Prevention of experimental allergic encephalomyelitis by intramuscular gene transfer with cytokine-encoding plasmid vectors.
Antiinflammatory cytokines such as transforming growth factor beta1 (TGF-beta1) and interleukin 4 (IL-4) can protect from autoimmune diseases. To study the immunoregulatory effects of these cytokines in vivo, we used a method of gene therapy that permits continuous cytokine delivery over a period of weeks. We injected naked plasmid DNA expression vectors encoding either TGF-beta1 (pVR-TGF-beta1) or an IL-4-IgG1 chimeric protein (pVR-IL-4-IgG1) intramuscularly. This resulted in production of TGF-beta1 or IL-4-IgG1, respectively, and protection from myelin basic protein (MBP)-induced experimental allergic encephalomyelitis (EAE). TGF-beta1 gene delivery had pronounced downregulatory effects on T cell proliferation and production of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha), on in vitro restimulation with MBP. IL-4-IgG1 vector administration also suppressed these responses, although much less than TGF-beta1, and enhanced secretion of endogenous IL-4. Therapy resulted in a significant decrease in the severity of histopathologic inflammatory lesions. In the CNS, treatment with either vector suppressed IL-12 and IFN-gamma mRNA expression, while IL-4 and TGF-beta1 mRNA levels were increased compared with control mice. Thus, cytokine plasmid treatment appeared to inhibit MBP-specific pathogenic Thl responses, while enhancing endogenous secretion of protective cytokines. We demonstrate that gene therapy with these vectors is an effective therapeutic strategy for EAE.
Piccirillo
C A
CA
Department of Pathology and Center for Clinical Immunobiology and Transplantation, McGill University, Montreal, Quebec, Canada.
Prud'homme
G J
GJ
D000818:Animals; D016207:Cytokines / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D007273:Injections, Intramuscular; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D004676:Myelin Basic Protein / Q000009:adverse effects; D010957:Plasmids / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D007074:Immunoglobulin G; D004676:Myelin Basic Protein; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D015847:Interleukin-4