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,§
Departments of
*
Neurology,
Biochemistry and Molecular Biology, and
Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, OR 97201; and
§
Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97201
We have previously described recombinant MHC class II ß1 and 
1
domains loaded with free antigenic peptides with potent inhibitory
activity on encephalitogenic T cells. We have now produced single-chain
constructs in which the peptide Ag is genetically encoded within the
same exon as the linked ß1 and 1 domains, overcoming the problem
of displacement of peptide Ag from the peptide binding cleft. We here
describe clinical effects of recombinant TCR ligands (RTLs) comprised
of the rat RT1.B ß11 domains covalently linked to the 72–89
peptide of guinea pig myelin basic protein (RTL-201), to the
corresponding 72–89 peptide from rat myelin basic protein (RTL-200),
or to cardiac myosin peptide CM-2 (RTL-203). Only RTL-201 possessed the
ability to prevent and treat active or passive experimental autoimmune
encephalomyelitis. Amelioration of experimental autoimmune
encephalomyelitis was associated with a selective inhibition of
proliferation response and cytokine production by Ag-stimulated lymph
node T cells and a drastic reduction in the number of encephalitogenic
and recruited inflammatory cells infiltrating the CNS. The exquisitely
selective inhibition could be observed between molecules that differ by
a single methyl group (the single amino acid residue difference between
RTL-200 (threonine) and RTL-201 (serine) at position 80 of the myelin
basic protein peptide). These novel RTLs provide a platform for
developing potent and selective human diagnostic and therapeutic agents
for treatment of autoimmune disease.
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