Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice

AUTOR(ES)

Paas-Rozner, Miri

FONTE

The National Academy of Sciences

RESUMO

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-regulated, antibody-mediated autoimmune diseases. The major autoantigen in MG is the nicotinic acetylcholine receptor (AChR). Two peptides, representing sequences of the human AChR α-subunit, p195–212 and p259–271, were previously shown to be immunodominant T cell epitopes in MG patients as well as, respectively, in SJL and BALB/c mice. A dual analog (termed Lys-262–Ala-207) composed of the tandemly arranged two single amino acid analogs of p195–212 and p259–271 was shown to inhibit, in vitro and in vivo, MG-associated autoimmune responses. Furthermore, the dual analog could down-regulate myasthenogenic manifestations in mice with EAMG that was induced by inoculation of a pathogenic T cell line. In the present study, the ability of the dual analog to treat EAMG induced in susceptible C57BL/6 mice by native Torpedo AChR was evaluated. Mice that were diagnosed to have clinical symptoms of EAMG were treated with the dual analog by oral administration, 500 μg per mouse three times a week for 5–8 weeks. Treatment with the dual analog down-regulated the clinical manifestations of the ongoing disease as assessed by the clinical score, grip strength (measured by a grip strength meter), and electromyography. The effects on the clinical EAMG correlated with a reduced production of anti-AChR antibody as well as a decrease in the secretion of interleukin-2 and, more dramatically, interferon-γ, in response to AChR triggering. Thus, the dual analog is an efficient immunomodulator of EAMG in mice and might be of specific therapeutic potential for MG.

Documentos Relacionados

• A dual altered peptide ligand down-regulates myasthenogenic T cell responses by up-regulating CD25- and CTLA-4-expressing CD4+ T cells
• Oral administration of an immunodominant T-cell epitope downregulates Th1/Th2 cytokines and prevents experimental myasthenia gravis
• Trypanosoma cruzi down-regulates mechanosensitive proteins in cardiomyocytes
• Experimental autoimmune myasthenia gravis.
• Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression.