Suppression of myasthenia gravis by antigen-specific mucosal tolerance and modulation of cytokines and costimulatory factors.
We have shown that mucosal administration of recombinant fragments corresponding to the human acetylcholine receptor (AChR) alpha subunit suppresses chronic ongoing experimental autoimmune myasthenia gravis (EAMG) in rats. Treated animals exhibit a Th1 to Th2/Th3 shift in their cytokine profile and downregulation of costimulatory factors. However, application of a xenogeneic recombinant fragment may have limitations when considered as a possible approach for the treatment of MG in humans. We therefore tested the potential of a syngeneic fragment and of long synthetic peptides to suppress EAMG. We found that a syngeneic fragment corresponding to the extracellular region of the rat AChR alpha subunit was as effective as the formerly described human xenogeneic fragment in suppressing ongoing EAMG. This is encouraging in view of the potential use of mucosally administered recombinant AChR fragments for the treatment of MG in humans. However, in severely affected individuals, this antigen-specific approach may need to be supported by direct modulation of cytokines and costimulatory factors known to be involved in the pathogenesis of EAMG. To test the potential of this approach, myasthenic rats were injected by antibodies either to the proinflammatory cytokine IL-18 or to the costimulatory factor CD40L. These treatments act via different mechanisms, but both lead to the alleviation of clinical symptoms even when given at the chronic phase of EAMG. We suggest that antagonists to key cytokines and/or costimulatory factors be used to augment antigen-specific treatments of myasthenia such as mucosal administration of AChR recombinant fragments.
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. miriso@oumail.openu.ac.il
Miriam C
MC
Souroujon
Prasanta K
PK
Maiti
Tali
T
Feferman
Sin-Hyeog
SH
Im
Lily
L
Raveh
Sara
S
Fuchs
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D018928:Immunity, Mucosal; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000378:metabolism; D009157:Myasthenia Gravis / Q000276:immunology / Q000628:therapy*; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000139:chemically induced / Q000517:prevention & control; D021122:Protein Subunits; D051381:Rats; D011950:Receptors, Cholinergic / Q000008:administration & dosage / Q000276:immunology; D011994:Recombinant Proteins; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D016207:Cytokines; D007376:Interleukin-2; D021122:Protein Subunits; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins