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R J North

Publications and source records attributed to R J North.

At least 91 records · Page 5Linked to original sources
PubMed1985

Ly 1+2- suppressor T cells down-regulate the generation of Ly 1-2+ effector T cells during progressive growth of the P815 mastocytoma.

It has been shown that progressive growth of the P815 mastocytoma in its semisyngeneic B6D2 host results, between days 6 and 9 of tumour growth, in the generation of Ly 1-2+ T cells which are capable, on passive transfer, of causing the regression of an established tumour in gamma-irradiated recipients, and of T cells which are capable of lysing P815 tumour cells in vitro. After 9 days of tumour growth, these effector T cells are progressively lost; this is associated with the progressive acquisition of Ly 1+2- suppressor T cells which are capable of inhibiting the expression of passively transferred immunity against an established tumour in T-cell deficient recipients. The results are consistent with the hypothesis that this P815 mastocytoma grows progressively, in spite of its immunogenicity, because it evokes the generation of suppressor T cells before enough effector T cells are generated to reject it.

Animals↗
PubMed1985

Effect of aging on antimicrobial immunity: old mice display a normal capacity for generating protective T cells and immunologic memory in response to infection with Listeria monocytogenes.

Old (19 to 30 mo) and young adult (11 to 16 wk) AB6F1 mice of both sexes were compared in terms of their capacity to resist infection with Listeria monocytogenes. The LD50 was found to be two to four times higher for old than for young mice, and the time to death was longer for old mice. Enumeration of bacteria in the livers and spleens showed that old mice restricted growth of Listeria more effectively than young mice during the preimmune phase of infection, the difference being detectable as early as 12 to 24 hr after bacterial inoculation. Therefore, to ensure a similar level of infection in old and young mice, old mice had to be given a larger inoculum. Indeed, it was found that, provided the size of the bacterial inoculum was adjusted to make the level of immunizing infection the same, old mice generated similar levels of anti-Listeria immunity as young mice, as measured by their ability to generate splenic T cells capable of adoptively immunizing young recipients against lethal challenge infection. Furthermore, the level of memory immunity to reinfection 28 to 117 days after immunizing infection was similar in old and young mice. The results indicate, therefore, that old mice have no defect in their capacity to generate T cell-mediated anti-Listeria immunity.

Aging↗
PubMed1984

Generation and decay of the immune response to a progressive fibrosarcoma. I. Ly-1+2- suppressor T cells down-regulate the generation of Ly-1-2+ effector T cells.

It was shown that the progressive growth of the immunogenic meth A fibrosarcoma in its semisyngeneic host results in the generation of concomitant immunity to the growth of a tumor implant. The generation of immunity occurred between days 6 and 9 of tumor growth and was associated with the generation of sensitized T cells that were capable, on passive transfer, of causing regression of a 3-d tumor in gamma-irradiated recipients. After day 9 of tumor growth, concomitant immunity and the T cells able to passively transfer it were progressively lost, and this was associated with the generation of splenic suppressor T cells able to suppress the expression of adoptive immunity against an established tumor in T cell-deficient ( TXB ) recipients. The T cells that passively transferred concomitant immunity were shown to be of the Ly-1-2+ phenotype, in contrast to the T cells that transferred suppression, which were shown with the same reagents to be Ly-1+2-. The results are consistent with the hypothesis that the progressive growth of an immunogenic tumor results in the generation of Ly-1-2+-sensitized effector T cells that fail to reach a number sufficient to destroy the tumor because their generation is down-regulated by tumor-induced Ly-1+2- suppressor T cells.

Animals↗
PubMed1984

Generation and decay of the immune response to a progressive fibrosarcoma. II. Failure to demonstrate postexcision immunity after the onset of T cell-mediated suppression of immunity.

This study shows that surgical removal of the meth A fibrosarcoma from its semisyngeneic host fails to result in postexcision immunity to growth of a tumor implant unless the host already has acquired a mechanism of concomitant immunity to growth of an implant. Therefore, tumor excision does not cause immunity to be generated but preserves a mechanism of concomitant immunity that already exists and which otherwise would eventually undergo down-regulation under the influence of suppressor T cells. Removal of the tumor after it has grown large enough to cause the T cell-mediated suppression of concomitant immunity does not result in the reemergence of immunity. Instead, the host remains unable to generate concomitant immunity to a second tumor for a long period of time and retains, for at least 31 d, suppressor T cells able to passively transfer suppression to appropriate recipients. Like the suppressor T cells responsible for active suppression of concomitant immunity, the suppressor T cells responsible for "memory" suppression are of the Ly-1+2- phenotype. The results indicate that progressive tumor growth results in a state of immunological tolerance of tumor-specific, transplantation antigens that can persist in the apparent absence of tumor antigens.

Animals↗
PubMed1984

Specificity of the T cells that mediate and suppress adoptive immunotherapy of established tumors.

This study was designed to investigate the specificity of the T cells that express and suppress antitumor immunity in a model of adoptive immunization against established tumors. Results obtained with the P815 mastocytoma, L5178Y lymphoma, and P388 lymphoma showed, in agreement with previous findings from this laboratory, that an intravenous infusion of splenic T cells from immunized mice can cause the regression of a tumor growing in T-cell-deficient mice. So far as specificity of adoptive immunity is concerned, reciprocal passive transfer experiments with these three tumors revealed that T cells from donor mice immunized against the P815 tumor are not capable of causing regression of the P388 tumor or L5178Y tumor, even if both the P815 and L5178Y tumors are growing in the same host. Similarly splenic T cells from mice immunized against the P388 tumor or L5178Y tumor had no effect on growth of the P815 tumor. Suppression of adoptive immunity was also specific, in that passively transferred suppressor T cells from mice bearing a progressive P815 tumor were capable of suppressing adoptive T-cell-mediated regression of the P815 tumor, but not the P388 tumor growing in T-cell-deficient recipients. Reciprocally, P388 suppressor spleen cells from mice bearing a progressive P388 tumor prevented adoptive T-cell-mediated regression of the P388 tumor, but not the P815 tumor. The results indicate, therefore, that the T cells from immunized mice that mediate adoptive antitumor immunity and the T cells from tumor-bearing mice that suppress the expression of this immunity are specific for the tumor that evokes their generation.

Animals↗
PubMed1984

Gamma-irradiation facilitates the expression of adoptive immunity against established tumors by eliminating suppressor T cells.

It was found that sublethal (550 rad) whole-body gamma-irradiation of mice bearing established immunogenic tumors enabled tumor-sensitized spleen cells infused intravenously 1 h later to cause complete tumor regression in all mice. In contrast, gamma-irradiation alone caused only a temporary halt in tumor growth, and immune cells gave practically no therapeutic effect at all. This result was obtained with the SA1 sarcoma, Meth A fibrosarcoma, P815 mastocytoma, and P388 lymphoma. Additional experiments with the Meth A fibrosarcoma revealed that the spleen cells from tumor-immune donors that caused tumor regression in gamma-irradiated recipients were T cells, as evidenced by their functional elimination by treatment with anti-Thy-1.2 antibody and complement. It was shown next that adoptive T-cell-mediated regression of tumors in gamma-irradiated recipients was inhibited by an intravenous infusion of spleen cells from donors with established tumors, but not by spleen cells from normal donors. The spleen cells that suppressed the expression of adoptive immunity were functionally eliminated by treatment with anti-Thy-1.2 antibody and complement. Moreover, they were destroyed by exposing the tumor-bearing donors to 500 rad of gamma-radiation 24 h before harvesting their spleen cells. The results are consistent with the interpretation that gamma-radiation facilitates the expression of adoptive T-cell-mediated immunity against established tumors by eliminating a population of tumor-induced suppressor T cells from the tumor-bearing recipient.

Animals↗
PubMed1984

The therapeutic significance of concomitant antitumor immunity. I. LY-1-2+ T cells from mice with a progressive tumor can cause regression of an established tumor in gamma-irradiated recipients.

It is shown that progressive growth of the SA1 sarcoma in its semisyngeneic AB6F1 host results in the generation of concomitant immunity to growth of a tumor challenge implant, and in the generation of T cells in the spleen capable, on passive transfer, of causing regression of an established tumor in gamma-irradiated recipients, but not in normal recipients. T cells that passively transferred concomitant immunity against an established tumor were first generated around day 6 of tumor growth, reached peak numbers on day 9, and slowly decreased in number thereafter. They were of the Ly-1-2+ phenotype, in that they were functionally eliminated by treatment with monoclonal anti-Ly-2 antibody and complement, but not by treatment with anti-Ly-1 antibody and complement. The paradoxical ability of T cells from a donor with a relatively large tumor to cause the regression of a tumor in sublethally gamma-irradiated recipients is explained with reference to the facts that the recipient tumor was only half as large as the donor tumor at the time of passive transfer, and that the recipient was incapable of generating suppressor T cells that would function to inhibit the expression of adoptive immunity.

Animals↗
PubMed1984

The therapeutic significance of concomitant antitumor immunity. II. Passive transfer of concomitant immunity with Ly-1+2- T cells primes established tumors in T cell-deficient recipients for endotoxin-induced regression.

Intravenous injection of 50 micrograms bacterial endotoxin can cause complete regression of an established SA1 sarcoma, but not if the tumor ir growing in mice that are incapable of generating concomitant immunity because they have been made T cell-deficient by thymectomy and gamma-radiation (TXB mice). It also was shown that endotoxin fails to cause complete regression of a tumor that is either too large or too small. Only when administered on day 9 of tumor growth, at the time of peak concomitant immunity, did endotoxin cause the tumor to undergo complete regression. Direct evidence that the antitumor effect of endotoxin is dependent on concomitant immunity consisted in the demonstration that an SA1 sarcoma growing in TXB recipients can be primed for endotoxin-induced regression by IV infusion of splenic T cells from concomitantly immune donors bearing an endotoxin-susceptible 9-day tumor. Surprisingly, the donor T cells that primed the recipient tumor for endotoxin-induced regression were of the Ly-1+2- phenotype, as evidenced by their susceptibility to treatment with anti-Ly-1 antibody and complement, and their complete resistance to treatment with anti-Ly-2 antibody and complement. They were different, therefore, from the T cells that cause the regression of smaller tumors in gamma-irradiated recipients without the aid of endotoxin. It is suggested that the antitumor function of endotoxin depends on its ability to cause intratumor macrophages to acquire and express tumoricidal function, but only after the macrophages have been activated by Ly-1+2-tumor-sensitized T cells.

Animals↗
PubMed1984

Adoptive immunization against an established tumor with cytolytic versus memory T cells. Immediate versus delayed onset of regression.

Intradermal injection of an admixture of P815 tumor cells and Corynebacterium parvum results in the emergence of a tumor that grows progressively for 9-10 days and then undergoes complete regression. Tumor regression is preceded by a cytolytic T cell response in the spleen that peaks on day 10 and then undergoes progressive decay until days 15-16 when cytolytic T cells can no longer be detected. Passive transfer of 10-day or 30-day spleen cells to T-cell-deficient recipients bearing a 4-day tumor resulted in complete tumor regression. However, whereas passively transferred 10 day spleen cells caused the onset of tumor regression within 2 days, passively transferred 30-day spleen cells did not cause tumor regression until after a 6-8-day delay. Again, the antitumor function of 10-day spleen cells could be eliminated by treatment with cyclophosphamide and vinblastine sulfate, whereas 30 day spleen cells were resistant to both agents. These results indicate that 10-day spleen cells are physiologically different from 30-day spleen cells. The results are consistent with the interpretation that passively transferred 10-day spleen cells cause rapid onset of tumor regression because they are cytolytic T cells and have an immediate capacity to destroy the tumor. In contrast, 30-day spleen cells are helper or memory T cells with no capacity at the time of transfer to destroy the tumor.

Adjuvants, Immunologic↗
PubMed1983

Expression of passively transferred immunity against an established tumor depends on generation of cytolytic T cells in recipient. Inhibition by suppressor T cells.

The results of this study with the P815 mastocytoma confirm the results of previous studies that showed that the passive transfer of tumor-sensitized T cells from immunized donors can cause the regression of tumors growing in T cell-deficient (TXB) recipients, but not in normal recipients. The key additional finding was that the expression of adoptive immunity against tumors growing in TXB recipients is immediately preceded by a substantial production of cytolytic T cells in the recipients' draining lymph node. On the other hand, failure of adoptive immunity to be expressed against tumors growing in normal recipients was associated with a cytolytic T cell response of much lower magnitude, and a similar low magnitude response was generated in TXB recipients infused with normal spleen cells and in tumor-bearing control mice. Because the passively transferred sensitized T cells possessed no cytolytic activity of their own, the results indicate that the 6-8-d delay before adoptive immunity is expressed represents the time needed for passively transferred helper or memory T cells to give rise to a cytolytic T cell response of sufficient magnitude to destroy the recipient's tumor. In support of this interpretation was the additional finding that inhibition of the expression of adoptive immunity by the passive transfer of suppressor T cells from tumor-bearing donors was associated with a substantially reduced cytolytic T cell response in the recipient's draining lymph node. The results serve to illustrate that interpretation of the results of adoptive immunization experiments requires a knowledge of the events that take place in the adoptively immunized recipient. They support the interpretation that suppressor T cells function in this model to "down-regulate" the production of cytolytic effector T cells.

Animals↗
PubMed1983

Advantages of measuring changes in the number of viable parasites in murine models of experimental cutaneous leishmaniasis.

Previously published studies of experimental cutaneous leishmaniasis in the mouse have relied almost exclusively on measuring changes in lesion size to follow the course of the infection. The purposes of the studies reported here were to develop a technique to quantitate the number of viable organisms in the tissues and to use the technique to follow the development and resolution of the primary infection as well as the development of acquired resistance to Leishmania tropica in a resistant (C3H/He) and a susceptible (BALB/c) mouse strain. It was found that individual L. tropica amastigotes derived from infected tissues would transform to promastigotes and repeatedly divide to form discrete, countable colonies on rabbit blood agar. The plating efficiency was approximately 88%. Using the blood agar plating technique to quantitate the organism against time of the infection, we obtained data that suggest that acquired resistance develops in C3H/He mice earlier than is suggested by reduction in lesion size. In addition, although this resistance eliminates the parasites from the primary lesion in 10 weeks, 1,000 to 10,000 parasites persist for months in the lymph node draining the lesion site. In these studies, we found no evidence of acquired resistance in the susceptible BALB/c mice. The organism grows progressively, and the infection can disseminate to the spleen within 2 weeks. These studies illustrate the advantages of quantitating viable parasites in studies of immunity in cutaneous leishmaniasis.

Animals↗
PubMed1982

Non-H-2 restriction of expression of passively transferred delayed sensitivity.

The results of this study of allogeneic restriction of passively transferred delayed sensitivity to Listeria antigens serve to illustrate the complexity of in vivo models. They show that the H-2 restriction observed when delayed-type hypersensitivity was transferred between H-2-congenic strains was no more severe than the restriction observed when delayed-type hypersensitivity was transferred between parental and F1 mice and between different strains sharing the same H-2 haplotype. It is obvious that genes, in addition to those of the H-2 locus, can be responsible for allogeneic restriction in vivo.

Animals↗
PubMed1982

Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells.

On the basis of preceding studies showing that tumor-induced, T cell-mediated immunosuppression serves as an obstacle to adoptive immunotherapy of the Meth A fibrosarcoma, it was predicted that cyclophosphamide treatment of tumor bearers would remove this obstacle and allow passively transferred immune T cells to cause tumor regression. It was found that infusion of immune spleen cells alone had no effect on tumor growth, and cyclophosphamide alone caused a temporary halt in tumor progression. In contrast, combination therapy consisting of intravenous injection of 100 mg/kg of cyclophosphamide followed 1 h later by intravenous infusion of tumor-immune spleen cells caused small, as well as large tumors, to completely and permanently regress. Tumor regression caused by combination therapy was completely inhibited by intravenous infusion of splenic T cells from donors with established tumors, but not by spleen cells from normal donors. These suppressor T cells were eliminated from the spleen by treating the tumor-bearing donors with 100 mg/kg of cyclophosphamide. Immune T cells, in contrast, were resistant to this dose of cyclophosphamide. These results show that failure of intravenously-infused, tumor-sensitized T cells to cause regression of the Meth A fibrosarcoma growing in its syngeneic or semi-syngeneic host is caused by the presence of a tumor-induced population of cyclophosphamide-sensitive suppressor T cells.

Animals↗
PubMed1982

Generation of enhanced macrophage-mediated antibacterial resistance in animals responding to tumor allografts.

Enhanced systemic antibacterial resistance was acquired by ACF1 (H-2ad) and B6D2F1 (H-2bd) mice bearing allogenetic BP-3 (H-2b) and SA-1 (H-2a) footpad tumors, respectively. This effect was dose dependent, in that the implantation of greater numbers of tumor cells produced larger tumors and higher levels of nonspecific resistance. Although the rejection of the tumor was T-cell dependent, the generation of nonspecific resistance was not. Thus, T-cell-deficient mice bearing progressively growing tumor allografts generated significant levels of antibacterial resistance. Two mechanisms were found to be involved in the generation of nonspecific resistance: (i) an acquired radioresistant mechanism responsible for initially destroying a large proportion of injected bacteria and (ii) an acquired radiosensitive mechanism responsible for destroying a significant number of bacteria after 24 h.

Animals↗