CHARACTERIZATION OF DISEASE-CAUSING ANTIBODIES IN EAMG

Project: Research project

Project Details

Description

The immunopathology of Experimental Autoimmune Myasthenia Gravis (EAMG) in
rats involves a neuromuscular impairment caused by a T cell dependent
antibody response against the post-junctional acetylcholine receptor
(AChR). The result is weakness and rapid fatiguing in the rats similar to
symptoms observed in human patients inflicted with myasthenia gravis.
However, although anti-AChR antibodies appear to be the direct cause of
neuromuscular dysfunction in human patients, it has been observed that
there is a disturbing lack of strong correlation between the titer of
circulating antibody and the severity of symptoms demonstrated. Thus, the
basic premise of this research proposal is that some, but not all, anti-
AChR antibodies can cause disease (perhaps related to differences of the
exact binding specificity of the antibodies produced). The primary goal
of the studies proposed herein is to determine which subsets of anti-AChR
antibodies are most responsible for causing EAMG in Lewis rats. Based on
information gained in preliminary studies, the identification of these
antibody subsets will involve the evaluation of several criteria: 1)
Myasthenogenic antibodies are expected to react with AChR of native but
not denatured conformation, 2) Myasthenogenic antibodies are expected to
be present in EAMG-sensitive Lewis rats but not EAMG-resistant Wistar
Furth rats, and 3) Myasthenogenic antibodies are expected to demonstrate
binding activity against AChR of muscle origin. The antibody subset that
fills these criteria will be distinguished and isolated with the use of
specialized anti-idiotypic probes combined with methods of separation
involving isoelectric focusing. Confirmation of myasthenogenicity will be
performed by intravenous transfer od subseted antibodies into rats
followed by direct analysis of AChR-dependent muscle contraction. In
addition, antibody-toxin conjugates (immunotoxins) will be prepared that
are composed of the A chain of ricin covalently linked to anti-idiotypic
antibodies with specificity for idiotypes associated with anti-AChR
antibodies showing high disease-causing potential; these conjugates will
be tested for their ability to selectively deplete AChR-responsive B cells
of their ability to produce the particular antibody specificities
identified as myasthenogenic. Information gained in these studies should
provide additional needed insights into two issues concerning myasthenia
gravis. First, questions involving regulation of the anti-AChR antibody
response could be more directly focused on that part of the response
directly responsible for disease induction and clear up discrepancies
between antibody titer and disease severity. Second, immunotherapeutic
strategies designed to eliminate the antibody that causes neuromuscular
impairment could be refocused on those anti-AChR antibodies with fine
specificities directly responsible for disease.
StatusFinished
Effective start/end date12/1/8911/30/94

Funding

  • National Institutes of Health
  • National Institutes of Health: $94,153.00
  • National Institutes of Health
  • National Institutes of Health: $87,055.00

ASJC

  • Medicine(all)
  • Neuroscience(all)

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