The focus of our research is to investigate the mechanisms involved in the regulation of antigen presentation and T cell activation in the central nervous system (CNS) autoimmune disease model, experimental autoimmune encephalomyelitis (EAE), and to apply this knowledge to the development of new treatments for multiple sclerosis (MS). Molecular, cellular, and both in vivo transgenic and knock-out approaches are utilized in our work.
EAE is a model for MS and is mediated by pathogenic CD4+ T cells (Th1 cells) that recognize myelin target proteins only in association with MHC class II molecules expressed on antigen presenting cells (APC). Our primary goal has been to understand MHC class II gene regulation and the role of antigen processing by CNS APC in the activation of encephalitogenic Th1 cells. The MHC class II transactivator (CIITA), a transcriptional co-activator, is considered the master regulator for class II expression and also controls the expression of invariant chain (Ii) and H-2M (HLA-DM), two molecules required for class II maturation and antigen processing. Using transgenic approaches to target CIITA gene expression and radiation bone marrow chimera techniques, we are evaluating the importance of different APC in CNS antigen processing and presentation. In our previous work, we have evaluated the role of astrocytes as APC in EAE (Stuve, et al. J. Immunol. 2002). We have recently generated separate lines of transgenic mice to evaluate the individual roles of monocytes/macrophages, dendritic cells and B cells as APC in EAE.
The EAE model is useful for preclinical testing of potential therapies in MS. My laboratory has been studying how cholesterol-lowering HMG-CoA reductase inhibitors ("statins") can be used to treat EAE. We observed that oral atorvastatin (Lipitor) could prevent or reverse chronic and relapsing EAE. Atorvastatin treatment induced the differentiation of protective Th2 regulatory cells and inhibited CIITA-inducible MHC class II expression in the CNS and suppressed upregulation of costimulatory molecules (Youssef, et al., Nature 2002). Based primarily upon these observations, we are conducting a multicenter placebo-controlled clinical trial to test whether Lipitor treatment is beneficial in early MS. My laboratory is continuing to investigate immunoregulatory mechanisms of statin treatment on APC and T cell activation. We are primarily focusing on isoprenoid intermediates in the mevalonate pathway and how statins influence isoprenylation of GTP binding proteins (e.g. ras, rho and rac) and how this influences T cell differentiation. We are also testing how statins may be used in combination to enhance the immunomodulatory activity of approved and novel agents for treatment in MS.
We have recently demonstrated that anti-inflammatory “type II” monocytes can adoptively transfer protection in the EAE model, reversing paralysis and inducing Th2 and Treg cells in recipient mice, while inhibiting Th17 and Th1 responses (Weber, M.S., et al. Nat. Med. 2007). A current focus is to identify the pathway(s) responsible for type II monocyte differentiation and to characterize molecules expressed by these APC that are responsible for induction of regulatory T cells in vivo.