Multiple sclerosis (MS) remains the major disabling neurological illness of young adults. The consensus that MS is a T cell mediated, organ specific autoimmune disease has led to the clinical use of various immunomodulatory therapies, systemic IFN beta being the best characterized and most utilized at present. Unfortunately, while IFN beta clearly has the potential to modify the clinical course of MS, the effect is partial and not curative. Furthermore, the relevant mechanism(s) of action of IFN beta in MS remain obscure, hindering both the search for more effective therapies as well as a better understanding of the immunopathogenesis. IL-12, a cytokine central to the generation of cell mediated immune responses, is critical to the pathogenesis of experimental autoimmune encephalomyelitis, the primary experimental surrogate for MS. Further there is compelling evidence relating IL-12 production to disease activity and progression in MS itself. These investigators have found that IFN beta potently suppresses the production of IL-12 by human monocyte/macrophages. The central hypothesis underlying these studies is that a principal mechanism of action of therapeutic IFN beta in MS is the suppression of IL-12 production. The ultimate goal of this research is to use knowledge of the molecular mechanisms underlying IFN beta mediated alterations in IL-12 responses to devise novel therapeutic strategies for MS. The studies in this application aim to further characterize the effects of therapeutic IFN beta on in vivo and ex vivo IL-12 production and to characterize, in vitro, the molecular mechanisms responsible for IFN beta-mediated suppression of IL-12 production.
| Tripathi, Pulak; Madan, Rajat; Chougnet, Claire et al. (2006) An adenoviral vector for probing promoter activity in primary immune cells. J Immunol Methods 311:19-30 |
| Atabani, Sowsan F; Thio, Chloe L; Divanovic, Senad et al. (2005) Association of CTLA4 polymorphism with regulatory T cell frequency. Eur J Immunol 35:2157-62 |
| Wysocka, Maria; Montaner, Luis J; Karp, Christopher L (2005) Flt3 ligand treatment reverses endotoxin tolerance-related immunoparalysis. J Immunol 174:7398-402 |
| Byrnes, Adriana A; McArthur, Justin C; Karp, Christopher L (2002) Interferon-beta therapy for multiple sclerosis induces reciprocal changes in interleukin-12 and interleukin-10 production. Ann Neurol 51:165-74 |
| Byrnes, A A; Ma, X; Cuomo, P et al. (2001) Type I interferons and IL-12: convergence and cross-regulation among mediators of cellular immunity. Eur J Immunol 31:2026-34 |
