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R J North

Publications and source records attributed to R J North.

At least 73 records · Page 4Linked to original sources
PubMed1989

Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamide-resistant murine tumor: a consequence of eliminating precursor L3T4+ suppressor T-cells.

It was shown that it is possible to use cyclophosphamide (Cy) to cause immunologically mediated regression of the immunogenic, Cy-resistant L5178Y lymphoma in syngeneic and semisyngeneic mice. In order to cause tumor regression it was necessary to give Cy shortly before or shortly after tumor implantation. However, regardless of whether Cy was given before or after tumor implantation, tumor regression did not commence until 10 days of progressive tumor growth, by which time the tumor was 1 cm in diameter. Tumor regression was associated with the presence in the spleen of an increased number of Lyt-2+ T-cells capable of passively transferring immunity to tumor-bearing recipients. This augmented level of immunity was sustained throughout the period of tumor regression. In contrast, a lower level of concomitant immunity generated by control tumor bearers decayed after Day 12 of tumor growth. Because the therapeutic effect of Cy could be inhibited by passive transfer of L3T4+ T-cells from normal donor mice it is apparent that the therapeutic effect of Cy is based on its ability to preferentially destroy L3T4+ suppressor T-cells. These putative precursor suppressor T-cells were regenerated 4 days after being destroyed by Cy. Taken together the results represent a striking example of the negative regulatory influence of suppressor T-cells on the immune response to an immunogenic tumor.

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PubMed1988

Interleukin 1-induced, T cell-mediated regression of immunogenic murine tumors. Requirement for an adequate level of already acquired host concomitant immunity.

Intraperitoneal injection of human rIL-1 in a dose of 0.5 microgram daily for 5 d, or 1 microgram daily for 3 d, was capable of causing complete regression of immunogenic SA1 sarcoma growing subcutaneously in syngeneic or semisyngeneic mice. Higher doses of IL-1 were not more therapeutic against the SA1 sarcoma, but needed to be given to cause complete regression of the immunogenic L5178Y lymphoma. On the other hand, the P815 mastocytoma was much less responsive to IL-1 therapy, in that it failed to undergo complete regression in response to doses of IL-1 capable of causing regression of the L5178Y lymphoma. IL-1 caused regression of the SA1 sarcoma when given on days 6-8 of tumor growth, but not when given on days 1-3. This refractoriness of a small tumor to IL-1 therapy suggests that the antitumor action of IL-1 is based on an underlying host-immune response that is not generated until after day 3 of tumor growth. Direct evidence for the participation of host immunity in IL-1-induced tumor regression was supplied by results showing that IL-1 was not therapeutic against the SA1 sarcoma growing in T cell-deficient (TXB) mice, unless these mice were first infused with Ly-2+ and L3T4+ T cells from donor mice bearing an established SA1 sarcoma. In contrast, normal T cells, or T cells from donor mice bearing a YAC-1 lymphoma, failed to provide TXB recipients with the ability to cause regression of their SA-1 sarcoma in response to IL-1 treatment. The results are in keeping with the interpretation that exogenous IL-1, by augmenting the production of tumor-sensitized T cells, converts a subtherapeutic level of host immunity to a therapeutic level. The results suggest, in addition, that IL-1 only stimulates the replication of T cells that are already engaged in the antitumor immune response.

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PubMed1988

Immunologically mediated regression of a murine lymphoma after treatment with anti-L3T4 antibody. A consequence of removing L3T4+ suppressor T cells from a host generating predominantly Lyt-2+ T cell-mediated immunity.

This study shows that intravenous injection of 1 mg of anti-L3T4 mAb (GK1.5) into thymectomized mice bearing the syngeneic L5178Y lymphoma results, after a delay of 2-3 d, in complete regression of this tumor and in long-term host survival. A flow cytofluorometric examination of the spleen cells of mAb-treated mice revealed that antibody treatment resulted in the elimination of greater than 98% of L3T4+ T cells, but had no effect on the Lyt-2+ T cells subset. Tumor regression was immunologically mediated, because L5178Y lymphoma cells were shown to be L3T4-, and regression of the tumor failed to occur in mice that had been lethally irradiated before anti-L3T4 mAb was given. Tumor regression was mediated by tumor-sensitized Lyt2+ T cells, as evidenced by the finding that treatment of tumor-bearing mice with anti-Lyt-2 mAb alone, or in combination with anti-L3T4 mAb, resulted in enhancement of tumor growth and a significant decrease in host survival time. Moreover, the spleens of mice whose tumors were undergoing regression in response to anti-L3T4 mAb treatment contained Lyt-2+ T cells capable, on passive transfer, of causing regression of a tumor in recipient mice. These results can be interpreted as showing that removal of tumor-induced L3T4+ suppressor T cells results in the release of Lyt-2+ effector T cells from suppression, and consequently in the generation of enough Lyt-2+ T cell-mediated immunity to cause tumor regression. This can only be achieved, however, if immunity to the tumor is mediated exclusively by Lyt-2+ T cells, as is the case for the L5178Y lymphoma. In the case of the P815 mastocytoma, treatment with anti-L3T4 mAb was without a therapeutic effect, and this was in keeping with the finding that immunity to this tumor is mediated by L3T4+, as well by Lyt-2+ T cells.

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PubMed1988

The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity.

The ability of murine recombinant tumor necrosis factor (rTNF) and natural TNF in tumor-necrotizing serum (TNS) to cause regression of the SA1 sarcoma was investigated. We found that to cause regression of a 9-d SA1 sarcoma, near lethal quantities of rTNF and TNS had to be given to the host. However, even at these highly toxic doses, rTNF was not reliable at causing complete tumor regression. On the other hand, both types of TNF were reliable at causing a tumor hemorrhagic reaction that resulted in the destruction of greater than 75% of the tumor's center in 24 h. The TNF-induced hemorrhagic reaction involved the development of numerous petechial hemorrhages in the tumor's vascular bed, which apparently resulted from destruction of the tumor's blood vessels. It was possible to follow the development of the hemorrhagic reaction against time after giving rTNF or TNS by measuring the intratumor extravasation of 51Cr-labeled syngeneic red cells. According to this method, TNF-induced intratumor hemorrhaging was in progress within 1 h of giving TNF and continued for about a 6-h period. However, the hemorrhagic reaction was greatly reduced and complete regression of the rim of the living tumor tissue that survived hemorrhagic necrosis failed to occur, if SA1 sarcoma was growing in T cell-deficient (TXB) mice. This indicates that the TNF-induced hemorrhagic reaction is partly dependent, and the tumor regression that follows is completely dependent on host immunocompetence. This suggests in turn, that rTNF does not directly destroy SA1 tumor cells in vivo, even though it was shown that it can destroy SA1 tumor cells in vitro. This interpretation is supported by the additional findings that rTNF was no more therapeutic against a 3-d (3-mm) SA1 than against a 9-d (8-mm) SA1, and was no more therapeutic when injected directly into the tumor than when injected intravenously. Lastly it was possible to completely inhibit the ability of rTNF and TNS to cause tumor hemorrhagic necrosis and regression by infusing the host with a monospecific, polyvalent anti-rTNF antibody that neutralized the cytotoxic action of rTNF in vitro.

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PubMed1988

The antitumor function of tumor necrosis factor (TNF) II. Analysis of the role of endogenous TNF in endotoxin-induced hemorrhagic necrosis and regression of an established sarcoma.

In agreement with the results of previous studies (1), it was shown that intravenous injection of endotoxin into mice bearing 9-d SA1 sarcoma resulted in a tumor hemorrhagic reaction that rapidly caused necrosis of most of the center of the tumor, and then the complete regression of the rim of living tumor tissue that survived the hemorrhagic reaction. The tumor hemorrhagic reaction was confined to the vascular bed of the tumor, and its rate and extent of development were measured in terms of the intratumor extravasation of 51Cr-labeled syngeneic red cells. The development of the hemorrhagic reaction was associated with the presence in the tumor over a 6-h period of endogenous TNF that was measured in terms of its capacity to kill L929B cells in vitro and identified by its susceptibility to neutralization with a monospecific, polyvalent anti-rTNF antibody. The same antibody was capable in vivo of inhibiting the endotoxin-induced tumor hemorrhagic reaction by only approximately 50%, even when present in the tumor in excess. However, it was capable when given in the same quantity of inhibiting the ability of endotoxin to cause complete tumor regression. The fact that TNF was generated in the tumor during the tumor hemorrhagic reaction, and that infusion of a sufficient quantity of anti-rTNF antibody severely interfered with hemorrhagic necrosis and prevented tumor regression represents convincing evidence that TNF is an essential participant in endotoxin-induced regression of an established SA1 sarcoma. Moreover, because tumor regression, as opposed to hemorrhagic necrosis, failed to occur if the tumor was growing in immunoincompetent mice, but did so if the mice were infused with tumor-sensitized T cells, it can be concluded that an adequate level of T cell-mediated immunity is also an essential requirement for endotoxin-induced tumor regression. The participation of other endotoxin-induced mediators in tumor regression cannot be ruled out.

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PubMed1988

Sublethal, whole-body ionizing irradiation can be tumor promotive or tumor destructive depending on the stage of development of underlying antitumor immunity.

It was shown that sublethal (500 rads), whole-body gamma-irradiation of mice bearing an established i.d. immunogenic tumor can result, after several days delay, in complete tumor regression and long-term survival, but only if radiation is given after the tumor is established and growing progressively. Exposing mice to the same dose of radiation several hours after tumor cells were implanted resulted, in contrast, in enhanced growth of the primary tumor and in earlier death from systemic disease. Irradiation-induced tumor regression failed to occur in mice that were incapable of generating antitumor immunity, because of having been made T cell deficient by thymectomy and irradiation. Again, irradiation-induced tumor regression could be blocked by infusion of spleen cells from donor mice bearing a well-established tumor. These and previously published results support the view that sublethal, whole-body ionizing irradiation causes tumor regression by preferentially destroying radiosensitive suppressor T cells, thereby enabling the host to generate a therapeutic level of concomitant immunity. It is suggested that the preferential destruction of suppressor cells by irradiation depends on the acquisition, during immunologic induction, of radioresistance by antigen-activated effector T cells, and that this is the reason irradiation causes regression only of established tumors. Not all tumors tested were immunogenic enough to undergo regression in response to gamma-irradiation.

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PubMed1988

Cyclophosphamide (Cy)-facilitated adoptive immunotherapy of a Cy-resistant tumour. Evidence that Cy permits the expression of adoptive T-cell mediated immunity by removing suppressor T cells rather than by reducing tumour burden.

A cyclophosphamide (Cy)-resistant immunogenic tumour, the L5178Y lymphoma, was used to demonstrate that Cy-treatment of a host bearing this tumour enables passively transferred tumour-sensitized T cells to cause complete tumour regression without any need for Cy to cause a reduction in tumour burden. It was shown that whereas infusion of tumour-sensitized T cells from immune donors had very little effect on growth of the tumour, and whereas treatment with 150 mg/kg of Cy caused appreciable enhancement of tumour growth, combination therapy with Cy plus immune T cells caused complete tumour regression and resulted in long-term survival. Evidence that Cy treatment facilitated the expression of adoptive immunity against the L5178Y lymphoma by eliminating tumour-induced suppressor T cells consisted of the demonstration that tumour regression caused by combination treatment with Cy and immune T cells could be inhibited by infusing the recipient with Cy-sensitive, L3T4+ T cells from tumour-bearing but not from normal donors.

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PubMed1987

Subtherapeutic numbers of tumour-sensitized, L3T4+, Ly 1+2- T cells are needed for endotoxin to cause regression of an established immunogenic tumour.

The immunological requirements for endotoxin-induced regression of an established subcutaneous tumour (SA 1 sarcoma) were investigated by employing tumour-bearing T-cell deficient mice as test recipients, and mice generating concomitant immunity, or Corynebacterium parvum-augmented concomitant immunity, as donors of sensitized T cells. It was found that endotoxin failed to cause regression of an established tumour in T-cell deficient recipients unless they were infused 2 days earlier with a subtherapeutic number of T cells from donors generating concomitant immunity. The donor T cells that primed the recipient tumour for endotoxin-induced regression displayed the L3T4+, Ly 1+2- membrane phenotype. T-cell priming for endotoxin-induced regression was specific and localized, as evidenced by the results of experiments that employed recipients simultaneously bearing two different syngeneic tumours. Infusing these recipients with T cells sensitized to one tumour primed that tumour, but not the other, for endotoxin-induced regression. The ultimate effector mechanism of regression also appeared to be specific, in that a mixed tumour made up of YAC1 lymphoma cells plus SA1 sarcoma cells underwent complete regression only in recipients infused with both YAC1-sensitized and SA1-sensitized T cells. These results indicate that, whereas endotoxin-induced tumour necrosis may not depend on an anti-tumour immune response, regression of the ring of living tumour tissue that surrounds the area of necrosis is specifically accomplished by an acquired population of tumour-sensitized L3T4+ T cells.

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PubMed1987

Frequency analysis of augmented CTL production associated with Corynebacterium parvum-induced tumour regression.

A limiting-dilution frequency assay was employed to estimate the increased production of cytolytic T lymphocytes (CTL) associated with Corynebacterium parvum-induced regression of the P815 mastocytoma growing subcutaneously in semisyngeneic mice. It was found that intratumour C. parvum functioned to augment greatly the underlying concomitant production of CTL that occurs normally in response to a progressively growing untreated immunogenic tumour. The lymph node draining a C. parvum-treated tumour contained about eight times more CTL than the lymph node draining a control tumour. Intratumour C. parvum also caused a large increase in CTL production in the spleen and an increase in the number of CTL that could accumulate in a peritoneal exudate. At the peak of the anti-tumour response, the largest number of CTL was found in the draining lymph node (1.66 X 10(5], followed by the spleen (3.47 X 10(4) and by a 24-hr casein-induced peritoneal exudate (6.01 X 10(3]. Presumably, this greatly augmented production of CTL explains why C. parvum given intralesionally early enough during tumour growth can cause the regression of the weakly immunogenic P815 mastocytoma.

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PubMed1986

Radiation-induced, immunologically mediated regression of an established tumor as an example of successful therapeutic immunomanipulation. Preferential elimination of suppressor T cells allows sustained production of effector T cells.

The results of this study confirm results published by others by showing that sublethal whole-body irradiation of mice bearing immunogenic tumors can result in complete tumor regression. The results show, in addition, that irradiation-induced tumor regression can be prevented by infusion, after irradiation, of Ly-1+,2-,L3T4+ suppressor T cells from the spleens of donors bearing an established tumor, but not by infusion of normal spleen cells. This evidence, plus the demonstration that irradiation fails to cause regression of tumors growing in immunocompetent mice, is consistent with the hypothesis that irradiation-induced regression is immunologically mediated, and that it depends on the ability of irradiation to preferentially eliminate suppressor T cells. By using passive transfer assays to measure the production of effector T cells and suppressor T cells against time of tumor growth, it was shown that irradiation of tumor-bearing mice on day 5 of tumor growth resulted in a failure to generate suppressor T cells on the one hand, and in a sustained production, effector T cells on the other. In other words, irradiation prevented the concomitant antitumor immune response from being downregulated by suppressor T cells. However, giving radiation on day 1 of tumor growth, in contrast to giving it 3-6 d later, caused immunodepression and enhancement of tumor growth. This is in keeping with published evidence showing that, whereas resting effector T cells are highly radiosensitive, antigen-activated effector T cells are relatively radioresistant. It is suggested that the radioresistance of activated effector T cells, coupled with the radiosensitivity of activated suppressor T cells, is the reason for the selectivity of ionizing radiation for suppressor T cells and why a tumor needs to be palpable to undergo regression in response to radiation therapy.

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PubMed1986

T cell suppressors of antitumor immunity. The production of Ly-1-,2+ suppressors of delayed sensitivity precedes the production of suppressors of protective immunity.

The results of this study show that during growth of the immunogenic Meth A fibrosarcoma, two different types of suppressor T lymphocytes are generated in sequence. One type is generated during early tumor growth, reaches peak number around day 6, and is progressively lost thereafter. It is defined by its ability, upon passive transfer, to suppress the expression of a DTH reaction to tumor antigens in tumor-immunized recipients. It bears the Ly1-,2+ membrane phenotype and is sensitive to relatively low doses of cyclophosphamide. In contrast, the second type of suppressor cell is not detected until after day 9 of tumor growth, and is defined by its ability to inhibit, upon passive transfer, the expression of adoptive immunity against an established tumor in T cell-deficient recipients. According to previous studies it bears the Ly1+,2-, L3T4a+ membrane phenotype and is less sensitive to cyclophosphamide than the T cell suppressor of DTH. It is argued that this second type of suppressor T cell seems likely to be responsible for the escape of immunogenic tumors from antitumor immunity, because it can suppress the expression of a powerful mechanism of antitumor immunity in recipient mice, and is generated progressively as the tumor-bearing host loses concomitant immunity. In contrast, although the Ly-1-,2+ T cell suppressors of DTH can efficiently suppress a DTH reaction to an implant of living tumor cells, they fail to suppress the expression of immunity to the same implant.

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PubMed1986

Immunological consequences of tumor excision: from active immunity to immunological memory.

Excision of the immunogenic Meth-A fibrosarcoma during generation by the host of concomitant antitumor immunity resulted in the appearance in sequence of two qualitatively distinct states of post-excision immunity. Immunity expressed on the day of excision was dependent on Ly-1-2+, cyclophosphamide-sensitive T cells, whereas immunity expressed 2 weeks later was dependent on cyclophosphamide-resistant T cells which can be functionally eliminated by either anti-Ly-1 or anti-Ly-2 monoclonal antibody and complement. The data suggest that antitumor immunity expressed shortly after tumor excision represents active concomitant immunity that is acquired by the host before excision is performed. In contrast, immunity expressed 2 weeks later is based on immunological memory.

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PubMed1986

Endotoxin-mediated necrosis and regression of established tumours in the mouse. A correlative study of quantitative changes in blood flow and ultrastructural morphology.

The fractional distribution of cardia output was measured in tumour-bearing mice treated with 50 micrograms intravenous endotoxin, and correlated with ultrastructural changes in tumour morphology. The proportion of the cardiac output going to the tumour decreased to less than 50% of its original value by 2 h and to 10%-30% by 6 h after giving endotoxin. Because endotoxin decreases absolute cardiac output, the actual perfusion of the tumour will be considerably less than these figures suggest. The decrease in perfusion correlated closely with changes in vascular morphology. Venous congestion on the tumour edge started within 1 h of giving endotoxin and by 3 h, endothelial damage and platelet aggregates were visible. At this time, all cells, tumour, connective tissue and infiltrate in the tumour centre were dead or damaged. By 24-48 h a conspicuous infiltrate of neutrophils and macrophages was present on the edge of the tumour and many of these cells were closely related to tumour cells. We suggest that the haemorrhagic necrosis may be caused by vascular obstruction leading to hypoxia and that the subsequent regression is mediated by activated macrophages and perhaps by neutrophils.

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PubMed1985

Suppression of generation of concomitant antitumor immunity by passively transferred suppressor T cells from tumor-bearing donors.

Infusion of normal recipient mice with suppressor T cells from donors bearing a progressive Meth A fibrosarcoma results in a diminished capacity of the recipients to generate concomitant and postexcision antitumor immunity. The passive transfer of suppressor cells which prevented the generation of immunity to the Meth A fibrosarcoma did not affect the capacity of the recipients to reject an allogeneic tumor. The data provides direct evidence in support of the hypothesis that suppressor T cells, generated at later stages of growth of Meth A fibrosarcoma, function to down-regulate an already acquired mechanism of concomitant immunity.

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PubMed1985

Ly-1+2- suppressor T cells inhibit the expression of passively transferred antitumor immunity by suppressing the generation of cytolytic T cells.

The results of this study confirm and extend previous findings from this laboratory by showing that the suppressor T cells that are generated during progressive growth of the P815 tumor and inhibit the antitumor cytolytic response in adoptively immunized T-cell-deficient recipients are of the Ly-1+2- phenotype. Thus, Ly-2+ cytolytic effector T cells and suppressor T cells in the system can be distinguished by the complete resistance of suppressor T cells to elimination by anti-Ly-2-antibody-plus-complement treatment. The suppressor cells in this system are different, therefore, from those in most other systems in which suppressor cells, like cytolytic T cells, are Ly2+ or the equivalent rat or human phenotype. The present results also more clearly define how suppressor T cells inhibit the expression of antitumor immunity by showing that passively transferred suppressor T cells inhibit the production of cytolytic T cells in adoptively immunized T-cell-deficient recipients, but not the antitumor function of cytolytic T cells already generated. Finally, the results show that the expression of passively transferred antitumor immunity in T-cell-deficient recipients requires the participation of noncytolytic Ly-1+2- donor T cells. It is apparent, however, that T cells of this phenotype have no direct antitumor activity but function, instead, to "help" in the generation of cytolytic T cells in the recipient.

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