PATHOGENIC MECHANISMS IN MYASTHENIA

Project: Research project

Description

Myasthenia gravis (MG) and its animal model, experimental autoimmune
myasthenia gravis (EAMG) are T-cell-dependent antibody (Ab)-mediated
autoimmune disease directed at the acetylcholine receptor (AChR) in the
endplate membrane of the neuromuscular junction (NMJ). Three pathogenic
mechanisms by which the Abs induce the characteristic abnormalities at the
NMJ have been proposed from studies of EAMG and MG: complement-mediated
endplate membrane destruction increased AChR turnover by Ab crosslinking of
adjacent AChRs, and functional blockage of intact AChRs. Our previous
studies and those from other laboratories have suggested the hypothesis
that the major mechanism is complement-mediated endplate membrane
destruction. To test this hypothesis-syngeneic recombinant/chimeric
(rec/chi) Abs will be produced from our library of rat anti-AChR monoclonal
Abs, which have been engineered to have reduced or absent complement
activating activity, but to retain the functions associated with the other
two possible pathogenic mechanisms. These rec/chi Abs will be analyzed in
vitro for their antigen binding and their effector functions and in vivo
for their ability to induce the passively-transferred form of EAMG in
syngeneic rats. Rec/chi Abs that are incapable of inducing EAMG will be
tested, singly or in combination, for their ability to bock both passively-
and actively-induced EAMG. Abs of this type will potentially represent a
new antigen-specific treatment of MG. Therefore, similar human autologous
rec/chi Abs will developed from anti-AChR B cells obtained from patients
with MG, and their effector functions analyzed in vitro.
StatusFinished
Effective start/end date7/1/846/30/97

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Myasthenia Gravis
Monoclonal Antibodies
Cholinergic Receptors
Antibodies
Autoimmune Diseases
Autoimmune Experimental Myasthenia Gravis
Antigens
Muscles
Complement Activation
Autoantibodies
Inflammation
Injections
Neuromuscular Junction
Membranes
Immunotherapy
Necrosis
Genes
Libraries

ASJC

  • Medicine(all)
  • Neuroscience(all)