Animal Care and Diet
動(dòng)物飼養(yǎng)條件和飲食
建立CAIA模型需要選擇7-8周齡小鼠。老齡鼠的發(fā)病率和病情嚴(yán)重程度較低。建議在無(wú)特定病原體(SPF級(jí)別)條件下飼養(yǎng)動(dòng)物,因?yàn)榧?xì)菌感染會(huì)降低宿主的免疫應(yīng)答,從而減輕關(guān)節(jié)炎癥。腸道菌群會(huì)影響宿主免疫系統(tǒng)對(duì)LPS 的易感性。LPS甚至?xí)鹉承?duì)LPS超級(jí)易感品系的小鼠致死。Chondrex公司建議在開(kāi)展實(shí)驗(yàn)前先測(cè)試實(shí)驗(yàn)用小鼠對(duì)LPS的易感性。盡管飲食影響可以不用考慮,但是Chondrex公司建議飼喂高脂肪食物,研究表明高脂肪食物更容易引發(fā)炎癥 (4)。
Mouse Strains
小鼠品系
注射抗二型膠原單克隆抗體合劑可以繞過(guò)宿主生成抗二型膠原自身抗體的需求,所以可以誘發(fā)MHC (例如H-2q和H-2r)缺陷的小鼠產(chǎn)生關(guān)節(jié)炎.所有能產(chǎn)生正常炎癥反應(yīng)和補(bǔ)體激活的小鼠品系都應(yīng)該對(duì)CAIA敏感。
圖一為目前為止測(cè)試過(guò)的小鼠品系。
DBA/1 (H-2q) and B10.RIII (H-2r) 小鼠對(duì)CIA和CAIA均有較高的敏感性(13)。
BALB/c (H-2d) 小鼠對(duì)CIA具有抗性,但對(duì)CAIA有較高敏感性,是目前最常用的品系(25-27)。
T細(xì)胞缺陷的C.B-17 scid/scid 小鼠可用于CAIA,因?yàn)樵谘装Y發(fā)生的過(guò)程中,不需要T細(xì)胞識(shí)別抗原來(lái)產(chǎn)生抗體(17)。這中品系小鼠相比正常T細(xì)胞的小鼠,會(huì)產(chǎn)生更嚴(yán)重的關(guān)節(jié)炎癥, T細(xì)胞在愈合過(guò)程中有調(diào)節(jié)炎癥的作用。
SWR(H-2q)小鼠具有CIA易感基因型,但由于C5缺陷,對(duì)CIA 和CAIA具有抗性。 其他C5缺陷小鼠,例如B10.D2/oSn 和 NOD/LtSz scid/scid 對(duì) CAIA 具 有 抗 性(12,19,27).
盡管裸大鼠對(duì)CAIA具有高易感性, 裸小鼠對(duì)CAIA具有抗性(29)。裸小鼠可能缺乏特定的促炎細(xì)胞因子的表達(dá)。
圖一-用于膠原 CIA 及 膠原蛋白抗體誘導(dǎo)(CAIA )的關(guān)節(jié)炎動(dòng)物模型研究的常用小鼠品系
*需要含結(jié)核桿菌的CFA佐劑誘導(dǎo)關(guān)節(jié)炎
C57BL/6小鼠是轉(zhuǎn)基因小鼠模型中最常用的品系。盡管C57BL/6小鼠對(duì)LPS不敏感,但CAIA聯(lián)合LPS 會(huì)使這些小鼠產(chǎn)生嚴(yán)重的關(guān)節(jié)炎癥。在這種品系的小鼠中建模需要使用高劑量單克隆抗體合劑,每只小鼠需要5mg(21,30).C57BL/6 與129/Sy小鼠雜交用于建立基因敲除小鼠。一些雜交小鼠會(huì)對(duì)LPS有應(yīng)答,所以1.5mg每只小鼠的劑量一會(huì)產(chǎn)生嚴(yán)重的關(guān)節(jié)炎癥(30-31) 。
以下基因敲除小鼠用于基因?qū)AIA模的影響 (29-39).
1) NOS2 knockout mice (30)
2) Osteopontin knockout mice (31)
3) COX-1 and COX-2 knockout mice (32)
4) MMP-2 (gelatinase A) and MMP-3 (gelatinase B) knockout
mice (33)
5) P2X7 receptor knockout mice (34)
6) c-Jun N-Terminal Kinase knockout mice (35)
7) Prostaglandin E2 receptor knockout mice (36)
8) CD69 null mice (37)
相關(guān)文獻(xiàn):
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13. K. Terato, D. Harper, M. Griffiths, D. Hasty, X. Ye, et al.,Collagen-induced Arthritis in Mice: Synergistic Effect of E. Coli Lipopolysaccharide Bypasses Epitope Specificity in the Induction of Arthritis With Monoclonal Antibodies to Type II Collagen.Autoimmunity 22, 137-47 (1995).
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27. S Larox, J. Fuseler, D. Merril, L. Gray, R. Reife, K. Terato,et al. #301 A novel model of polyarthritis induced in mice using monoclonal antibodies to type II collagen. Characterization and
effects of chemically modified tetracycline. Arthritis Rheum 42:s121 (supplement).
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30. H. Kato, K. Nishida, A. Yoshida, I. Takada, C. McCown, et al., Effect of NOS2 Gene Deficiency on the Development of Autoantibody Mediated Arthritis and Subsequent Articular Cartilage Degeneration. J Rheumatol. 30, 247-55 (2003).
31. K. Yumoto, M. Ishijima, S. Rittling, K. Tsuji, Y. Tsuchiya, et al., Osteopontin Deficiency Protects Joints Against Destruction in Anti-Type II Collagen Antibody-Induced Arthritis in Mice. Proc Natl Acad Sci U S A 99, 4556-61 (2002).
32. L. Myers, A. Kang, A. Postlethwaite, E. Rosloniec, S. Morham, et al., The Genetic Ablation of Cyclooxygenase 2 Prevents the Development of Autoimmune Arthritis. Arthritis Rheum 43, 2687-93 (2000).
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34. J. Labasi, N. Petrushova, C. Donovan, S. McCurdy, P. Lira,et al., Absence of the P2X7 Receptor Alters Leukocyte Function and Attenuates an Inflammatory Response. J Immunol 168,6436-45 (2002).
35. Z. Han, L. Chang, Y. Yamanishi, M. Karin, G. Firestein, Joint Damage and Inflammation in c-Jun N-terminal Kinase 2 Knockout Mice With Passive Murine Collagen-Induced Arthritis. Arthritis Rheum 46, 818-23 (2002).
36. J. McCoy, J. Wicks, L. Audoly, The Role of Prostaglandin E2 Receptors in the Pathogenesis of Rheumatoid Arthritis. J Clin Invest 110, 651-8 (2002).
37. R. Newton, K. Solomon, M. Covington, C. Decicco, P. Haley, et al., Biology of TACE Inhibition. Ann Rheum Dis 60 Suppl 3, 25-32 (2001).
38. R. Holmdahl, L. Jansson, M. Andersson, E. Larsson,Immunogenetics of Type II Collagen Autoimmunity and
Susceptibility to Collagen Arthritis. Immunology. 65, 305-10(1988).
39. S. Thornton, G. Boivin, K. Kim, F. Finkelman, R. Hirsch, Heterogeneous Effects of IL-2 on Collagen-Induced Arthritis. J Immunol 165, 1557-63 (2000).
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