Possibilities and limitations in the rational design of modified peptides for T cell mediated immunotherapy.
Therapeutic intervention in experimental autoimmune diseases by modulation of the T cell mediated autoimmune response has been accomplished in the past using altered peptide ligands (APLs). These peptides are usually created by applying alterations to the T cell epitope recognized by the autoaggressive T cells. In this study, we investigated whether it was possible to design APLs in a rational way, using knowledge of molecular interaction in the MHC-peptide-T cell receptor (TCR) complex, for the therapeutic intervention in experimental autoimmune encephalomyelitis (EAE). Additionally, the value of peptidomimetic modification and alterations based on posttranslational modifications for the design of APLs was examined. Based on a molecular model of the MHC-peptide complex, the T cell receptor contact residues were identified and selected alterations were applied. The designed APLs were tested for MHC binding capacity, T cell recognition, blocking of the autoreactive T cell response, immunogenicity, encephalitogenicity, and therapeutic activity. Based on the results of the in vitro assays, it was expected that some of our APLs would be able to modulate EAE. Nevertheless, none of these APLs displayed clear therapeutic activity in vivo. Thus, rational design of modified peptides for immunotherapy has to await further insights into the relationships between structure and peptide/peptidomimetic induced T cell activation, and until that, there is no possibility to take advantage of the tailor made origin of peptidomimetics.
de Haan
Ellen C
EC
Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands.
Moret
Ed E
EE
Wagenaar-Hilbers
Josée P A
JP
Liskamp
Rob M J
RM
Wauben
Marca H M
MH
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000628:therapy*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000276:immunology*; D006168:Guinea Pigs; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D004676:Myelin Basic Protein / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D000596:Amino Acids; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C118872:myelin basic protein 72-85