Histopathology of tumor regression after intralesional injection of Mycobacterium bovis. Development of immunity to tumor cells and BCG

Hanna, M. G.; Snodgrass, Michael J.; Zbar, Berton; Rapp, Herbert J.

doi:10.1097/00006534-197410000-00077

Cited by 43 publications

(59 citation statements)

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“…Boak (1978) did report histological changes after an injection of 0 5-7 0 mg of CP in carcinoma of the breast: the ipsilateral axillary lymph nodes were enlarged when removed after 9-18 days, and demonstrated marked sinus histiocytosis, though the histiocytes were unable to prevent the development of lvmph-no(le metastases. Such an effect 205 had been described for BCG (Hanna et al, 1972;Snoddgrass, 1973;Bast et al, 1974).…”

Section: Discussionmentioning

confidence: 70%

“…It also induces macrophage reactions in the draining node, though these reactions have later onsets, namely at 6-14 days (Gaafar & Turk, 1970;Hanna et al, 1972;Khalil et al, 1975) and they are much more prolonged (up to 85 days; Khalil et al, 1975). The collection of histiocytes in these BCG reactions may increase considerably in size, and sometimes the whole node is almost completely replaced by histiocytes (Gaafar & Turk, 1970 Hanna, 1973).…”

Section: Discussionmentioning

confidence: 99%

“…The immunological functions of peripheral lymphoid cells tested in these patients suggest that the clinical benefit is brought about by an improved macrophage and T-cell function (Mignot et al, 1981). BCG, one of the most extensively studied immune stimulants, induces clear macrophage reactions in draining lymph nodes as sinus histiocytosis and granuloma formation (Gaafar & Turk, 1970;Hanna et al, 1972;Khalil et al, 1975). The T-and B-cell compartments are stimulated as well: lymphoblasts appear in the paracortex as a sign of T-cell stimulation, whereas later germinal centres are seen in the cortex, and plasma cells in the medulla, as signs of B-cell stimulation (Gaafar & Turk, 1]970;Khalil et al, 1975 (Wellcome, 1978).…”

Section: Cortexmentioning

confidence: 99%

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Morphology of draining lymph nodes after local immune stimulation with C. parvum: comparison of pelvic nodes in carcinoma of cervix and popliteal and inguinal nodes of guinea-pig

Mignot¹,

Lens²,

Stolk³

et al. 1982

Br J Cancer

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Summary.-Morphological changes are described in pelvic lymph nodes excised 10 days after C. parvum (CP) treatment of patients with cervical carcinoma. Guineapig popliteal and inguinal lymph nodes were investigated from Days 1 to 10 after an injection of 70 ,ug CP into the footpad. Eosinophils were detected from the first few hours after stimulation, initially in the marginal sinus, then in the medullary sinuses and subsequently in the efferent lymphatics. From Day 2 to Day 6, histiocyte accumulations with the appearance of epithelioid cells were found mainly in subcapsular and interfollicular areas, and small granulomas were also seen in the paracortex.The granuloma formation in the lymph node was considered as an indication of the activation of histiocytes. Besides small granulomas in the paracortex, activated interdigitating cells, surrounded by scattered lymphoblasts and eosinophils, were also present. We considered this lymphoblastic response and eosinophilic accumulation as likely to be due to blastogenic factor and eosinophil stimulation promotor. Eight to 10 days after CP stimulation, the macrophage lymphoblast eosinophil response was replaced by a B-cell reaction: germinal-centre activation and medullary plasma cells. Such a B-cell reaction was also found in the human pelvic nodes removed at operation, but this reaction could not be attributed to CP treatment alone, since cervical-carcinoma patients not treated with CP also showed such reactions. In contrast, pelvic lymph nodes removed at necropsy from females killed in traffic accidents showed no predominance of either B-or T-cell stimulation.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Cortexmentioning

confidence: 99%

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Morphology of draining lymph nodes after local immune stimulation with C. parvum: comparison of pelvic nodes in carcinoma of cervix and popliteal and inguinal nodes of guinea-pig

Mignot¹,

Lens²,

Stolk³

et al. 1982

Br J Cancer

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“…An anti-tumour effect of BCG in experimental animal models has often been reported (Hanna et al, 1972), but in many systems this effect is prophylactic rather than therapeutic (Finklestein et al, 1972). When, however, therapeutic effects were found against solid tumours, it was usually necessary also to inject the BCG directly into the lesion (Hanna et al, 1972).…”

Section: Discussionmentioning

confidence: 99%

“…In this respect, various bacterial vaccines such as BCG have been demonstrated to enhance nonspecifically a number of immune responses (Miller et al, 1973) and are reported to produce a clinical improvement in some cases of leukaemia (Mathe et al, 1974) and melanoma (Morton et al, 1970). Also in various animal models, like the one described in this report, BCGr treatment can exert a marked curative effect (Hanna et al, 1972 Poupon, 1978) BCG "Immuno BCG", which retains 950o viability after 3 months storage at 4°C, wvas kindly provided by the Pasteur Institute (Paris, France) and injected as described in the results. High doses (3 mg) i.v.…”

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confidence: 91%

Possible role of macrophage-like suppressor cells in the anti-tumour activity of BCG

Castes¹,

Lynch²,

Lespinats³

et al. 1981

Br J Cancer

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Summary.-The i.v. injection of high doses (3 mg) of BCG into C3H mice bearing a transplantable 3-methylcholanthrene-induced fibrosarcoma caused the regression of a significant proportion. This effect was most evident when the BCG was injected on the day of the graft, or 7 days later. The injection of this agent either 14 days before the graft, or in low doses (0.1 or 0 5 mg), or directly into the tumour (i.t.) only prolonged the survival of the animals. Spleen cells from systemic high-dose BCGtreated mice were found to exert a strong nonspecific cytostatic effect in vitro that was not an artefact of the test conditions, and was not expressed by cells from lowdose animals. The cytostatic effect was shown to be caused by cells with the characteristics of macrophages, i.e. they were strongly adherent, unaffected by treatment with anti-Thy 1.2 + C', radioresistant but heat-sensitive, and were detected in BCG-treated "B" mice.The spleens of high-dose BCG-treated mice also contained suppressor cells that were capable of inhibiting the in vitro reactivity of normal T cells to PHA. Like the cytostatic effect, this suppressor activity was not detected in low-dose mice, and the cells responsible had the properties of macrophages; the effect was lost after the removal of adherent cells by sequential exposure to plastic and colloidal iron, but was conserved after treatment with anti-Thy 1.2 + C'. T-cell-deprived animals, such as "B" or nude mice, also developed suppressor-cell activity when treated with systemic high-dose BCG.Close parallels became evident between the in vivo anti-tumour activity of BCG, the in vitro cytostatic effect, and the suppressor-cell activity. We here discuss the possible role of suppressor cells in the mechanism of action of this agent.

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Efficacy of intralesional bcg therapy in guinea pigs with disseminated tumor

Hanna

Peters

1975

Cancer

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It has been previously demonstrated that transplanted syngeneic tumors established in the skin of inbred (strain-2) guinea pigs regressed and regional lymph node metastases were eliminated after intralesional injection of viable Mycobacterium bovis (BCG). During the course of this reaction there is the development of tumor-specific immunity. This experimental model was further manipulated in order that it would more closely approximate a clinical reality. I n the present study an evaluation was made of the effectiveness of the developing tumor-specific immunity in this BCG therapy model, to abrogate artifically induced distant tumor deposits and to assess the requirement for tumor-specific immunity in the local BCG-mediated tumor regression. During BCG-mediated regression of established intradermal tumor, the developing tumor-specific immunity inhibited the growth of artificially induced vascular metastases in animals receiving a 101 or 105 tumor cell dose. However, there is a direct causal relationship between the distant tumor burden and the escape of skin tumor and regional lymph node metastases from BCG-mediated regression. Thus, multiple tumor deposits as low as lo4 cells are capable of competing for or preempting tumor-specific immune reactivity, which must be a requirement during some phase of the intralesional BCG-mediated therapy of established tumor and regional lymph node metastases. Thus, a significant therapeutic effect could be achieved in guinea pigs with established skin tumors and limited vascular metastases when the modality of therapy included BCG intralesional injection, followed 6 weeks later by surgery of the treated skin tumor and regional lymph node. syngeneic hepatocarcinoma established in the skin of guinea pigs and the elimination of regional lymph node metastases are achieved in the majority of animals after intralesional injection of viable BCG.7~8~17J8 Critical factors with respect to success of therapy in this model are the size of the intradermal tumor and the amount of viable BCG in the intralesional inoculum.6slS It has been demonstrated that this therapy model has important local and systemic features. Recent results of our investigation of the mechanism of BCG-mediated therapy in this model suggest that activated cells of the macrophage-histiocyte compartment play a primary and essential role in the destruction of tumor cells established both in the skin and regional lymph nodes.7~'~ A requirement for early sensitization to BCG antigens has been demonstrated, and there is eventual development of tumor-specific humoral and cellmediated immunity.a T h e induced tumorspecific immunity is such that a second-set 1298

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Histopathology of tumor regression after intralesional injection of Mycobacterium bovis. Development of immunity to tumor cells and BCG

Cited by 43 publications

References 0 publications

Morphology of draining lymph nodes after local immune stimulation with C. parvum: comparison of pelvic nodes in carcinoma of cervix and popliteal and inguinal nodes of guinea-pig

Morphology of draining lymph nodes after local immune stimulation with C. parvum: comparison of pelvic nodes in carcinoma of cervix and popliteal and inguinal nodes of guinea-pig

Possible role of macrophage-like suppressor cells in the anti-tumour activity of BCG

Efficacy of intralesional bcg therapy in guinea pigs with disseminated tumor

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