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*
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; and
The Open University of Israel, Tel-Aviv, Israel
We recently demonstrated that oral or nasal administration of
recombinant fragments of the acetylcholine receptor (AChR) prevents the
induction of experimental autoimmune myasthenia gravis (EAMG) and
suppresses ongoing EAMG in rats. We have now studied the role of
spatial conformation of these recombinant fragments in determining
their tolerogenicity. Two fragments corresponding to the extracellular
domain of the human AChR 
-subunit and differing in conformation were
tested: H1–205 expressed with no fusion partner and H1–210
fused to thioredoxin (Trx), and designated Trx-H1–210. The
conformational similarity of the fragments to intact AChR was assessed
by their reactivity with -bungarotoxin and with anti-AChR mAbs,
specific for conformation-dependent epitopes. Oral administration of
the more native fragment, Trx-H1–210, at the acute phase of disease
led to exacerbation of EAMG, accompanied by an elevation of
AChR-specific humoral and cellular reactivity, increased levels of
Th1-type cytokines (IL-2, IL-12), decreased levels of Th2 (IL-10)- or
Th3 (TGF-ß)-type cytokines, and higher expression of costimulatory
factors (CD28, CTLA4, B7-1, B7-2, CD40L, and CD40). On the other hand,
oral administration of the less native fragments H1–205 or
denatured Trx-H1–210 suppressed ongoing EAMG and led to opposite
changes in the immunological parameters. It thus seems that native
conformation of AChR-derived fragments renders them immunogenic and
immunopathogenic and therefore not suitable for treatment of myasthenia
gravis. Conformation of tolerogens should therefore be given careful
attention when considering oral tolerance for treatment of autoimmune
diseases.
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