The long-term objective of the proposal is to understand the immune mechanisms responsible for the relapsing episodes of paralysis which occur in patients with multiple sclerosis (MS). The debilitating paralysis of MS results from damage initiated by certain white blood cells (myelin-specific T lymphocytes) that have become harmful within the spinal cord. Following an episode of paralysis, a patient with MS may experience temporary remission or recovery from paralysis, which may in turn be followed by a relapse or worsening of the paralysis. Such a remitting/relapsing clinical course is often associated with a progression of the severity of the disease. Currently, there are few effective treatments available to MS patients (over 300,000 Americans). Experimental autoimmune encephalomyelitis (EAE), is an experimental autoimmune disease in laboratory rats and mice that is similar to MS. Studies in EAE suggest that initial episodes of paralysis and subsequent relapses may involve distinct clones of T lymphocytes, each specific for a distinct target (epitope) in the CNS. However, requirements of distinct, multiple clones of epitope-specific T cells in relapsing EAE have not been tested experimentally. Such information would benefit efforts to develop effective, specific immunosuppressive therapies since treatments designed to inhibit distinct T cell populations or clones are likely to be the most effective in MS if the targeted cells are actually required for the disease. For this proposal, EAE will be induced in T cell-deficient mice with single or multiple clones of myelin epitope-specific SJL or [SJL X SCID]F1 mouse T cells in order to define requirements for single and multiple clones of T cells in relapsing EAE.
In Aim 1, clones of myelin epitope-specific T cells will be generated and characterized.
In Aim 2, requirements for epitope-specific T cells in relapsing EAE will be defined by examining the course of disease induced with single or multiple T cell clones in lymphocyte deficient (SJLXSCID) mice.
In Aim 3, the in vivo function of T cells in the CNS will be assessed during disease.
| Robinson, Kristine M; Njus, Jeffrey M; Phillips, Daniel A et al. (2010) MR imaging of inflammation during myelin-specific T cell-mediated autoimmune attack in the EAE mouse spinal cord. Mol Imaging Biol 12:240-9 |
| Buenafe, Abigail C; Sherwood, Courtney; Moes, Nicole et al. (2009) Recombinase-activating gene 1-associated expression of the myelin basic protein 1-11-specific transgenic T-cell receptor in H-2b mice. J Neurosci Res 87:42-9 |
| Polanczyk, Magdalena J; Jones, Richard E; Subramanian, Sandhya et al. (2004) T lymphocytes do not directly mediate the protective effect of estrogen on experimental autoimmune encephalomyelitis. Am J Pathol 165:2069-77 |
| Jones, Richard E; Bourdette, Dennis; Moes, Nicole et al. (2003) Epitope spreading is not required for relapses in experimental autoimmune encephalomyelitis. J Immunol 170:1690-8 |
