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，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: (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). 其中兩個單克隆抗體（F10-21和D8-6）識別在LysC-2(291-374)的83個氨基酸肽段，該肽段有LysC內(nèi)切酶作用產(chǎn)生。 另外三個單克隆抗體（A2-10,D1-2G和D2-112） 能夠識別二型膠原蛋白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。第一，起病時間短，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，詳情請見表二.

圖一顯示CIA模型和CAIA模型特點的比較。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分

引用文獻(xiàn)：

1. E. Trentham, A. Townes, A. Kang, Autoimmunity to Type II Collagen an Experimental Model of Arthritis. J Exp Med. 146,857-68 (1977).

2. J. Courtenay, M. Dallman, A. Dayan, A. Martin, B. Mosedale,Immunisation Against Heterologous Type II Collagen Induces Arthritis in Mice. Nature. 283, 666-8 (1980).

3. S. Cathcart, K. C. Hayes, W. A. Gonnerman, A. A. Lazzari,C. Franzblau, Experimental Arthritis in a Nonhuman Primate. I.Induction by Bovine Type II Collagen. Lab Invest. 54, 26-31(1986).

4. P. Wooley, Collagen-induced arthritis in the mouse.Methods Enzymol 162, 361-373 (1988).

5. P. Wooley, H. Luthra, M. Griffiths, J. Stuart, A. Huse, C.David, et al., Type II Collagen-Induced Arthritis in Mice. IV.Variations in Immunogenetic Regulation Provide Evidence for Multiple Arthritogenic Epitopes on the Collagen Molecule. JImmunol. 135, 2443-51 (1985).

6. R. Holmdahl, L. Jansson, E. Larsson, K. Rubin, L.Klareskog, Homologous Type II Collagen Induces Chronic and Progressive Arthritis in Mice. Arthritis Rheum. 29, 106-13 (1986).

7. R. Ortmann, E. Shevach, Susceptibility to Collagen-Induced Arthritis: Cytokine-Mediated Regulation. Clin Immunol. 98, 109-18 (2001).

8. W. C. Watson, A. S. Townes, Genetic Susceptibility to Murine Collagen II Autoimmune Arthritis. Proposed Relationship to the IgG2 Autoantibody Subclass Response, Complement C5,Major Histocompatibility Complex (MHC) and non-MHC Loci. JExp Med. 162, 1878-91 (1985).

9. K. Campbell, J. A. Hamilton, I. P. Wicks, Collagen-induced Arthritis in C57BL/6 (H-2b) Mice: New Insights Into an Important Disease Model of Rheumatoid Arthritis. Eur J Immunol. 30, 1568-75 (2000).

10. E. Micha?lsson, V. Malmstr?m, S. Reis, A. Engstr?m, H.Burkhardt, R. Holmdahl, et al., T Cell Recognition of Carbohydrates on Type II Collagen. J Exp Med 180, 745-9(1994).

11. M. Andersson, R. Holmdahl, Analysis of Type II CollagenReactive T Cells in the Mouse. I. Different Regulation of Autoreactive vs. Non-Autoreactive Anti-Type II Collagen T Cells in the DBA/1 Mouse. Eur J Immunol 20, 1061-6 (1990).

12. R. Reife, N. Loutis, W. Watson, K. Hasty, J. Stuart, SWRMice Are Resistant to Collagen-Induced Arthritis but Produce Potentially Arthritogenic Antibodies. Arthritis Rheum. 34, 776-81

(1991).

13. K. Terato, D. Harper, M. Griffiths, D. Hasty, X. Ye, et al.,Collagen-induced Arthritis in Mice: Synergistic Effect of E. ColiLipopolysaccharide Bypasses Epitope Specificity in the Induction

of Arthritis With Monoclonal Antibodies to Type II Collagen.Autoimmunity 22, 137-47 (1995).

14. S. Yoshino, E. Sasatomi, Y. Mori, M. Sagai, Oral Administration of Lipopolysaccharide Exacerbates CollagenInduced Arthritis in Mice. J Immunol. 163, 3417-22 (1999).

15. B. Cole, M. Griffiths, Triggering and Exacerbation of Autoimmune Arthritis by the Mycoplasma Arthritidis Superantigen MAM. Arthritis Rheum. 36, 994-1002 (1993).

16. Y. Takaoka, H. Nagai, M. Tanahashi, K. Kawada,Cyclosporin A and FK-506 Inhibit Development of SuperantigenPotentiated Collagen-Induced Arthritis in Mice. Gen Pharmacol.30, 777-82 (1998).

17. T. Kagari, H. Doi and T. Shimozato. The importance of IL-1β and TNF-α, and the noninvolvement of IL-6, in the development of monoclonal antibody-induced arthritis. J Immunol 169,1459-1466 (2002).

20. K. Terato, K. Hasty, R. Reife, M. Cremer, A. Kang, J. Stuart,et al., Induction of Arthritis With Monoclonal Antibodies to Collagen. J Immunol 148, 2103-8 (1992).

21. P. Hutamekalin, T. Saito, K. Yamaki, N. Mizutani, D. Brand,et al., Collagen Antibody-Induced Arthritis in Mice: Development of a New Arthritogenic 5-clone Cocktail of Monoclonal Anti-Type II Collagen Antibodies. J Immunol Methods 343, 49-55 (2009).

22. K. Terato, K. A. Hasty, M. A. Cremer, J. M. Stuart, A. S.Townes, A. H. Kang, et al., Collagen-induced Arthritis in Mice.Localization of an Arthritogenic Determinant to a Fragment of the Type II Collagen Molecule. J Exp Med. 162, 637-46 (1985).

23. L. Myers, H. Miyahara, K. Terato, J. Seyer, A. Kang,Collagen-induced arthritis in B10.RIII mice (H-2r): identification of an arthritogenic T cell determinant. Immunol 84, 509-513 (1995).

更多資料或相關(guān)產(chǎn)品，請聯(lián)系Chondrex全國授權(quán)代理-欣博盛生物