It has been known that both the effector mechanisms against cancer and the inhibitor mechanisms against the effectors are multiple; the host responses to BCG are also multiple. The mode ofantitumor action of BCG is, therefore, very intricated and dynamic depending on many variable factors.
This review focusses first on the mode of action in “local immunotherapy” with BCG.
The effector mechanisms in local BCG therapy are composed of 3 different steps which arise sequentially after BCG administration. Mechanism A is an immediate-type inflammation caused by BCG. The effector cells in this mechanism are macrophages (Mp) activated directly by BCG with out T cell collaboration. Mechanism B is a tuberculin-type inflammation, in which the effector cells are Mp activated by lymphokines (Lk) released from BCG-sensitized T cells. The activated Mp candestroy tumor cells nonspecifically at the site of the activation. The site of this inflammation provides an adequate place for inducing a strong cell-mediated immunity to an antigen present at thesite. For instance, delayed-type skin reaction to bovine serum albumin (BSA) was easily inducedin BCG-sensitized guinea pigs injected id with a mixture of small amounts of BSA and PPD. Therefore, if the tumor cells possess tumor-specific antigen, this field must be a very favorable place to inducetumor-specific immunity. Mechanism C is the induction of the tumor-specific immunity. Interaction of BCG-stimulated, polyclonally proliferating T cells with Mp which have ingested both BOGand tumor cell debris may be important for the effective induction of tumor-specific killer T cellsand/or DTH T cells. In fact, however, Mechanism C is difficult to be expressed in cancer patients, because of lack of tumor-specific antigen or of reduced ability of immune response.
The anti-tumor effect of “systemic immunotherapy” with BCG is weak, because the effector cellsof the Mechanisms A and B can not be activated at the tumor-site. Possible merits of systemic BCG administration, such as the activation of reticulo-endotherial system and of natural killer cells, and the dominant induction of T cells concerning delayed-type hypersensitivity rather than suppressor T cells, are discussed.

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Immunotherapy has been evaluated as a significant adjuvant therapy in addition to the conventional therapies such as surgery, radiotherapy and chemotherapy. In particular, living BCG is stillmost widely employed for various kinds of malignant diseases with apparent clinical effect on prolonging survival period and disease-free intervals of the patients. In general these effects are apparentwhen BCG are administered intratumorally. However, serious side effects including hepatic granulomawere also reported by many investigators. Moreover, the activity of living BCG differs according tostrain, and some problems due to living bacteria remain unsolved. In order to establish the immunotherapy with nonviable bacterial adjuvant, some efforts have been continued. Methanol extractionresidue (MER) has an advantages of nonviability and precise dose. However, it is a partial purification product and still contains protein component. Previous experiemnts have been shown thatcell-wall skeleton (CWS), having a principal structure of mycolic acid-arabinogalactan-mucopeptidecomplex, is a biologically active component in immunopotentiation. Further studies with BCG-CWS revealed a potent immunotharapeutic activity for human tumors as well as syngeneic tumors in miceand rats. In clinical trials for large numbers of cancer patients, no serious side effect were experienced.
Thus, it can be concluded that adjuvant immunotherapy with BCG-CWS is a useful therapeuticmodality for cancer patients.

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The relationship between the growth rate of tubercle bacilli and the concentration of antituberculous agents was studied. The growth rate was observed by two methods: First, the ratio of the timeof appearance of visible colonies on a medium, to which 20 to 50 viable organisms were inoculated, taking the time on control medium as 1 (Tsukamura & Noda: Med. & Biol., 45: 150, 1957) (The appearance of colonies occurred after 13.8-1.0 days, when inoculated 33.6-6.3 viable organisms); second, the generation time measured by the method of Youmans and Youmans (J. Bacteriol., 58: 247, 1949) (Ogawa egg medium was used).
The test organism was Mycobacterium tuberculosis H37Rv and the Ogawa egg medium was usedthroughout. After homogenizing by shaking with glass beads, the bacteria were suspended in saline anda bacterial suspension, 10mg wet weight/ml, was prepared. This suspension and its dilutions, 10-1to 10-5, were used as the source of inoculation. The inoculation was done using a spiral loop, whichdelivers a 0.02ml amount (Tsukamura & Noda: Kekkaku, 32: 639, 1957). The tubes inoculatedwere stoppered by a gum cap with a pin hole and incubated at 37°, and the growth of colonies wasobserved every day. Antituberculous agents were added to the medium before sterilization. Themedium was poured at 7ml quantities into tubes, 165 by 16.5mm, and was made as slopes by sterilization at 90° for 60 minutes.
The results are shown in Fig. 1 and 2. The degradation of antituberculous agents in mediumduring the incubation at 37° was tested as shown in Table 1. It was shown that, out of the ten agentstested, only rifampicin and ethionamide are degraded during the incubation. The degradation ofrifampicin was more marked than that of ethionamide. The results showed necessity of modificationof curves in cases of these two agents. It was suggested that, after such modification, the curve ofrifampicin be similar to a straight line.
From the results obtained, the antituberculous agents could be classified into three groups.
Group I. The agents which belong to this group showed a straight line-relationship betweenthe growth rate of tubercle bacilli and the concentration of an agent. Increase of the concentration of the agents in suggested to produce increased activity in lesions, showing a straight line-relationship.
The following agents belong to this group: Streptomycin, kanamycin, p-aminosalicylate, ethambutol, rifampicin, cycloserine, and amithiozone.
Group II. Capreomycin and ethionamide belong to this group. Increase of the concentrationis accompanied by marked increase of activity. The increase of the activity is suggested to be higherthan expected from the straight line-relationship. It is also possible that decrease of the concentration may cause a marked decrease of the activity. It is desired to make efforts to elevate the concentration of these agents in lesions.
Group III. Only isoniazid belongs to this group. This agent does show no activity if the concentration is lower than its critical concentration, but it shows almost complete inhibition of the growthwhen the concentration reaches the critical concentration. The use of higher concentrations thanthe critical one will not give mich effectiveness. Use of a large dose of this agent will have only meaning to maintain effective concentration for a longer period.

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Intravenous injection of β-1, 3 glucan obtained from cell walls of Saccharomyces cercisiae inducedmarked splenomegaly in ddY mice and inhibited the multiplication of infecting tubercle bacilli in thatorgan.

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Chest roentgenograms of ten patients with miliary tuberculosis were studied with special referenceto its nodular shadows.
The size of nodules in miliary tuberculosis ranged widely from 1 to 11mm. Five out of ten casesshowed usual miliary shadow of tiny discrete foci of about 2mm, but two showed very large, one verysmall, and two vague nodules. In some cases, nodules of various size were found in the same one case.
All the patients with unusual miliary shadows had underlying diseases.As chest roentgenogram of miliary tuberculosis, especially in patients with underlying diseases, showed unusual findings, careful observation of chest X-ray films, sufficient examinations for acid-fastbacilli, lung biopsy, and liver biopsy are needed in patients suspicious of miliary tuberculosis.

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It was a long roundabout way extending nearly a century since the discovery of TB germs to thedebut of therapia sterilisans magna. Robert Koch was keenly enthusiastic in the search for “antituberculous drug” rather than for “anti-bacillary drug.” It was, as it were, a wrong fastening of thefirst button, leading to a successive wrong fastenings of the following buttons. In fact, it gave birthto a myth “No effective drug for TB, ” then came the second myth “Cavity is the cause of incurabilityof TB, ” finally developed into the third myth of “Prevention is better than treatment in TB.” Sucha history was an unconditional surrender of therapeutic medicine to TB.
In 1944, at the time when SM was first discovered, medical treatment for TB as an infectiousdisease came finally upon the highway. Because of the necessity of the evaluation of various therapeutic approaches, more objective and scientific methods had been introduced to clinical medicine.
Along this line, objective classification of chest X-ray findings, standards for the evaluation of clinicalefficacy, controlled trial for the comparison of effects of several therapeutic methods, etc. have beendeveloped successively.
Clinical medicine is in itself human-oriented. It was the immaturity of clinical medicine whichinterfered to attain this goal. For example, “fresh air, rest and diet therapy” which had been advocated as a royal road to recovery for more than a century; collapse therapy and lung resection whicheffectively challenged for the cure of the cavity; and even “long-term chemotherapy” of previous days;all these could not be appreciated highly as they were not human-oriented. The myth “TB germscannot be sterilized by a drug” still survived.
However, the advance of short-course chemotherapy broke this myth. Now, newly detected TBpatients are cured without restraint from time and with brilliant hope of quick recovery whileenjoying ordinary human life. It was indeed a long journey to reach the present status.
Nevertheless, the success in chemotherapy has brought about an illusion in the mind of peopleas if they have solved all TB problems completely. Although kmany problems yet remain to be solved, short-course chemotherapy overwhelms all the problems like a bulldoser. Will that be all right? Asa clinician, we have to find out and investigate prudently unsolved problems.

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This presentation will attempt to review some of the basic characteristics and functions of macrophages andindicate newer approaches to understand these mechanisms in molecular terms.
1. Origins. Macrophages derive initially from a pluripotential stem cell in the bone marrow, transforms intoa monoblast, which, in the presence of colony stimulating factor differentiates into a promonocyte which then leavesthe bone marrow, appears in the blood as the monocyte and has the potential of localizing in the tissues. Thereare approximately 0.6-105 mouse monocytes produced per hour, and the turnover time of promonocytes is approximately 32 hours. Inflammatory reactions increase their production 1.5. While monocytes exist in the circulation for only 36 to 104 hours, they can live for very long periods of time in the tissues, as evidenced by tatoos.
2. Characteristics of monocytes.
a) Functions. Macrophages are highly motile, highly endocytic cells, which ingest large particles by phagocytosis and smaller particles or liquid phase materials by pinocytosis through a variety of specific and non-specificmechanisms.
b) Ten to 20% of macrophages appear to possess Ia antigens and are required for antigen presentation tosome T-cell subsets.
c) Macrophages have the capability of carrying out intracellular and extracellular killing of parasites andtumor cells, digestion of intracellular materials and release of products which may be involved in tissue damage.
d) Receptors and markers. Macrophages are known to possess receptors for immunoglobulins, and throughthe use of monoclonal antibodies produced by hybridomas it has been possible unambiguously to define them as beingreceptors for IgGI, IgG2a and IgG3 in the mouse. In addition they have receptors for C3b and for a variety of hormones, including insulin.
e) Enzymes. The enzyme constituitively secreted by macrophages and no other blood cells is lysozyme, which becomes an important marker for identifying macrophages. In addition, they have lysosomal hydrolases whichinclude esterases, proteases, lipases, nucleases, glycocylases, amidases, hydrases, phosphoamidases, all of which workbest at the acid pH found in the lysosome, pH 3.0-4.0.3. Endocytosis. There are a number of pathways by which extracellular materials are constantly being takenup by the macrophage including fluid phase pinocytosis, adsorptive pinocytosis, and phagocytosis of larger particles.
This is followed by fusion of the phagocytic or pinocytic vesicle with primary lysosomes containing proteolytic enzymes, killing and/or digestion of material in those secondary lysosomes, release of degraded material and recycling of themembrane. As an example of the normal degradative power of the macrophage, an adult individual has 5-1013 red blood cells of which 1/120 or 5-1011 are removed each day by splenic macrophages. In one year, splenic mononuclear phagocytize, eat and digest 2.7 kg of hemoglobin.a) Energy requirements. While pinocytosis is linear from 2°-38° phagocytosis fails to occur at temperaturesless than 18°. Phagocytosis is inhibited by glycolytic but not respiratory inhibitors, e. g. NaF, but not DNP. Theenergy for phagocytosis comes from ATP and creatine phosphate. The energy for pinocytosis requires both glycolysisand respiration, and can be inhibited by NaCN.

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