Myasthenia gravis (MG), which is by far the most common clinical disorder of the neuromuscular junction, is due to an antibody-mediated autoimmune attack against acetylcholine receptors (AChRs). The major challenge in MG is to use the detailed knowledge of its pathogenesis to design immunotherapeutic strategies that will a) specifically eliminate the anti-AChR autoimmune responses; b) have long-lasting effects, and c) eventually be applicalbe to human MG: We will develop and test a series of novel strategies for specific immunotherapy in the experimental model of myasthenia gravis in the rat (EAMG). 1) We will induce and propagate AChR-specific suppressor T lymphocytes, using two approaches that have already been successful in preliminary experiments in our hands: a) incubation with lymphocytes from EAMG rats with Cyclosporin A (CsA) plus AChR in vitro, b) incubation of lymphocytes from EAMG rats syngeneic lymphocytes with covalently coupled AChR. The suppressor cells induced by these methods, or soluble suppressor factors produced by them, will first be tested in a cell culture system, and then will be used to treat rats with EAMG. 2) We will attempt to treat EAMG by immunizing rats with a pure population of AChR-sensitized lymphoblasts. This method induces a powerful and broad spectrum anti-idiotypic reaction that should down-regulate the anti-AChR immune response. 3) We will use the promising method of """"""""total lymphoid irradiation"""""""" (TLI) to attempt to induce long lasting and specific suppression of the anti-AChR response in animals with EAMG. ULtimately, the mehtods developed in this model system should be applicable to the treatment of human MG, and other autoimmune neuromuscular disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS023719-05
Application #
3407513
Study Section
Neurology C Study Section (NEUC)
Project Start
1986-07-01
Project End
1993-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
McIntosh, K R; Drachman, D B (1999) Induction of apoptosis in activated T cell blasts by suppressive macrophages: a possible immunotherapeutic approach for treatment of autoimmune disease. Cell Immunol 193:24-35
McIntosh, K R; Linsley, P S; Bacha, P A et al. (1998) Immunotherapy of experimental autoimmune myasthenia gravis: selective effects of CTLA4Ig and synergistic combination with an IL2-diphtheria toxin fusion protein. J Neuroimmunol 87:136-46
Drachman, D B; Okumura, S; Adams, R N et al. (1996) Oral tolerance in myasthenia gravis. Ann N Y Acad Sci 778:258-72
McIntosh, K R; Linsley, P S; Drachman, D B (1995) Immunosuppression and induction of anergy by CTLA4Ig in vitro: effects on cellular and antibody responses of lymphocytes from rats with experimental autoimmune myasthenia gravis. Cell Immunol 166:103-12
Drachman, D B (1994) Myasthenia gravis. N Engl J Med 330:1797-810
Okumura, S; McIntosh, K; Drachman, D B (1994) Oral administration of acetylcholine receptor: effects on experimental myasthenia gravis. Ann Neurol 36:704-13
Abu-Shakra, S R; Cole, A J; Adams, R N et al. (1994) Cholinergic stimulation of skeletal muscle cells induces rapid immediate early gene expression: role of intracellular calcium. Brain Res Mol Brain Res 26:55-60
Drachman, D B; McIntosh, K R; Reim, J et al. (1993) Strategies for treatment of myasthenia gravis. Ann N Y Acad Sci 681:515-28
Kuncl, R W; Wittstein, I; Adams, R N et al. (1993) A novel therapy for myasthenia gravis by reducing the endocytosis of acetylcholine receptors. Ann N Y Acad Sci 681:298-302
Freimer, M L; McIntosh, K; Adams, R A et al. (1993) Gangliosides elicit a T-cell independent antibody response. J Autoimmun 6:281-9

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