Abstract

The principal goal of this research is to develop antigen-specific immunotherapy for an autoimmune disease of skeletal muscle, myasthenia gravis (MG). Related goals are the definition of genetic factors influencing susceptibility to MG, and the immunologic mechanisms involved in effecting and suppressing the disease process. Antigenic determinants of nicotinic acetylcholine receptors (AChR) that are involved in the pathogenesis of MG will be defined using monoclonal antibodies. Antibodies produced by B-lymphocytes from MG patients hybridized with a suitable myeloma line should give direct information about determinants of AChR that are relevant to the pathogenesis of MG. The role of the thymus in MG will be a focus of our investigations, particularly the role of non-lymphoid thymic elements. The antigenicity of AChR in non-innervated muscle (such as is found in the thymus, the putative site where MG is initiated) will be compared with that of innervated muscle, and the antigenicity of thymus and oculobulbar muscle AChR (of putative neuroectodermal origin) will be compared with that of AChR in limbs (of mesodermal origin). The association between thymoma and autoimmunity to AChR will be investigated, both in patients with MG and in the thymoma-prone AKR/J strain of mouse, which has anomalous immune responsiveness to AChR.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS015057-09
Application #
3395930
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1978-05-01
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
9
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905

  Publications

Lennon, V A; Lambert, E H; Leiby, K R et al. (1991) Recombinant human acetylcholine receptor alpha-subunit induces chronic experimental autoimmune myasthenia gravis. J Immunol 146:2245-8
Griesmann, G E; McCormick, D J; Lennon, V A (1991) An avidin-biotin-peroxidase assay to detect synthetic peptides bound to polystyrene plates. J Immunol Methods 138:25-9
Brimijoin, S; Lennon, V A (1991) Selective destruction of preganglionic sympathetic nerves by antibodies to acetylcholinesterase. J Neural Transm Suppl 34:139-45
Griesmann, G E; McCormick, D J; De Aizpurua, H J et al. (1990) Alpha-bungarotoxin binds to human acetylcholine receptor alpha-subunit peptide 185-199 in solution and solid phase but not to peptides 125-147 and 389-409. J Neurochem 54:1541-7
Brimijoin, S; Lennon, V A (1990) Autoimmune preganglionic sympathectomy induced by acetylcholinesterase antibodies. Proc Natl Acad Sci U S A 87:9630-4
Brimijoin, S; Balm, M; Hammond, P et al. (1990) Selective complexing of acetylcholinesterase in brain by intravenously administered monoclonal antibody. J Neurochem 54:236-41
Lennon, V A; Griesmann, G E (1989) Evidence against acetylcholine receptor having a main immunogenic region as target for autoantibodies in myasthenia gravis. Neurology 39:1069-76
Lennon, V A; Huang, Z X; McCormick, D J et al. (1988) Synthetic peptide of human acetylcholine receptor alpha-subunit sequence 125-147 (methionine 144), a more potent autoantigen than its norleucine 144 analog. Ann N Y Acad Sci 540:516-9
McCormick, D J; Griesmann, G E; Huang, Z X et al. (1987) Myasthenogenicity of human acetylcholine receptor synthetic alpha-subunit peptide 125-147 does not require intramolecular disulfide cyclization. J Immunol 139:2615-9
Pascuzzi, R M; Phillips 2nd, L H; Johns, T R et al. (1987) The prevalence of electrophysiological and immunological abnormalities in asymptomatic relatives of patients with myasthenia gravis. Ann N Y Acad Sci 505:407-15

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