Development of a new humanized mouse model to study acute inflammatory arthritis

Journal of Translational Medicine

Harris Perlman³  Richard S Hotchkiss¹  Angelical K Gierut³  Shawn Rose³  G Kenneth Haines²  Alexander V Misharin³ 

[1] Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA;Department of Pathology, Yale University, School of Medicine, New Haven, CT 06510, USA;Department of Medicine/Rheumatology, Northwestern University, Feinberg School of Medicine, 240 East Huron Street, Room Chicago, IL 60611, USA

关键词: Etanercept;    Rheumatoid arthritis;    Leukocytes;    Humanized mouse;   

Others  :  829578
DOI  :  10.1186/1479-5876-10-190

 received in 2012-06-29, accepted in 2012-09-10,  发布年份 2012

【 摘 要 】

Background

Substantial advances have been generated in understanding the pathogenesis of rheumatoid arthritis (RA). Current murine models of RA-like disease have provided great insights into the molecular mechanism of inflammatory arthritis due to the use of genetically deficient or transgenic mice. However, these studies are limited by differences that exist between human and murine immune systems. Thus, the development of an animal model that utilizes human immune cells, will afford the opportunity to study their function in the initiation and propagation of inflammatory arthritis.

Methods

One to two-day old irradiated NOD-scid IL2rγ^null (NSG) mice were reconstituted with human CD34+ cord blood stem cells. Leukocytes were analyzed by flow cytometry and circulating antibodies were determined by ELISA. Arthritis was induced by injecting complete Freund’s adjuvant into knee or ankle joints. Mice were also treated with the TNF inhibitor, Etanercept, or PBS and joints were analyzed histologically.

Results

Humanized mice were established with high reconstitution rates and were able to spontaneously produce human immunoglobulins as well as specific IgG in response to immunization. Intraperitoneal injection of thioglycolate or injection of complete Freund’s adjuvant into joints resulted in migration of human immune cells to the injected sites. Arthritic humanized mice treated with Etanercept had markedly less inflammation, which was associated with decreased total numbers of human CD45+ cells, including human lymphocytes and neutrophils.

Conclusions

The humanized mouse model is a new model to study inflammatory arthritis disease using human leukocytes without rejection of engrafted tissue. Future studies may adapt this system to incorporate RA patient cord blood and develop a chimeric animal model of inflammatory arthritis using genetically predisposed immune cells.

【 授权许可】

   
2012 Misharin et al.; licensee BioMed Central Ltd.

【 图 表 】

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