STRUCTURE-IMMUNOGENICITY RELATIONSHIP OF MELITTIN, ITS TRANSPOSED ANALOGS, AND D-MELITTIN

Melittin, a 26-residue bee venom peptide, is known to induce murine Ab s specific for its hydrophilic C-terminus of residues 20-26 and T cell responses specific for its hydrophobic mid-region of residue 11-19. S ynthetic melittin analogues with transposed sequences of Ac(21-26) (1- 20) and Ac(26-21) (1-20) are found to induce murine Abs specific for t he transposed peptide segment and to induce T cell responses that are cross-reactive with melittin. Compared with melittin, the transposed m elittin analogues are weaker immunogens and have lower hemolytic activ ities, lower helical contents, and a lower degree of association in mi celles. A melittin analogue with a lactoside group at its C-terminus w as found to induce lactoside-specific murine Abs. Present studies show that another analogue with a lactoside group at its N-terminus induce s only Abs specific for the C-terminal region of melittin, and no lact oside-specific Abs are detected. These immunochemical observations sug gest that the immunogenicity of melittin or its analogues is a consequ ence of its binding to cell membranes with subsequent oligomer formati on in lipid bilayers. Apparently melittin or its analogues bind to cel l membrane in an asymmetric manner with the exposed and the buried seg ments functioning as B and T cell epitopes, respectively. D-melittin i s nonimmunogenic in mice, although D-melittin has the same hemolytic a ctivity as melittin. This finding may be correlated with the known res istance of D-melittin to proteolysis and hence to processing for Ag pr esentation to T lymphocytes.