Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and maturation. EAE is used as a model for the study of multiple sclerosis (MS). In this model, antigen-specific CD4+ Th1 cells mediate inflammatory damage in the central nervous system (CNS). A growing body of evidence suggests that Notch signaling plays an integral role in the peripheral maturation of CD4+ T cells. Examination of the role of Notch in murine antigen specific autoimmune encephalomyelitis has led us to the observation that Notch signaling is involved in the initiation of the disease in a ligand-dependent manner and that Jaggedl and Jagged2 play an immuno-regulatory role in the periphery. This proposal outlines molecular and cellular methods for studying the role of Notch signaling in encephalomyelitis. The major goal of this project is to identify and characterize Notch ligand(s) involvement in tolerance. This project will lead to the use of fusion proteins and monoclonal antibody therapy approaches to investigate tolerance strategies in vivo. Therapeutic opportunities that could arise from the manipulation of Notch signaling in immune disorders such as autoimmunity, cancer immunotherapy and transplantation, may prove to be a novel approach to suppress aberrant immune activation.
|Bassil, Ribal; Zhu, Bing; Lahoud, Youmna et al. (2011) Notch ligand delta-like 4 blockade alleviates experimental autoimmune encephalomyelitis by promoting regulatory T cell development. J Immunol 187:2322-8|
|Bradshaw, Elizabeth M; Raddassi, Khadir; Elyaman, Wassim et al. (2009) Monocytes from patients with type 1 diabetes spontaneously secrete proinflammatory cytokines inducing Th17 cells. J Immunol 183:4432-9|
|Elyaman, Wassim; Kivisakk, Pia; Reddy, Jay et al. (2008) Distinct functions of autoreactive memory and effector CD4+ T cells in experimental autoimmune encephalomyelitis. Am J Pathol 173:411-22|
|Elyaman, Wassim; Bradshaw, Elizabeth M; Wang, Yue et al. (2007) JAGGED1 and delta1 differentially regulate the outcome of experimental autoimmune encephalomyelitis. J Immunol 179:5990-8|