Towards peptide immunotherapy in rheumatoid arthritis: competitor-modulator concept

By the introduction of single-amino acid substitutions in well-defined T cell epitopes of autoimmunogenic proteins, e.g., mycobacterial heat shock protein (hsp60) in adjuvant arthritis (AA) and myelin basic protein (MBP) in experimental allergic encephalomyelitis (EAE), efficiently blocking MHC binding peptides were selected. Despite the finding that a substituted variant of epitope 180-188 of hsp60 was 'blocking' not only responses of the 180-188 specific arthritogenic T cell A2b, but also responses of the MBP specific encephalitogenic T cell Z1a, in vivo testing of this competitor peptide revealed a very prominent disease inhibitory activity in AA but not in MBP-induced EAE. The selectivity of this peptide in suppressing the disease in which native 180-188 appears to be of critical relevance, offers the possibility of achieving disease specific immunological intervention. Based on the results collected so far, it seems that, in vivo in addition to blocking activity, a variant peptide itself could trigger responses that confer protective activity in AA. Such combined activities may well be required for achieving full in vivo inhibition of a disease in which multiple distinct epitopes may play a role, possibly through presentation by more than one MHC product.