Latent TGF-beta1-transduced CD4+ T cells suppress the progression of allergic encephalomyelitis.
Systemic injection of small amounts of transforming growth factor-beta (TGF-beta), 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-beta has side-effects, which might be avoided if the cells producing TGF-beta 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-beta. 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-beta1-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-beta1-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-beta1-producing Th2 cells were detectable in the spinal cords of the injected mice.
Murano
Mitsuyuki
M
Department of Pathology, NYU Cancer Institute, School of Medicine, New York, NY, USA.
Xiong
Xiaozhong
X
Murano
Naoko
N
Salzer
James L
JL
Lafaille
Juan J
JJ
Tsiagbe
Vincent K
VK
D019264:Adoptive Transfer; D000818:Animals; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000628:therapy; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000637:transplantation; D018418:Th2 Cells / Q000276:immunology; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D053773:Transforming Growth Factor beta1
D018398:Homeodomain Proteins; D004676:Myelin Basic Protein; D011948:Receptors, Antigen, T-Cell; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C064658:RAG-1 protein