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Published online before print October 21, 2005

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(Journal of Leukocyte Biology. 2006;79:140-146.)
© 2006 by Society for Leukocyte Biology

Latent TGF-ß1-transduced CD4⁺ T cells suppress the progression of allergic encephalomyelitis

Mitsuyuki Murano^*,1, Xiaozhong Xiong^*,1, Naoko Murano^*, James L. Salzer, Juan J. Lafaille^* and Vincent K. Tsiagbe^*,2

^* Departments of Pathology and NYU Cancer Institute and
Cell Biology, New York University School of Medicine, New York

² Correspondence: New York University School of Medicine, Department of Pathology, Room 538 MSB, 550 First Avenue, New York, NY 10016. E-mail: tsiagv01{at}med.nyu.edu

Systemic injection of small amounts of transforming growth factor-ß (TGF-ß), a cytokine produced by lymphoid and other cells, has a profound effect in protecting mice from the inflammatory demyelinating lesions of experimental allergic encephalomyelitis (EAE; an animal model for multiple sclerosis). However, TGF-ß has side-effects, which might be avoided if the cells producing TGF-ß can be delivered to the affected site in the nervous system to insure its local release in small amounts. Myelin basic protein (MBP)-specific, cloned CD4⁺ T cells were engineered by retroviral transduction to produce latent TGF-ß. Studies about the spontaneous form of EAE in T cell receptor (TCR)-transgenic recombination-activating gene (RAG)-1^–/– mice showed that essentially all of the MBP-specific, TCR-transgenic RAG-1^–/– (BALB/cxB10.PL)F1 mice develop spontaneous EAE by the age of 11 weeks. By 12 weeks, 25–50% of the mice have died from disease. A single injection of TGF-ß1-transduced T helper cell type 1 (Th1) cells significantly protected the mice from EAE, and untransduced Th1 cells did not protect. MBP-specific BALB/c Th2 clones, transduced with TGF-ß1-internal ribosome entry site-green fluorescent protein (GFP) significantly reduced EAE induction by untransduced Th1 cells in RAG-1^–/– B10.PL mice. Furthermore, the GFP⁺ TGF-ß1-producing Th2 cells were detectable in the spinal cords of the injected mice.

Key Words: cytokines • gene therapy • multiple sclerosis