IMMUNE NETWORK IN MYASTHENIA

  • Agius, Mark A (PI)

Project: Research project

Project Details

Description

The immune idiotype:anti-idiotype (Id:anti-Id) network is important in
immunoregulation and tolerance. Its analysis in experimental autoimmune
myasthenia gravis (EAMG) should provide insight into the abnormal
immunoregulation in a defined antibody-mediated autoimmune disease, We have
produced isogeneic monoclonal anti-Id antibodies directed against
EAMG-inducing anti-acetylcholine receptor (AChR) monoclonal antibodies
(mAbs) to be used as tools to analyze the immune network in EAMG. We have
purified and characterized five anti-Id mAbs directed against two of these
anti-AChR mAbs. Immunochemical analysis reveals that these anti-Ids are
noncompetitive inhibitors of antigen (Ag) (i.e., ACHR) binding to the
anti-AChR mabs. The Ids defined by the anti-Ids are moderately crossreactive with other
anti-AChR mabs and with EAMG sera without being present in dominant levels.
We have, nonetheless, suppressed the total serum anti-AChR antibody levels
and prevented the development of EAMG by pretreating animals, prior to
immunization with AChR, with physiologic doses of individual anti-Id mAb.
These anti-Id thus play a major immunoregulatory role in EAMG. In our
present proposal, the aim is to analyze the mechanism(s) involved in this
observed suppression of the total anti-AChR response induced by
manipulating an Id that is moderately crossreactive but not dominant in
EAMG sera. Experiments are proposed to: a) further analyze the parameters
important to the development of suppression (animal age, Ag dose, adjuvants
used, and dose and timing of anti-Id) in order to characterize this
biological system and to maximize the suppression; b) analyze the
structural and cellular mechanisms involved in the observed suppression. To
analyze structural mechanisms at a molecular level, we will clone and
sequence the variable regions of the anti-AChR mAb 132A and the
corresponding anti-Id-mAb HC-4A. To analyze cellular mechanisms, altered B
cell secretions of Ab by anti-Id, and the role of specific B cell
populations (Id + and anti-Id +) will be determined. This analysis of the
immune network in EAMG should have implications for the understanding and
treatment of human MG and other autoimmune diseases.
StatusFinished
Effective start/end date9/20/908/31/94

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $70,189.00

ASJC

  • Medicine(all)
  • Neuroscience(all)

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