Open Access Highly Accessed Research

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

Alexander V Misharin1, G Kenneth Haines2, Shawn Rose1, Angelical K Gierut1, Richard S Hotchkiss3 and Harris Perlman1*

Author Affiliations

1 Department of Medicine/Rheumatology, Northwestern University, Feinberg School of Medicine, 240 East Huron Street, Room Chicago, IL 60611, USA

2 Department of Pathology, Yale University, School of Medicine, New Haven, CT 06510, USA

3 Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA

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Journal of Translational Medicine 2012, 10:190  doi:10.1186/1479-5876-10-190

Published: 13 September 2012

Abstract

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 IL2rγnull (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.

Keywords:
Humanized mouse; Leukocytes; Rheumatoid arthritis; Etanercept