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R J North

Publications and source records attributed to R J North.

At least 109 records · Page 6Linked to original sources
PubMed1981

T cell-mediated immunosuppression as an obstacle to adoptive immunotherapy of the P815 mastocytoma and its metastases.

Progressive growth of the P815 mastocytoma in semisyngeneic mice evokes the generation of a T cell-mediated mechanism of immunosuppression that inhibits the capacity of passively transferred, tumor-sensitized T cells from regressing this tumor in recipient mice. This conclusion is based on two findings: (a) that it is possible to demonstrate adoptive T cell-mediated regression of established tumors, but only if the tumors are growing in T cell-deficient recipients, and (b) that adoptive T cell-mediated regression of tumors in these recipients can be inhibited by the infusion of splenic T cells from T cell-intact, tumor-bearing donors. The results of additional experiments designed to measure the effect of decreasing the number of suppressor cells and the time that they are infused, relative immune cells, indicate that the function of suppressor cells in this model is to inhibit the replication of passively transferred immune T cells. The results obtained with the P815 mastocytoma are similar to those obtained previously with a chemically induced fibrosarcoma. They show, in addition, that passively transferred immune cells are capable of destroying already seeded metastases in T cell-deficient recipients.

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PubMed1981

Mechanisms of anti-tumor action of Corynebacterium parvum. I. Potentiated tumor-specific immunity and its therapeutic limitations.

The anti-tumor mechanism in mice induced by a subcutaneous injection of syngeneic tumor cells admixed with Corynebacterium parvum was investigated. When mice were implanted in a hind footpad with x 2 1096) tumor cells admixed with 100 microgram C. parvum, the tumor that emerged grew progressively for about 9 d and then underwent progressive and complete regression. It was found that this C. parvum-induced regression was associated with the acquisition of a systemic, T cell-mediated mechanism of immunity to tumor-specific transplantation antigens, which enabled the host to cause the regression of an untreated test tumor growing simultaneously at a distant site. The generation of a C. parvum-potentiated anti-tumor response was dependent on the presence of tumor cells in close association with C. parvum, tumor immunogenicity, and the quantity of tumor antigen in the admixture. The anti-tumor immunity was specific for the tumor in the therapeutic admixture and could be adoptively transferred to normal recipients with Thy-1.2-positive lymphocytes, but not with serum. Complete regression of a distant test tumor by the C. parvum-tumor admixture was limited to tumors below a certain critical size.

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PubMed1981

Mechanisms of anti-tumor action of Corynebacterium parvum. II. Potentiated cytolytic T cell response and its tumor-induced suppression.

It was shown that subcutaneous implantation of P815 tumor cells admixed with Corynebacterium parvum resulted in the emergence of a tumor that grew for 9-10 d and then regressed. The onset of tumor aggression was preceded by the substantial generation in the draining lymph node and spleen of T cells capable of specifically lysing P815 target cells in vitro. The finding that the magnitude of this cytolytic response was much greater than the cytolytic response to a control tumor that grew progressively is consistent with the hypothesis that the anti-tumor action of C. parvum is based on its capacity to augment the production of T cells sensitized to tumor-specific transplantation antigens. This adjuvant action of C. parvum was revealed by additional experiments in which irradiated, nonreplicating tumor cells were substituted for living tumor cells in the admixture. The results support the conclusion that the potentiated cytolytic response to subcutaneous injection of an admixture of irradiated tumor cells and C. parvum is responsible for the ability of this admixture to cause the regression of a test tumor growing at a distant site. Finally, it was shown that the failure of the therapeutic admixture to cause the regression of distant test tumors above a certain size was associated with a failure of the admixture to cause a potentiated, anti-tumor cytolytic response. We discussed the possibility that this failure was caused by the presence of a tumor-induced state of immunosuppression.

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PubMed1981

Immunologic consequences of antibiotic-induced abridgement of bacterial infection: effect on generation and loss of protective T cells and level of immunologic memory.

Ampicillin was employed in mice to determine the effect of rapidly abridging bacterial infection on the generation of T cell-mediated antibacterial immunity. It was found that antibiotic-induced abridgement of infection with Listeria monocytogenes had a pronounced effect on the generation of splenic T cells capable of adoptively immunizing normal recipients against a Listeria challenge infection. Ampicillin given at the time of maximum bacterial growth at 24 hr caused a striking reduction in the number of protective T cells produced at the time of peak response on day 6. Although the greatest effect was caused by giving ampicillin early in infection, a significant reduction in peak T cell production occurred even when Ampicillin was given as late as day 5. On the other hand, the effect of abridging infection at the onset of decay of the anti-Listeria response was to cause protective T cells to be lost from the spleen at a much faster rate. These results clearly show that regardless of any immunoregulatory mechanism involved, the duration of generation, and the onset and duration of decay of the anti-Listeria response are determined by the number of replicating Listeria in the tissues. Moreover, Ampicillin-induced abridgement of infection, either before or at the time of peak primary response, resulted in the expression of greatly reduced levels of immunologic memory at a later time. This indicates that memory cells are generated throughout the entire course of the primary anti-Listeria response, including the period of its decay.

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PubMed1980

T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor.

The results of this paper are consistent with the hypothesis that progressive growth of the Meth A fibrosarcoma evokes the generation of a T-cell-mediated mechanism of immunosuppression that prevents this highly immunogenic tumor from being rejected by its immunocompetent host. It was shown that it is possible to cause the regression of large, established Meth A tumors by intravenous infusion of tumor-sensitized T cells from immune donors, but only if the tumors are growing in T-cell-deficient recipients. It was also shown that the adoptive T-cell-mediated regression of tumors in such recipients can be prevented by prior infusion of splenic T cells from T-cell-intact, tumor-bearing donors. The results leave little doubt that the presence of suppressor T cells in T-cell-intact, tumor-bearing mice is responsible for the loss of an earlier generated state of concomitant immunity, and for the inability of intravenously infused, sensitized T cells to cause tumor regression. Because the presence of suppressor T cells generated in response to the Meth A did not suppress the capacity of Meth A-bearing mice to generate and express immunity against a tumor allograft, it is obvious that they were not in a state of generalized immunosuppression.

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PubMed1980

Increased toxicity of endotoxin for tumor-bearing mice and mice responding to bacterial pathogens: macrophage activation as a common denominator.

Mice bearing the syngeneic SA-1 sarcoma or treated with live Mycobacterium bovis BCG or Formalin-killed Corynebacterium parvum acquired a greatly increased susceptibility to the lethal effects of endotoxin. In all three experimental models, the acquisition of increased sensitivity to endotoxin was concordant with the generation of a systemically activated macrophage system.

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PubMed1980

Macrophage accumulation in murine ascites tumors. I. Cytoxan-induced dominance of macrophages over tumor cells and the anti-tumor effect of endotoxin.

The host cellular response to i.p. growth of the SA-1 spindle cell sarcoma was studied in semisyngeneic AB6F1 hybrid mice. At progressive stages of tumor growth mice were sacrificed, their ascites were collected, and changes in the numbers of tumor cells, macrophages, lymphocytes, and granulocytes were determined. It was found that macrophages were the predominant host cell that accumulated locally in response to tumor growth. Cytoxan treatment caused a 90% reduction in tumor cells without affecting the accumulation of macrophages. Six days after treatment with cytoxan, macrophages exceeded all other cell types present in the peritoneal cavity and outnumbered tumor cells by 20:1. However, in spite of this macrophage dominance, the tumor cells ultimately regrew to kill the host. Ascites tumors could be completely regressed, however, by following cytoxan treatment with an appropriately timed intratumor injection of endotoxin. The relatively long delay before endotoxin caused the tumor to regress suggests that endotoxin acted by stimulating the generation of anti-tumor immunity, rather than by directly augmenting the tumoricidal activity of macrophages.

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PubMed1979

Suppressive effect of bacterial endotoxin on the expression of cell-mediated anti-Listeria immunity.

Intravenous injection of bacterial endotoxin into mice at any time during ongoing infection with Listeria monocytogenes resulted in a markedly increased multiplication of this organism in the liver and spleen. Experiments designed to investigate the basis of this infection-enhancing effect revealed that endotoxin was also capable of inhibiting the expression of adoptive T-cell-mediated anti-Listeria immunity if given to normal recipient mice up to 48 h before they were infused with protective T-cells. On the other hand, endotoxin had only a marginal effect on the expression of adoptive immunity if given to donor mice before their spleen cells were harvested for adoptive transfer. Taken together, these results indicate that endotoxin probably interferes with the antibacterial function of macrophages rather than with mediator lymphocytes. The additional finding that the infection-enhancing action of endotoxin could be greatly reduced by making mice "tolerant" to endotoxin suggests that the acquisition of tolerance to this effect of endotoxin may be an important adaptive mechanism in acquired resistance to infection with gram-negative bacteria.

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PubMed1978

The immunological basis of endotoxin-induced tumor regression. Requirement for T-cell-mediated immunity.

It was shown that although intravenous administration of bacterial endotoxin caused extensive hemorrhagic necrosis of four different syngeneic murine tumors, only two of these tumors subsequently underwent complete regression: the two that were shown to be immunogeneic as classically defined. An immunologic basis for endotoxin-induced regression was further indicated by the additional findings that regression, but not hemorrhagic necrosis, of the two immunogenic tumors failed to occur in mice that were immunodepressed by whole-body gamma-irradiation, or that were made T-cell deficient by thymectomy and irradiation. That endotoxin-induced regression is T-cell mediated was suggested by the findings that tumor regression was followed by a state of long-lived immunity to a tumor cell challenge implant, and with the possession by the host of T cells that were capable of passively transferring this state of immunity to normal recipients. It is concluded that although parenteral injection of endotoxin causes hemorrhagic necrosis of most solid murine tumors, it is only those tumors that are immunogenic enough to evoke the generation of T-cell-mediated immunity which subsequently go on to completely regress.

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PubMed1978

The immunological basis of endotoxin-induced tumor regression. Requirement for a pre-existing state of concomitant anti-tumor immunity.

It was shown that of four syngeneic, murine tumors investigated, only those that evoked the generation of a state of concomitant anti-tumor immunity were susceptible to endotoxin-induced regression. Moreover, the temporal relationship between the generation of concomitant immunity and the onset of susceptibility to endotoxin-induced regression points to the likely possibility that tumor regression depends on the preceding acquisition of the specifically-sensitized, effector T cells that express concomitant immunity. It is suggested that endotoxin-induced hemorrhagic necrosis which invariably precedes tumor regression serves to create conditions inside the tumor that are conducive to the entry and the functioning of effector T cells. It is also suggested that tumor necrosis factor causes hemorrhagic necrosis rather than tumor regression.

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PubMed1977

Subversion of host defense mechanisms by malignant tumors: an established tumor as a privileged site for bacterial growth.

Mice carrying any one of three murine tumors in their right hind foot pad were incapable of eliminating an inoculum of the bacterial parasite Listeria monocytogenes from the progressive tumor. In contrast, they were as capable as control mice in efficiently eliminating the organism from their contralateral tumor-free foot pad, and from their lymph nodes and livers. The results serve to show, therefore, that conditions within an established tumor are not only antagonistic to the expression of concomitant anti-tumor immunity, but that they are also antagonistic to the expression of T-cell-mediated anti-bacterial immunity. The possibility was discussed that the tumor contains factors that act pharmacologically to locally suppress the function of sensitized T cells and activated macrophages.

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PubMed1977

T-cell-mediated concomitant immunity to syngeneic tumors. I. Activated macrophages as the expressors of nonspecific immunity to unrelated tumors and bacterial parasites.

Progressive growth of the SA1 sarcoma was shown to result in the generation of a state of concomitant resistance to growth of a second implant of the same tumor. The responding lymph nodes of concomitantly immune mice were shown to contain theta-positive T cells that could specifically neutralize the growth of tumor cells in a normal test recipient. Nevertheless, the concomitantly immune host itself was capable to a limited extent of suppressing the growth of unrelated tumors. The generation of immunity, moreover, was associated with the generation of a powerful state of macrophage-mediated, nonspecific resistance to the bacterial parasite, Listeria monocytogenes. It was concluded that systemic macrophage activation was the consequence of the generation of T-cell-mediated immunity to the progressively growing tumor, and that this not only gave the host the capacity to inhibit the growth of unrelated tumors, but also to protect itself against microbial infection. The results gives credence to the view that macrophages play a central role in defense against microbial and neoplastic growth.

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PubMed1976

Subversion of host defense mechanisms by murine tumors. I. A circulating factor that suppresses macrophage-mediated resistance to infection.

The subcutaneous injection of cells of any one of five unselected murine tumors resulted very rapidly in the liberation into the circulation of a small molecular weight factor that severely impaired the capacity of the host to resist experimental infection with Listeria monocytogenes and Yersinia enterocolitica. It was found that the factor appeared in blood within 8 h of injecting tumor cells subcutaneously. That it possessed potent physiological activity was evidenced by the demonstration that an infusion of as little as 0.015 ml of tumor-bearer serum strikingly suppressed the capacity of normal recipients to resist bacterial infection. It was reasoned on the basis of the knowledge that the only cells in mice with the capacity to destroy Listeria are macrophages, that suppression of antibacterial resistance was caused by the ability of the tumor-suppressor factor to interfere, either directly or indirectly, with the antibacterial functions of these mononuclear phagocytic cells. The results are consistent with the hypothesis that at least some malignant neoplastic cells are naturally selected to avoid destruction by native and acquired antitumor mechanisms of mononuclear phagocytes.

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PubMed1976

Subversion of host defense mechanisms by murine tumors. II. Counter-influence of concomitant antitumor immunity.

Subcutaneous injection of murine tumor cells first resulted in a state of severely suppressed macrophage-mediated antibacterial resistance and then in a contrasting state of greatly enhanced antibacterial resistance. Whereas, the state of suppressed antibacterial resistance corresponded to a state of suppressed resistance to a tumor cell challenge, the generation of enhanced antibacterial resistance corresponded to the acquisition of concomitant antitumor immunity. It was suggested on the basis of this evidence that changes in the level of macrophage-mediated antibacterial resistance that occur during growth of the primary tumor reflected changes in the level of the host's resistance to the tumor itself. It was further suggested that the coincidental suppression of antibacterial and antitumor resistance that occurs during the initial stages of growth of the primary tumor represents the operation of a mechanism that enables the tumor to avoid destruction by macrophages. The results support the view that macrophages play an important role in native and acquired resistance to malignant tumors.

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