DESCRIPTION Myasthenia gravis (MG) is a disease manifested by muscle weakness and exaggerated fatigue due to impaired signal transduction at the neuromuscular junction. This dysfunction is caused by the action of high-affinity IgG antibodies directed against the nicotinic acetylcholine receptor (AChR) on the post-synaptic membrane. Autoantibody production is presumed to be driven by CD4+ helper T lymphocytes. In an animal model of MG (EAMG) induced by immunization with AChR, the activation of AChR-specific T cells is critical. Responding T cells show limited T cell receptor (TCR) V segment usage and CDR3 sequence homologies. The importance of these studies derives from the potential for immune-based intervention with novel specific immunosuppressive therapy in human autoimmune disease. MG is often considered a primary candidate for initial trials of such therapy. If the T cell response to AChR can be defined the transition to human intervention trials could be straightforward. In addition, information on TCR expression in MG may help to understand the pathogenesis of this illness, which is currently obscure. Despite restricted expression anti-TCR based therapy has so far been ineffective in preventing disease in EAMG. In order to explain this lack of success and to determine whether anti-TCR strategies are applicable to human MG, three specific aims are proposed for further study. In aim 1, the conventional EAMG model will be probed for additional T cell populations involved in pathogenesis. In aim 2, a new model in which mice express human MG-associated HLA-DR3 molecules will be characterized for TCR usage in response to AChR. In aim 3, the TCR repertoire of MG patients will be studied by novel PCR-based techniques known collectively as spectratyping. Upon completion of these aims, a much clearer picture of the role of T cells in pathogenesis and the potential for specific immunotherapy in MG should be available.
|Effective start/end date||8/8/97 → 5/31/01|
- National Institutes of Health: $160,262.00
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