Specific Aims Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that affects an estimated 1 million Americans1. The cause of MS is unknown, there is no cure, and the current therapies have limited efficacy. My laboratory focuses on identifying molecules critical to the pathogenicity of encephalitogenic T cells. Since the CNS is an immune-privileged tissue and immunological surveillance is limited, we hypothesize that encephalitogenic T cells express unique molecules that enhance their encephalitogenic capacity, which are distinct from the CD4 T cells that protect us from infection, and that these molecules may be therapeutic targets for MS. The goal of this study is to identify molecular targets in encephalitogenic effector CD4 T cells that could be therapeutically manipulated to minimize the differentiation of encephalitogenic T cells, as well as extinguish or anergize established encephalitogenic T cells, while sparing pathogen-specific CD4 T cells. We hypothesize that encephalitogenic T cells, regardless of whether they are Th1 or Th17, share specific molecular pathways that can be therapeutically targeted to halt progression of CNS autoimmunity.
Aim 1 : Determine the role of genes differentially expressed in both encephalitogenic Th1 and Th17 cells.
Aim 2 : Analyze the validity of encephalitogenic molecules as MS-specific therapeutic targets with minimal immune compromise. The role that these encephalitogenic-associated molecules play in the generation and/or function of encephalitogenic T cells will be determined in both mouse and human CD4 T cells, as well as whether there is a differential role of these molecules in pathogenic versus protective T cells. Many studies have focused on the differentiation of encephalitogenic T cells, but far fewer studies have analyzed the unique characteristics of encephalitogenic effector/memory T cells in MS. This data will help identify therapeutic targets in newly differentiating encephalitogenic T cells to limit the generation of potentially pathogenic T cells in MS. Importantly, this study will also identify molecules that are critical to the function of encephalitogenic effector/memory CD4 T cells that may be contributing to disease progression and may be less vulnerable to therapies that target T cell differentiation or specific T cell subsets. This study is novel in that the focus is on T cell encephalitogenicity, irrespective of whether the T cells have a Th1 or Th17 phenotype. Furthermore, this study will compare protective versus pathogenic CD4 T cell responses in MS patients to identify therapeutic targets that would not compromise protection to infections.
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that causes progressive neurological deficits, affecting 1 million people in the USA with an annual cost of exceeding $20 billion. The prevalence and incidence of MS are on the increase worldwide, necessitating strategies to prevent MS. This study will define unique characteristics of the pathogenic cells in MS to advance the development of specific therapies.
