膠原誘導性關節炎小鼠(CIA)作為人類類風濕關節炎模型應用廣泛,但CIA引起的關節炎起病比較緩慢，造模周期較長，一般為6-8周(1-12)。Chondrex公司已開發出單一種單克隆抗體合劑誘導的小鼠關節炎模型（CAIA），明顯縮短了造模周期。與CIA相比，CAIA模型具有以下優點: (1)可在大多數小鼠上誘發關節炎，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濕性關節炎治療藥物；（3）應用于轉基因小鼠來研究基因對關節炎發病的影響；（4）用于研究與人類類風濕性關節炎相關的各種炎癥介質和因素在疾病中的作用，例如細菌和病毒毒素（13-17）。

CAIA without LPS

膠原抗體誘導的關節炎（不加LPS）

CIA是由于自身抗體形成的免疫復合物通過激活補體而誘發關節炎癥，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關節炎(20-21)。根據MHC類型，這些自身反應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（關節炎抗原表位）（22-23）。

Chondrex公司生產的能誘發小鼠關節炎的抗體合劑含有 ： 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內切酶作用產生。 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

膠原抗體誘導的關節炎（加LPS）

研究表明，聯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）可誘發嚴重的小鼠關節炎（13）。通過胃腸道吸收的細菌毒素（如LPS）與低致炎水平的二型膠原自身抗體對引發關節炎有發協同作用（24）。這種模型相比于傳統CIA 模型有多重優勢。第一，起病時間短，發病率高達100%。第二，可在大多數小鼠上誘導關節炎，包括CIA不敏感的小鼠，T細胞缺陷的小鼠，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小時即可見關節炎發作，在第5-7天病情達到高峰。（b）圓形：CIA誘發小鼠關節炎模型一般需要4周起病，即使使用CIA易感品系，如DBA/1J和B10.RIII小鼠。

表二 關節炎炎癥程度的臨床評分

引用文獻：

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).

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