国产区av中文字幕在线观看-熟女一区二区三区另类激情-免费观看美女无遮挡喷水网站-中日乱码精品一区二区三区软件

技術(shù)文章您現(xiàn)在的位置:首頁 > 技術(shù)文章 > Chondrex膠原抗體誘導(dǎo)小鼠關(guān)節(jié)炎模型

Chondrex膠原抗體誘導(dǎo)小鼠關(guān)節(jié)炎模型

更新時(shí)間:2023-08-14   點(diǎn)擊次數(shù):389次

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(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。

膠原抗體誘導(dǎo)小鼠關(guān)節(jié)炎模型

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

得分發(fā)病情況
0Normal 正常
1Mild, but definite redness and swelling of the ankle or wrist, or apparent redness and swelling limited to individual digits, regardless of the number of affected digits 輕度的、踝關(guān)節(jié)、腕關(guān)節(jié)發(fā)紅、腫脹
2Moderate redness and swelling of ankle or wrist 踝關(guān)節(jié)或腕關(guān)節(jié)中度發(fā)紅腫脹
3Severe redness and swelling of the entire paw including digits 爪子嚴(yán)重發(fā)紅、腫脹,包括指端
4Maximally inflamed limb involving multiple joints 四肢最-大-程-度發(fā)炎,包括多關(guān)節(jié)


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(qǐng)聯(lián)系Chondrex全國授權(quán)代理-欣博盛生物