Cross-reactivity between haptenic muramyl di- or tripeptide derivatives and Mycobacterium bovis BCG: potential application for enhancing tumor immunity.

Muramyl di- or tripeptide (MDP or MTP) hapten derivatives bearing various structures were synthesized, and the correlation of these structures with cross-reactivity with Mycobacterium bovis BCG and their applicability to enhance induction of syngeneic tumor immunity were investigated. The cross-reactivity of MDP or MTP haptens to BCG was examined by T-cell proliferation responses of lymph node cells from BCG-primed C3H/He mice in the stimulation with MDP- or MTP-coupled syngeneic cells. A haptenic MDP derivative (designated L4-MDP) stimulated proliferative responses appreciably. Derivatives in which alanine in the peptide portion of L4-MDP was replaced by methylalanine or valine failed to induce stimulation. However, the cross-reactivity with BCG was regained in the MTP derivative that was formed by adding lysine to dipeptide containing methylalanine or valine. Whether this cross-reactive pattern was correlated with enhanced induction of tumor immunity was further investigated. According to the established protocol for the augmented induction of tumor immunity, BCG-primed C3H/He mice were immunized with various haptenic MDP-coupled syngeneic X5563 tumor cells. Immunization with tumor cells conjugating BCG-cross-reactive haptens resulted in enhanced tumor immunity, whereas immunization with tumor cells coupling non-cross-reactive haptens failed to produce anti-X5563 tumor immunity. These results indicate that the peptide portion in these haptenic structures is critical in the generation of BCG cross-reactivity leading to enhanced tumor immunity.