Therapeutic potential of TCR antagonists is determined by their ability to modulate a diverse repertoire of autoreactive T cells.
The use of altered peptide ligands (APL) with TCR antagonist properties holds promise as an antigen-specific therapy for autoimmune disorders. We are investigating the therapeutic potential of APL in experimental autoimmune encephalomyelitis (EAE) using the Ac1-9 peptide of myelin basic protein in H-2u mice. Encephalitogenic T cells recognize Ac1-9 using residues 3Gln and 6Pro as the major TCR contact sites. Use of position 6 APL is compromised by the heterogeneous nature of the Ac1-9-specific repertoire. Here we identify two position 3 APL that act as TCR antagonists on transgenic T cells expressing Ac1-9-specific TCR and that inhibit EAE in H-2u mice. However, the therapeutic capacity of these two APL correlated directly with the ability to maximally inhibit activation of a heterogeneous T cell pool. The implications of these findings for the requirements for EAE induction, the relative contribution of a given T cell subpopulation to pathology and the mechanism underlying EAE inhibition in this model are discussed.
Anderton
S M
SM
Department of Pathology and Microbiology, University of Bristol, GB. s.m.anderton@Bristol.ac.uk
Kissler
S
S
Lamont
A G
AG
Wraith
D C
DC
D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000628:therapy; D015551:Autoimmunity / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy; D016056:Immunodominant Epitopes / Q000235:genetics; D007167:Immunotherapy; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell; D010047:Ovalbumin