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Antigen Specific Immunomodulation of Neuronal Autoimmune Disorders:
Experimental Myasthenia Gravis as a Model
Sin-Hyeog Im, Ph.D.
Department of Life Science, Gwangju Institute of Science and Technology,
1 Oryong-dong, Puk-ku, Gwangju 500-712 Korea
Attacking of self-components by auto-reactive T cells and/or B cells causes a damage or
loss of organ function resulting in diverse immune disorders. Autonomic neuropathies
often caused by specific anti-self antibodies such as anti-nuclearantibodies, neuronal
nicotinic acetylcholine receptor antibodies, Ca2+ channel antibodies and paraneoplastic
antibodies. Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis
(EAMG) are antibody-mediated autoimmune diseases at the neuromuscular junction in
which the nicotinic acetylcholine receptor (AChR) is the major autoantigen. In order to
induce AChR-specific tolerance without affecting systemic immune response we have
developed AChR-specific immunotolerogen and demonstrated the immunoregulatory
function of recombinant AChR fragments in ongoing EAMG.. Induction of oral
tolerance associated with alleviation of clinical symptoms is mediated by downregulation of AChR-reactive T cell proliferation, IgG level (IgG2), inflammatory
cytokines (IFN-gamma, IL-12), costimulatory factors (B7-1, B7-2 and CD40L)) and upregulation of immunomodulatory cytokines (IL-10 and TGF-beta). In addition we
addressed the importance of tolerogen conformation in modulation of ongoing EAMG..
The less native recombinant fragment of the human AChR suppressed ongoing EAMG
while more native recombinant AChR exacerbate EAMG by stimulating AChR-reactive
B cell proliferation and activation of T cells. Currently with an aim to develop safer and
more effective MG-specific oral tolerogen we are under development of chimeric AChR
recombinant tolerogens that are lack of B-cell epitopes but contain most of T-cell
epitopes encompassing  and  subunit. Safety and efficacy of chimeric
recombinant AChR will be tested in ongoing EAMG. Our studies on development of
AChR-specific chimeric recombinant fragment will lead to antigen-specific
immunotherapy of myasthenia gravis. This work was supported by the Neurobiology
Research Program from the Korea Ministry of Science and Technology