We have focused our studies on an analysis of the pathogenesis of Experimental Allergic Encephalomyelitis (EAE), an animal model for the human demyelinating disease, multiple sclerosis. The cytokine, IL-12, which is produced by monocytes and dendritic cells, has been shown to play a critical role in the generation of the subpopulation of T lymphocytes (T helper 1[Th1] cells) which mediate EAE. Our studies have demonstrated that the successful differentiation and/or function of autoimmune effector cells is dependent on their ability to respond to quantities of IL-12 that are available in the microenvironment during critical time points. The interleukin (IL)-12 receptor beta2 subunit is the key molecule involved in maintaining IL-12 responsiveness and controlling Th1 lineage commitment. Both IL-12 and interferon-gamma were shown to play separate as well as complementary roles in regulating IL-12 receptor beta2 expression on antigen-specific CD4+ T cells. The B10.S strain of mice is resistant to the development of EAE and was shown to have an antigen-specific defect in the expression of the IL-12 receptor beta2 subunit. Defective expression was secondary to a failure of the MBP-specific Th1 cells to express the membrane antigen, CD40 ligand, which is required for the T cell mediated induction of IL-12 production by macrophages/dendritic cells. IL-12 receptor expression as well as the capacity of Th1 cells from B10.S mice to induce EAE could be restored by the addition of IL-12. As these studies suggest that the development of immunotherapies that target the IL-12 receptor may be useful in the treatment of autoimmune diseases, we have initiated an extensive analysis of the regulation of IL-12 receptor expression by soluble factors and cell associated molecules. IL-18 was originally described as a cytokine which induced interferon- gamma production by established Th1 cells in an IL-12 independent manner. However, subsequent studies demonstrated that exogenous IL-18 in the absence of IL-12 failed to drive Th1 differentiation of na?ve T cells and induced interferon-gamma from established Th1 cells only in combination with IL-12. We have demonstrated that the primary effect of IL-18 on Th1 differentiation is mediated by its capacity to directly upregulate IL-12 receptor expression which thereby enhances IL-12 mediated signaling. The enhancement of IL-12 receptor expression by IL- 18 may be particularly important for the differentiation of foreign antigen- or autoantigen-specific Th1 cells when the stimulatory concentration of IL-12 in the microenvironment is just below the threshold required for Th1 development. The other major factors which we have identified as important in regulation of IL-12 receptor expression are costimulatory signals delivered to the antigen-specific T cells by interactions of the CD80/CD86 molecules on antigen presenting cells with CD28 on the T cell. We have demonstrated that costimulation is required for production of both IL-2 and IL-12 and that both of these cytokines are critical for the ability of T cells to express IL-12 receptors and to differentiate into pathogenic autoreactive T cells. - Autoimmune disease, multiple sclerosis, central nervous system, experimental allergic encephalomyelitis, T helper 1 lymphocytes

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000630-08
Application #
6288901
Study Section
Special Emphasis Panel (LI)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Mendel, Itzhak; Natarajan, Kannan; Ben-Nun, Avraham et al. (2004) A novel protective model against experimental allergic encephalomyelitis in mice expressing a transgenic TCR-specific for myelin oligodendrocyte glycoprotein. J Neuroimmunol 149:10-21
Segal, Benjamin M; Glass, Deborah D; Shevach, Ethan M (2002) Cutting Edge: IL-10-producing CD4+ T cells mediate tumor rejection. J Immunol 168:1-4
Mendel, Itzhak; Shevach, Ethan M (2002) The IL-10-producing competence of Th2 cells generated in vitro is IL-4 dependent. Eur J Immunol 32:3216-24
Smeltz, Ronald B; Chen, June; Ehrhardt, Rolf et al. (2002) Role of IFN-gamma in Th1 differentiation: IFN-gamma regulates IL-18R alpha expression by preventing the negative effects of IL-4 and by inducing/maintaining IL-12 receptor beta 2 expression. J Immunol 168:6165-72
Mendel, Itzhak; Shevach, Ethan M (2002) Differentiated Th1 autoreactive effector cells can induce experimental autoimmune encephalomyelitis in the absence of IL-12 and CD40/CD40L interactions. J Neuroimmunol 122:65-73
Smeltz, R B; Chen, J; Hu-Li, J et al. (2001) Regulation of interleukin (IL)-18 receptor alpha chain expression on CD4(+) T cells during T helper (Th)1/Th2 differentiation. Critical downregulatory role of IL-4. J Exp Med 194:143-53
Ortmann, R A; Shevach, E M (2001) Susceptibility to collagen-induced arthritis: cytokine-mediated regulation. Clin Immunol 98:109-18
Yap, G S; Ortmann, R; Shevach, E et al. (2001) A heritable defect in IL-12 signaling in B10.Q/J mice. II. Effect on acute resistance to Toxoplasma gondii and rescue by IL-18 treatment. J Immunol 166:5720-5
Ortmann, R; Smeltz, R; Yap, G et al. (2001) A heritable defect in IL-12 signaling in B10.Q/J mice. I. In vitro analysis. J Immunol 166:5712-9
Segal, B M; Chang, J T; Shevach, E M (2000) CpG oligonucleotides are potent adjuvants for the activation of autoreactive encephalitogenic T cells in vivo. J Immunol 164:5683-8

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