Treatment of autoimmune diseases by targeted DNA vaccines encoding proinflammatory mediators
Conceptually, gene therapy has been used as an efficient methodology to circum-vent genetic deficiency by transfection of cDNA encoding the appropriate functional gene product. It is therefore conceivable that best candidates for this way of therapy would be genetic diseases associated with a single-gene mutation, such as X-linked agammaglobulinemia or cystic fibrosis. Paradoxically, it appears that gene therapy needs to confront similar levels of technological challenges when encountering genetic disorders, such as X-linked agammaglobulinemia or cystic fibrosis, to those required for a successful intervention in multifactorial diseases. Yet, while genetic disorders that evolve a mutation in a single gene are rare, multifactorial diseases are a major cause of illness and death in the developed countries. This has motivated scientists to explore gene therapy strategies in multifactorial disorders. The current review discusses the use of a modification of gene therapy named DNA vaccination to suggest novel ways for interfering in the regulation of the inflammatory process in T-cell-mediated auto-immune diseases, such as multiple sclerosis (MS), rheumatoid arthritis (RA), and others.
KeywordsExperimental Autoimmune Encephalomyelitis Myelin Basic Protein Proinflammatory Mediator Immunol Today Experimental Autoimmune Enceph
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- Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, et al (1997) A new class of membrane-bound chemokine with a CX3C motif. Nature 385: 640–644 Ben-Nun A, Wekerle H, Cohen IR (1981a) The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol 11: 195–199Google Scholar
- Fukaura H, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Hafler DA (1996) Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta 1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J Clin Invest 98: 70–77PubMedCrossRefGoogle Scholar
- Karin N, Mitchell JD, Brocke S, Ling N, Steinman L (1994) Reversal of experimental autoimmune enceph-alomyelitis by as soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of IFN-g and TNF-a production. J Exp Med 180: 2227–2237PubMedCrossRefGoogle Scholar
- Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD (1995) An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated auto-immune disease, experimental autoimmune encephalomyelitis. J Immunol 155: 5003–5010PubMedGoogle Scholar
- Katz JD, Benoist C, Mathis D (1995) T helper subsets in insulin dependent diabetes. Science 268: 1185–1188 Khoruts A, Miller SD, Jenkins MK (1995) Neuroantigen-specific Th2 cells are inefficient suppressors of experimental autoimmune encephalomyelitis induced by effector Thl cells. J Immunol 155: 5011–5017Google Scholar
- Khoury SJ, Hancock WW, Weiner HL (1992) Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglan-din E expression in the brain. J Exp Med 176: 1355–1364Google Scholar
- Kim JJ, Ayyavoo V, Bagarazzi ML, Chattergoon MA, Dang K, Wang B, et al (1997a) In vivo engineering of a cellular immune response by coadministration of IL-12 expression vector with a DNA immunogen. J Immunol 158: 816–826Google Scholar
- Wildbaum G, Youssef S, Karin N (2000b) A targeted DNA vaccine augments the natural immune response to self TNF-alpha and suppresses ongoing adjuvant arthritis. J Immunol 165: 5860–5866Google Scholar