Emerging principles for the design of promiscuous HLA-DR-restricted peptides: an example from the major bee venom allergen.

Mechanisms underlying successful immunotherapy of allergic patients operate at the level of CD4+ helper T cells. T cell epitopes from allergens may thus constitute interesting molecules for immunotherapy, provided they are efficient for all patients and are not recognized by IgE. In an attempt to define such peptides for allergy to bee venom, we have investigated the capacity of peptides encompassing the sequence of the major bee venom allergen to stimulate PBMC from allergic patients and to react specifically with their IgE. The region 77-110 emerged as the most frequently T cell stimulating. We then analyzed the binding modes of the sequence 81-97 for ten different HLA-DR molecules and introduced punctual mutations to enhance the peptide affinity for these molecules. Six different modes have been identified on the sequence 81-97, one mode being common to eight HLA-DR molecules. Four HLA-DR molecules can bind the P85-97 peptide by two different modes with an equivalent affinity. The peptide N89L has a higher affinity for DRB1*0301 and DRB3*0101 and remains as active as the native peptide towards the other HLA-DR molecules.