PEPTIDE STRATEGY FOR PREVENTION OF AUTOIMMUNE MYASTHENIA

Project: Research project

Project Details

Description

A number of important human diseases, including rheumatoid arthritis (RA),
insulin dependent diabetes mellitus (IDDM), multiple sclerosis (MS),
myasthenia gravis (MG) and others, are associated with polymorphisms of
major histocompatibility complex class II molecules. This suggests that
highly specific immunological interventions directed at these polymorphisms
may be an effective therapeutic strategy, replacing the nonspecific,
chronic immunosuppression which is a mainstay of current therapy. A
potential candidate intervention is the use of synthetic peptides which
block the binding of disease-inducing antigens to the relevant MHC class
II polymorphic structures, preventing the activation of autoimmune T
lymphocytes. Recent success in preventing experimental autoimmune
encephalitis, a mouse model of MS, provides an outline for the current
study. This proposal will study experimental autoimmune myasthenia gravis
(EAMG), induced in susceptible C57BL/6 (B6) mice by immunization with
acetylcholine receptor (AChR). EAMG is both immunologically and
pathophysiologically more complex than EAE and should provide a challenging
test of the general applicability of the peptide strategy. B6 mice will be
immunized with AChR and cloned AChR-reactive T cell lines established. The
T cell recognition sites of AChR will be precisely defined by using
synthetic peptides representing AChR sequences. Peptide residues
recognized by T cells (epitopes) and residues which mediate binding to MHC
class II molecules (agretopes) will be defined. Substituted peptides which
possess AChR agretope residues but not epitope residues contained within
the immunodominant T cell sites should be capable of preventing the
activation of T cell clones in vitro, lymph node T cells ex vivo and EAMG
induction in vivo. The project uses standard methology, but brings
together the expertise of three key collaborators: AJI - T cell clones, KAW
- peptide synthesis and KAK- EAMG model.
StatusFinished
Effective start/end date7/29/911/31/99

Funding

  • National Institutes of Health
  • National Institutes of Health: $140,039.00
  • National Institutes of Health: $147,355.00
  • National Institutes of Health: $151,386.00
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Neuroscience(all)

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