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Biomedical subjects

G B Mackaness

Publications and source records attributed to G B Mackaness.

At least 55 records · Page 3Linked to original sources
PubMed1969

The effect of cytotoxic agents on the primary immune response to Listeria monocytogenes.

Four drugs, representing four different categories of cytotoxic agents, were studied for their effect on the immune response to Listeria infection in mice. The development of the host's immune response is revealed by a progressive change in the slope of the bacterial growth curve in spleen and liver. It has its onset at 24 hr in untreated mice, but in the presence of effective immunosuppression the organism multiples uninterruptedly until the animal dies from overwhelming infection. When administered as single injections at the time of infection, cyclophosphamide, vinblastine, and azathioprine all produced an effective immunosuppression, characterized by continuous bacterial multiplication. Methotrexate was also immunosuppressive, but unlike the others its effects were reversible. They could be sustained, however, by further treatment. Studies of the time-response relationship indicated that cyclophosphamide was highly active over a broad time-span ranging from 2 days before infection to 4 days after infection. Vinblastine on the other hand was maximally active when given on the day of infection, while methotrexate had its greatest effect when given 48 hr after infection. These differences indicate that these three drugs act on different cell populations involved in the host's immune response. The effects observed have been discussed in relation to what is known of the modes of action of the drugs tested. An observation of interest was the phenomenon of enhanced immunity in animals treated with cyclophosphamide or vinblastine 7-11 days before, and with methotrexate 4 days before infection; reactive hyperplasia of lymphoid tissue following withdrawal of drug was again advanced as an explanation for the occurrence of this paradoxical effect. The experimental model employed is simple, requiring only routine bacteriological facilities and minimal equipment. It seems to offer a useful means of assessing the immunosuppressive activity of drugs and of determining the time-course of their action; it could also be of value in the screening of anticancer agents.

Animals↗
PubMed1969

The effect of cytotoxic agents on the passive transfer of cell-mediated immunity.

A system involving the passive transfer of committed lymphoid cells from Listeria-immune donors has been used to study the phases of the immune response which are sensitive to the immunosuppressive action of various cytotoxic agents. The agents investigated included cyclophosphamide, vinblastine, methotrexate, azathioprine, and X-irradiation. Complete suppression of passive immunization was obtained by the administration of cyclophosphamide or vinblastine to recipients at the time of cell transfer or by prior X-irradiation of recipients a day before cell transfer. Methotrexate was only partially suppressive, whereas azathioprine had no effect at all. The donor cell responsible for the transfer of immunity to recipients was shown to be a resting cell which is sensitive to the action of cyclophosphamide but not to vinblastine. The results of this investigation suggest that the donor cells undergo multiplication in the tissues of the recipient, presumably in response to specific stimulation by Listeria antigens. This in turn results in the activation of host macrophages. The immunosuppressive action of cyclophosphamide, vinblastine, and irradiation in the cell-transfer system has been discussed in relation to a direct cytotoxic action on the immune lymphoid cells of the donor and specific interference with their proliferation in the recipient, as well as impairment of macrophage production on the part of the recipient itself.

Animals↗
PubMed1969

The host response to Calmette-Guérin bacillus infection in mice.

Heterologous organisms (L. monocytogenes and S. typhimurium) were used to study the rate of development, magnitude, and persistence of the antimicrobial resistance engendered in mice by vaccination with BCG. These same methods were used to investigate the influence of prior vaccination on the host response to reinfection. The rate of onset and magnitude of the resistance produced by BCG varied with the vaccinating dose. Increased resistance was detected within 48 hr of injecting large numbers of BCG (approximately 10(8) viable units), but concurrent treatment with isoniazid interrupted its further development. An equal number of heat-killed organisms failed to influence host resistance significantly. The development of tuberculin sensitivity was also dependent upon the continued survival of the immunizing population of BCG. When vaccinated mice were reinfected with BCG, host resistance in spleen and liver was rapidly augmented to the accompaniment of striking changes in the morphology and microbicidal activity of the peritoneal macrophages. These changes occurred most rapidly in mice with a high level of delayed hypersensitivity at the time of reinfection.

Animals↗
PubMed1969

The influence of immunologically committed lymphoid cells on macrophage activity in vivo.

It has been shown that the immune response of mice to infection with L. monocytogenes gives rise to a population of immunologically committed lymphoid cells which have the capacity to confer protection and a proportionate level of delayed-type hypersensitivity upon normal recipients. The cells were most numerous in the spleen on the 6th or 7th day of infection, but persisted for at least 20 days. Further study revealed that the immune cells must be alive in order to confer protection, and free to multiply in the tissues of the recipient if they are to provide maximum resistance to a challenge infection. The antibacterial resistance conferred with immune lymphoid cells is not due to antibacterial antibody; it is mediated indirectly through the macrophages of the recipient. These become activated by a process which appears to depend upon some form of specific interaction between the immune lymphoid cells and the infecting organism. This was deduced from the finding that immune lymphoid cells from BCG-immunized donors, which were highly but nonspecifically resistant to Listeria, failed to protect normal recipients against a Listeria challenge unless the recipients were also injected with an eliciting dose of BCG. The peritoneal macrophages of animals so treated developed the morphology and microbicidal features of activated macrophages. It is inferred that acquired resistance depends upon the activation of host macrophages through a product resulting from specific interaction between sensitized lymphoid cells and the organism or or its antigenic products. Discussion is also made of the possibility that activation of macrophages could be dependent upon antigenic stimulation of macrophages sensitized by a cytophilic antibody.

Animals↗
PubMed1969

The effect of anti-lymphocyte globulin on cell-mediated reistance to infection.

The specificity of anti-lymphocyte globulin (ALG) has been used to analyze an immune mechanism which is mediated by immunologically committed lymphoid cells to the apparent exclusion of humoral antibody. Rabbit antimouse lymphocyte globulin completely suppressed the immunity which can be passively transferred with Listeria-immune lymphoid cells from actively infected donors. When prospective donors were given a single dose of 1.0 mg of ALG, it remained active against immune lymphoid cells transferred 24 hr later; yet immune cells in the spleens of donors could not be inactivated in situ by even larger doses of ALG given 24 hr prior to cell harvest. In keeping with this finding, the immunity to reinfection with Listeria was not suppressed by a single dose of ALG, indicating that the immunologically active cells in the spleen are not accessible to intravenously administered ALG. On the other hand, protracted treatment with ALG did abolish most of the memory of a previous infection in intact animals. From this and other evidence, it was concluded that immunologically committed cells are vulnerable to attack by ALG only if they circulate. While in circulation, they make contact both with ALG and the phagocytic elements of the reticuloendothelial system which appear to be responsible for their destruction. Four lines of evidence indicated that the suppression of anti-Listeria resistance with ALG depends upon destruction of immune lymphoid cells and not to any action it has on host macrophages. It is possible to infer from this that immunity to L. monocytogenes depends upon a two cell system in which the donor lymphoid cells provide the immunological reactivity to the organism and recipient macrophages provide the mechanism through which resistance is expressed. Accompanying papers provide additional support for this view, and reasons for believing that delayed-type hypersensitivity and acquired cellular resistance are mediated by the same population of immunologically committed lymphoid cells.

Animals↗
PubMed1967

Cellular immunity.

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Hypersensitivity, Delayed↗
PubMed1966

Host-parasite relations in mouse typhoid.

The development of acquired resistance to Salmonella typhimurium has been studied in mice infected intravenously with small numbers of streptomycin-sensitive or streptomycin-resistant organisms. By the 14th day of a primary infection the mouse develops a mechanism capable of destroying completely a super infecting dose of organisms, but is unable to eliminate organisms of the primary infection. The latter are constantly returned to the circulation from necrotic foci at the sites of implantation. Passive transfer of serum from actively infected or vaccinated animals, and immunization with heat-killed organisms, increase the capacity of the host to clear organisms from the blood, but do not interfere to any significant extent with their subsequent multiplication in the tissues. It is concluded that the resistance of actively infected animals depends on a nonhumoral mechanism capable of destroying organisms from endogenous or exogenous sources.

Animals↗
PubMed1966

Mechanisms of acquired resistance in mouse typhoid.

Experiments in vitro comparing normal mouse peritoneal macrophages with cells from Salmonella typhimurium-infected mice have shown that the "immune" macrophages have conspicuously enhanced microbicidal properties. Whereas normal macrophages could inactivate only 50 to 60% of intracellular S. typhimurium pretreated with immune serum, cells from infected animals killed virtually all ingested organisms and did so at an accelerated rate. Macrophages from Listeria monocytogenes-infected mice were shown to possess similarly enhanced microbicidal activity against S. typhimurium. Furthermore, the growth of S. typhimurium in the liver and spleen was more effectively restricted in Listeria-infected mice than in animals vaccinated with heat-killed S. typhimurium, even though the Listeria-infected animals possessed no demonstrable cross-reacting antibody to S. typhimurium. The lack of resistance in the mice vaccinated with heat-killed organisms could not be attributed to any deficiency of humoral factors, since the serum from these animals was as effective at promoting phagocytosis and killing by macrophages as serum from actively infected (and demonstrably resistant) mice. Conversely, Salmonella-infected mice were totally resistant to intravenous challenge with L. monocytogenes. The level of resistance in individual animals was related to the numbers of residual Salmonellae remaining in the tissues; mice with heavier residual infections being the more resistant. Specific antiserum from mice vaccinated with heat-killed S. typhimurium was found to be significantly protective only when the intraperitoneal route of challenge was employed. The foregoing studies have been interpreted to mean that enhancement of the microbicidal ability of macrophages is the mechanism of major importance in acquired resistance to S. typhimurium infection in mice.

Animals↗