IMMUNOCHEMISTRY OF TUBERCLE BACILLI, WITH SPECIAL REFERENCE TO ADJUVANT ACTIVITY

The 56th Annual Meeting Special Lecture

Abstract

Tubercle bacilli have been shown to have various biological activities. Especially, the immunoadjuvant activity activity was known by so-called “Freund's complete adjuvant”. In this lecture, I have reported the adjuvant activity of the cell-wall skeleton of tubercle bacilli and its clinical application to cancer immunotherapy. The chemical synthesis and immunological properties of low molecular weight adjuvants related to bacterial cell-wall skeletons were also described.
We have shown that chemical structure of cell-wall skeleton (CWS) of tubercle bacilli, such as BCG, was shown to be “mycolic acid-arabinogalactan-mucopeptide”. The details of biochemical and immunological properties of BCG-CWS were examined. Oil-treated BCG-CWS was shown to have potent adjuvant and antitumor activities in experimental tumor systems such as: suppression and regression of syngeneic transplantable tumor, prevention of carcinogenesis and the restore of the depressed immune function to normal level in tumor-bearing animals. BCG-CWS was applied to the treatment of patients with lung cancer and acute myelogenous leukemia. Significant prolongation of survival period of cancer patients was observed by the immunotherapy with BCG-CWS in addition to conventional therapy, compared to the control group which was treated with conventional therapy alone. We have also found that the cell-wall skeleton of Nocardia rubra had more advantages than BCG-CWS as cancer immunotherapeutic agent. The efficacy of N. rubra-CWS as immunotherapeutic agent is now being examined by randomized control clinical trials in patients with lung cancer, leukemia and gastro-intestinal cancer.
In 1974, Ellouz and her coworkers have reported that the minimum adjuvant-active subunit of bacterial cell-wall was N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP). We have chemically synthesized various MDP analogs and derivatives and their immunological properties were examined in detail with special reference to the relationship between the chemical structure and adjuvant activity. MDP and its analogs were shown to have potent adjuvant activity, however, they have no antitumor activity in any transplantable tumor system. Among the MDP derivatives, we have found that 6-O-mycoloyl-N-acetyl-muramyl-L-seryl-D-isoglutamine and methyl ester of 6-O-quinonyl (-Q, ^S₁₀)-N-acetylmuramyl-L-valyl-D-isoglutamine were active as cancer immunotherapeutic agent in transplantable tumors in syngeneic mice and guinea pigs.
The above results clearly suggested that tubercle bacilli and related substances are very important materials for the study of immunology and also for the treatment of malignant diseases.