The debilitating paralysis of multiple sclerosis (MS) results from damage initiated by certain white blood cells (myelin-specific T lymphocytes) within the central nervous system (CNS). Following an episode of paralysis, an MS patient may experience a 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 disease course is often associated with an overall progression in the severity of disease. MS patients may also experience disease progression without periods of remission. Current therapeutic approaches in MS are limited by an inadequate level of understanding regarding the cause of the disease. The objective of this proposal is to advance our understanding of the disease by identifying and defining cellular and/or molecular mechanisms responsible for disease progression. By revealing these mechanisms, it should be possible to identify new cellular or molecular targets for therapy. ? ? One mechanism has been proposed in which sequentially activated T lymphocyte clones specific for distinct target myelin epitopes are responsible for disease progression. Additional animal studies showed that multiple, distinct clones of epitope-specific T cells were not required for relapses and disease progression, suggesting that an additional mechanism is involved. Mechanisms of disease progression that do not depend upon T cell immune reactivity against multiple myelin epitopes remain largely unexplored. Preliminary results in an established animal model of MS showed that certain hematopoietic bone marrow-derived cells migrate to the CNS and promote disease progression. This proposal seeks to expose new potentially effective therapeutic targets by advancing our understanding of the mechanisms linking hematopoietic myelomonocytic lineage cells with disease progression in this established experimental animal model of MS, murine experimental autoimmune encephalomyelitis (EAE). The identification of new therapeutic targets represents one important initial approach for developing new effective treatment strategies in the future. ? ? Aim 1 will define minimal numbers of hematopoietic bone marrow-derived cells and T cells necessary for optimizing the experimental manipulations proposed for Aims 2 and 3.
Aim 2 will isolate and characterize distinct bone marrow cells responsible for promoting disease progression.
Aim 3 will evaluate the number and phenotype of regulatory T cells capable of blocking or reducing 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 |
