HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, Y. Articles by Chen, J. Search for Related Content PubMed PubMed Citation Articles by Chen, Y. Articles by Chen, J.

Redirection of T Cell Effector Function In Vivo and Enhanced Collagen-Induced Arthritis Mediated by an IL-2R/IL-4R Chimeric Cytokine Receptor Transgene¹

Ying Chen^*, Ed Rosloniec, Mehmet I. Goral, Mark Boothby and Jin Chen^2,*

^* Division of Rheumatology, Departments of Medicine, Cell Biology, Pathology, and Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232; and Department of Internal Medicine, University of Tennessee, and The Research Service of the Veterans Administration Medical Center, Memphis, TN 38104

Chronic inflammatory autoimmune diseases such as diabetes, experimental autoimmune encephalomyelitis, and collagen-induced arthritis (CIA) are associated with type 1 (Th1, Tc1) T cell-dependent responses against autoantigens. Immune deviation toward type 2 (Th2, Tc2) response has been proposed as a potential means of gene therapy or immunomodulation to treat autoimmune diseases based on evidence that type 2 cytokines can prevent or alleviate these conditions. In this report we assessed the effects of elevated type 2 responses on CIA using transgenic mice expressing an IL-2R/IL-4R chimeric cytokine receptor transgene specifically in T cells. In response to IL-2 binding, this chimeric receptor transduces IL-4-specific signals and dramatically enhances type 2 responses. In contrast to published reports of Th2-mediated protection, CIA was exacerbated in IL-2R/IL-4R chimeric receptor transgenic mice, with increased disease incidence, severity, and earlier disease onset. The aggravated disease in transgenic mice was associated with an increase in type 2 cytokines (IL-4, IL-5, IL-10) and an increase in collagen-specific IgG1 levels. However, IFN- production is not affected significantly in the induction phase of the disease. There is also an extensive eosinophilic infiltration in the arthritic joints of the transgenic animal, suggesting a direct contribution of type 2 response to joint inflammation. Taken together, our findings provide novel evidence that enhancement of a polyclonal type 2 response in immunocompetent hosts may exacerbate an autoimmune disease such as CIA, rather than serving a protective role. This finding raises significant caution with regard to the potential use of therapeutic approaches based on immune deviation toward type 2 responses.

This article has been cited by other articles:

				L. Pace, S. Rizzo, C. Palombi, F. Brombacher, and G. Doria Cutting Edge: IL-4-Induced Protection of CD4+CD25- Th Cells from CD4+CD25+ Regulatory T Cell-Mediated Suppression J. Immunol., April 1, 2006; 176(7): 3900 - 3904. [Abstract] [Full Text] [PDF]

				N. Young, N. Mikhalkevich, Y. Yan, D. Chen, and W.-p. Zheng Differential Regulation of Osteoblast Activity by Th Cell Subsets Mediated by Parathyroid Hormone and IFN-{gamma} J. Immunol., December 15, 2005; 175(12): 8287 - 8295. [Abstract] [Full Text] [PDF]

				N. Takasawa, Y. Munakata, K. K. Ishii, Y. Takahashi, M. Takahashi, Y. Fu, T. Ishii, H. Fujii, T. Saito, H. Takano, et al. Human Parvovirus B19 Transgenic Mice Become Susceptible to Polyarthritis J. Immunol., October 1, 2004; 173(7): 4675 - 4683. [Abstract] [Full Text] [PDF]