǎo)關(guān)節(jié)炎，包括CIA不敏感的小鼠，T細(xì)胞缺陷的小鼠，特定基因敲除變異的小鼠，詳情請(qǐng)見表二.

圖一顯示CIA模型和CAIA模型特點(diǎn)的比較。CAIA造模周期是CIA建模周期的十分之一。

圖一 CAIA vs. CIA: (a)三角形：100%的小鼠在LPS注射后24-48小時(shí)即可見關(guān)節(jié)炎發(fā)作，在第5-7天病情達(dá)到高峰。（b）圓形：CIA誘發(fā)小鼠關(guān)節(jié)炎模型一般需要4周起病，即使使用CIA易感品系，如DBA/1J和B10.RIII小鼠。

表二 關(guān)節(jié)炎炎癥程度的臨床評(píng)分

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