Vk. Kuchroo et al., A SINGLE TCR ANTAGONIST PEPTIDE INHIBITS EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS MEDIATED BY A DIVERSE T-CELL REPERTOIRE, The Journal of immunology, 153(7), 1994, pp. 3326-3336
Previously, six T cell clones, which are specific for an encephalitoge
nic determinant of myelin proteolipid protein (PLP) peptide residues 1
39 to 151 (HSLGKWLGHPDKF), were derived from SJL mice and shown to use
diverse TCR genes. To design TCR antagonist peptides that could inter
fere with the activation of these clones in vitro and inhibit experime
ntal allergic encephalomyelitis (EAE) in vivo, we first determined the
TCR and MHC contact residues of the encephalitogenic peptide. The ana
lysis indicated that residues 144 (tryptophan) and 147 (histidine) wer
e the TCR binding sites and that residues 145 (leucine) and 148 (proli
ne) were important for MHC class II (IA(s)) binding. On the basis of t
his information, a peptide analogue (leucine 144/arginine 147), in whi
ch both of the major TCR contact residues were substituted, was synthe
sized. This analogue acts as a TCR antagonist for the panel of PLP 139
-151-specific T cell clones, does not cause EAE by itself, blocks the
induction of disease by the native 139-151 peptide, and prevents clini
cal disease progression if administered at the first signs of disease.
Thus, although multiple TCR genes are used by PLP 139-151-specific cl
ones, a single peptide analogue can interfere with the disease process
. This approach should be feasible for designing peptide analogues tha
t can be tested for therapeutic efficacy in human autoimmune diseases
in which the pathogenic Ags are known and TCR use is diverse.