A SINGLE TCR ANTAGONIST PEPTIDE INHIBITS EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS MEDIATED BY A DIVERSE T-CELL REPERTOIRE

Citation
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
Citations number
40
Categorie Soggetti
Immunology
Journal title
The Journal of immunology
ISSN journal
00221767 → ACNP
Volume
153
Issue
7
Year of publication
1994
Pages
3326 - 3336
Database
ISI
SICI code
0022-1767(1994)153:7<3326:ASTAPI>2.0.ZU;2-8
Abstract
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.