Biomedical subjects

R J North

Publications and source records attributed to R J North.

At least 55 records · Page 3Linked to original sources

PubMed1992

Monoclonal antibody NIMP-R10 directed against the CD11b chain of the type 3 complement receptor can substitute for monoclonal antibody 5C6 to exacerbate listeriosis by preventing the focusing of myelomonocytic cells at infectious foci in the liver.

Treatment of mice with a monoclonal antibody (mAb) designated NIMP-R10, directed against the CD11b polypeptide of the CD18/CD11b heterodimeric type 3 complement receptor (CR3), exacerbates listeriosis by preventing myelomonocytic cells from focusing at sites of infected hepatocytes in the liver. Under these conditions an otherwise sublethal Listeria inoculum grows unrestrictedly within hepatocytes and causes death in 3 days. The results obtained with NIMP-R10 are similar to those previously obtained with a different anti-CD11b mAb (5C6), although mAb NIMP-R10 is more effective at enhancing infection. Therefore, both mAbs can be used to analyze host antibacterial defenses in vivo.

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PubMed1992

Early pathogenesis of infection in the liver with the facultative intracellular bacteria Listeria monocytogenes, Francisella tularensis, and Salmonella typhimurium involves lysis of infected hepatocytes by leukocytes.

The results show that Listeria monocytogenes, Francisella tularensis, and Salmonella typhimurium are facultative intracellular bacteria with a capacity to invade and grow in nonphagocytic cells in vivo. In the liver, all of these pathogens were seen to invade and to multiply extensively in hepatocytes. In all three cases, inflammatory phagocytes were rapidly marshalled to foci of infection where they appeared to cause the destruction of infected hepatocytes, thereby releasing bacteria into the extracellular space, in which presumably they could be ingested and destroyed by the phagocytes. If phagocytic cells were prevented from accumulating at foci of liver infection by treatment of the mice with a monoclonal antibody (NIMP-R10) directed against the type 3 complement receptor of myelomonocytic cells, then lysis of hepatocytes failed to occur and bacteria proliferated unrestrictedly within them. Under these circumstances, otherwise sublethal infections became rapidly lethal. These findings strongly suggest that lysis of infected hepatocytes by phagocytic cells is an important general early-defense strategy against liver infection with at least three different intracellular bacteria.

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PubMed1992

Roles of Listeria monocytogenes virulence factors in survival: virulence factors distinct from listeriolysin are needed for the organism to survive an early neutrophil-mediated host defense mechanism.

Avirulent mutant strains of Listeria monocytogenes which fail to produce phosphatidylinositol-specific phospholipase C, or which produce reduced amounts of hemolytic listeriolysin O, are incapable of causing progressive infection in normal mice. However, both strains can grow progressively in mice that have been rendered incapable of focusing neutrophils at sites of infection as a result of being treated with monoclonal antibody 5C6, specific for the type 3 complement receptor of myelomonocytic cells. In 5C6-treated mice, phospholipase C-negative and listeriolysin-defective mutant strains of L. monocytogenes, like the wild-type strain, give rise in the liver to large numbers of discrete foci of infected hepatocytes that retain their morphological integrity during the first 24 h, despite their large bacterial burden. In normal mice, in contrast, sites of infection in the liver are indicated by discrete focal accumulations of neutrophils that occupy the space originally occupied by infected hepatocytes. It is apparent that in normal mice neutrophils function to lyse infected hepatocytes and thereby to release L. monocytogenes for ingestion and killing by neutrophils themselves and by macrophages. However, whereas a proportion of wild-type organisms survive this early mechanism of defense to give rise to progressive infection, the phospholipase C-negative organisms are totally eliminated. On the basis of these and other results, it is suggested that virulence factors other than listeriolysin are needed by L. monocytogenes to counteract the early neutrophil-mediated mechanism of defense. Listeriolysin, itself, is an intrinsic virulence factor that allows L. monocytogenes to survive and multiply in a proportion of the fixed phagocytes of the liver (permissive phagocytes) and which enables the organism to go on to infect and replicate in adjacent hepatocytes. It was found that a mutant strain of L. monocytogenes incapable of producing any listeriolysin was incapable of establishing progressive infection, even in 5C6-treated mice.

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PubMed1991

Neutrophil-mediated dissolution of infected host cells as a defense strategy against a facultative intracellular bacterium.

The rate of growth of Listeria monocytogenes in the livers of mice infected intravenously with a lethal or sublethal inoculum of this facultative intracellular bacterium is greatly increased if neutrophils and other host cells are prevented from accumulating at foci of infection during the first 24 h by treatment with a monoclonal antibody (5C6) specific for the type 3 complement receptor of myelomonocytic cells. A histological examination of the livers of control mice showed that the accumulation of neutrophils at infectious foci resulted in the focal destruction of infected hepatocytes. In contrast, failure of neutrophils to accumulate at these sites in 5C6-treated mice allowed Listeria to multiply extensively in hepatocytes without destroying them. The results indicate that neutrophils play an important role in early defense against listeriosis in the liver by destroying infected hepatocytes, thereby reducing the opportunity for Listeria to multiply in permissive cells. In this way, neutrophils serve to break the chain of cell-to-cell spread of infection.

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PubMed1991

Selective radiation resistance of immunologically induced T cells as the basis for irradiation-induced T-cell-mediated regression of immunogenic tumor.

Sublethal, whole-body gamma-irradiation of immunocompetent, but not T cell deficient, mice bearing an established immunogenic tumor results in T-cell-mediated complete tumor regression and in long-term host survival. This striking T-cell-dependent immunotherapeutic action of irradiation was paradoxically associated with the destruction of over 90% of host T cells and with a state of severe immunodepression as evidenced by the inability of irradiated mice to reject a tumor allograft. Furthermore, whereas exposure to 500 rads caused regression of a syngeneic tumor implanted 6 days before irradiation, it caused enhanced growth of a different syngeneic tumor growing on the same animal and implanted 1 day before. This ability of irradiation to cause regression of a 6 day tumor, but accelerated growth of a 1 day tumor, was also seen when the tumors were implanted in the reverse order. This means that, between days 1 and 6 of a tumor growth, tumor-specific T cells are converted from a radiosensitive to a highly radioresistant state, almost certainly because of having been activated and inducted into the antitumor immune response. This explanation for the selective radioresistance of effector T cells is based on publications showing that activated, in contrast to resting, T cells are highly radioresistant. Thus irradiation-induced, T-cell-mediated tumor regression depends not only on the destruction of radiosensitive suppressor T cells but also on the selective sparing of radioresistant activated effector T cells that are needed to destroy the tumor in the absence of suppression.

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PubMed1991

Effect of advanced aging on ability of mice to cause regression of an immunogenic lymphoma in response to immunotherapy based on depletion of suppressor T cells.

This study shows that two therapeutic agents, anti-CD4 mAb and vinblastine, capable of causing T-cell-mediated regression of an established L5178Y lymphoma in 3-month-old mice, are incapable of causing regression of this tumor in 20- to 22-month-old mice. It is known that both agents are immunoaugmentative because of their ability to destroy tumor-induced CD4+ suppressor T cells preferentially. Therefore, the results indicate, that aged mice, unlike young mice, are not capable of generating therapeutic numbers of CD8+ effector T cells in the absence of suppressor cells.

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PubMed1991

Rapid acquisition of an enhanced capacity to produce tumor necrosis factor, alpha/beta interferon, and interleukin 6 after implantation of tumor cells.

This study shows that the ability of mice to produce tumor necrosis factor (TNF), alpha/beta interferon (IFN-alpha/beta), and interleukin 6 (IL-6), but not interleukin 1 (IL-1), in response to endotoxin was dramatically augmented within 24 h of intradermal implantation of 10(6) tumor cells. Tumor cell implantation also caused endotoxin-independent appearance of IFN-alpha/beta and IL-6 in serum within 24 h. Priming for endotoxin-induced TNF production was not evident during the first 12 h of tumor cell implantation and it had decreased by 72 h. However, this decrease was followed by a second peak of priming on day 6 of tumor growth. Priming for endotoxin-induced TNF production was not induced by injection of dead tumor cells, the products of live tumor cells, or syngeneic or allogeneic splenocytes. Priming for TNF production was associated with an increased susceptibility of mice to endotoxin toxicity. These data suggest the existence of a cytokine-dependent host defense mechanism that is rapidly elicited in response to tumor cell implantation.

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PubMed1991

The importance of route of infection in determining the extent of exacerbation of listeriosis by anti-interferon-gamma monoclonal antibody.

Treating mice with a neutralizing rat monoclonal antibody (mAb) against murine interferon-gamma (IFN-gamma) prevented them from controlling an otherwise sublethal Listeria infection initiated via an extravascular route, but not via an intravenous route. In mice inoculated extravascularly, anti-IFN-gamma mAb treatment caused rapid uncontrolled growth of Listeria at the site of inoculation, and the continuous systemic dissemination of large numbers of bacteria to the liver and spleen. The infection-enhancing effects of anti-IFN-gamma treatment in mice infected intravenously was seen as an increase in the number of bacteria in the liver and spleen, but in subsequent control and eventual resolution of infection beginning 5 days after inoculation. The results serve to show that the exacerbating effect of anti-IFN-gamma treatment on murine listeriosis is greater for infections initiated at extravascular sites.

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PubMed1991

A role for tumor necrosis factor in poly(I:C)-induced hemorrhagic necrosis and T-cell-dependent regression of a murine sarcoma.

It was found that intravenous injection of the synthetic double-stranded ribonucleic acid, polyinosinic-polycytidylic acid [poly(I:C)], which is a well-studied interferon (IFN)-inducing agent, can result in extensive hemorrhagic necrosis of the center of an established murine sarcoma and in subsequent complete regression of the surviving rim of the tumor. The poly(I:C)-induced intratumor hemorrhagic reaction was associated with production of appreciable quantities of tumor necrosis factor (TNF) by the host. Neutralization of TNF by treatment with anti-rTNF immunoglobulin G (IgG) caused substantial inhibition of hemorrhagic necrosis and prevented tumor regression from proceeding. Tumor regression was prevented in all mice by depleting them of CD8+ T cells 1 day before poly(I:C) was given. Taken as a whole, the results indicate that the antitumor action of poly(I:C), like that of endotoxin, is based on its capacity to induce the host to make enough TNF to cause a hemorrhagic reaction extensive enough to reduce the tumor burden to a size capable of being dealt with by an underlying host antitumor immune response.

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PubMed1991

Resolution of primary murine listeriosis and acquired resistance to lethal secondary infection can be mediated predominantly by Thy-1+ CD4- CD8- cells.

Mice depleted of CD4+, CD8+, Thy-1+ CD4- CD8-, or all three types of cells by appropriate monoclonal antibody treatment were tested for their ability to express resistance against a primary and secondary Listeria monocytogenes infection. It was found that mice depleted of CD8+, CD4+, or both of these subsets of T cells remained capable of controlling and then resolving both a primary infection and a secondary infection lethal for normal animals. In contrast, depleting mice of a population of Thy-1+ CD8- CD4- cells that remain after CD4+ and CD8+ T cells had been removed, rendered them incapable of resolving a sublethal primary infection or of expressing acquired immunity to a lethal secondary infection. The results point to the possibilities that Thy1+ CD4- CD8- alpha beta T cells, Thy1+ CD4- CD8- gamma delta T cells, Thy-1+ NK cells, or all three types of these host cells are involved in anti-L. monocytogenes resistance.

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PubMed1991

Limitations of the adoptive immunity assay for analyzing anti-Listeria immunity.

The usefulness of adoptive immunization as a method for analyzing mechanisms responsible for resolution of Listeria monocytogenes infection was studied. Results showed that, although mice resolving primary infection acquire CD8+ T cells that are exclusively capable of adoptively immunizing recipient mice against an L. monocytogenes challenge infection, these T cells are protective only if given to recipients at very early stages of infection (soon after the infection is cleared from the blood by fixed phagocytes of the liver and spleen). In contrast the same T cells failed to mediate adoptive immunity against infection if given to recipients 24 h after infection was initiated, when L. monocytogenes is no longer in fixed phagocytes but is confined to granulomas. These results indicate that specific CD8+ T cells produced in response to infection contribute minimally to resolution of established infection in the donor.

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PubMed1991

Early gamma interferon production by natural killer cells is important in defense against murine listeriosis.

A spot enzyme-linked immunosorbent assay was used to show that subcutaneous inoculation of a sublethal number of Listeria monocytogenes resulted in the early appearance of gamma interferon (IFN-gamma)-producing cells in the draining lymph nodes. In contrast, inoculation of UV-killed L. monocytogenes failed to cause the appearance of IFN-gamma-producing cells. The appearance of IFN-gamma-secreting cells in response to the living organisms peaked at 24 h of infection and then declined. The draining lymph node cells responsible for secreting IFN-gamma belonged to a cell population that was positive for the NK1.1, asialo-GM1, and Thy-1 markers but negative for the CD4 and CD8 T cell subset markers. Early elimination of natural killer (NK) cells by treatment with anti-NK cell antibodies resulted in severe exacerbation of infection, as did early neutralization of endogenous IFN-gamma by treatment with a rat anti-murine IFN-gamma monoclonal antibody. In contrast, depletion of CD4+ and CD8+ T cells failed to exacerbate infection. The results serve to show that the early production of IFN-gamma by NK cells, rather than by T cells, is an essential event in resistance to listeriosis.

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PubMed1991

Effect of advanced ageing on the ability of mice to cause tumour regression in response to immunotherapy.

The effect of ageing on tumour immunotherapy was investigated by comparing the ability of aged mice (20 months old) and young mice (3 months old) to cause regression of an established SA1 sarcoma in response to parenteral injection of endotoxin, or to sublethal, whole-body exposure to ionizing radiation. It was found that whereas treatment with either of these agents caused T-cell-dependent regression of the tumour in young mice, it failed to cause regression of the tumour in aged mice. The results are in keeping with extensive literature showing that ageing is associated with a decline in immune competence.

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PubMed1990

Radiosensitive barrier to T-cell-mediated adoptive immunotherapy of established tumors.

This study shows that it is not possible to cause regression of the immunogenic SA-1 sarcoma by adoptive immunotherapy with tumor-sensitized T-cells, unless the tumor-bearing recipient is exposed to a sublethal dose of gamma-irradiation to remove a barrier that prevents adoptive immunity from being expressed. This barrier to adoptive immunotherapy was found to be regenerated between 2 and 4 weeks following irradiation, and its regeneration was associated with general repopulation of host T-cells. However, it was not regenerated in the absence of the thymus, thus showing that it is T-cell dependent. Evidence that it is caused by the presence of CD4+ suppressor T-cells was shown by the finding that it can be removed by depleting mice of CD4+ T-cells with anti-L3T4 monoclonal antibodies, but not by depleting them of CD8+ T-cells with anti-Lyt-2 monoclonal antibodies. Again, the barrier could be restored to irradiated recipients by infusing them with CD4+ T-cells, but not with CD8+ T-cells, from tumor-bearing donors. The barrier to adoptive immunotherapy was found to be tumor induced and to be paradoxically generated in concert with host concomitant immunity.

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PubMed1990

Elimination of cycling CD4+ suppressor T cells with an anti-mitotic drug releases non-cycling CD8+ T cells to cause regression of an advanced lymphoma.

This paper describes a model of successful immunotherapy of advanced lymphoma based on the selective elimination of cycling tumour-induced suppressor T cells. It shows that a single injection of the anti-mitotic drug, vinblasting (Vb), results in complete regression of a large L5178Y lymphoma and its metastases, but not if it is growing in an immunocompetent host. Vb-induced, immunologically mediated tumour regression was dependent on the anti-tumour function of CD8+ T cells, because regression was prevented by depleting the host of this subset of T cells 24 hr after Vb was given. Regression was also prevented by infusing the host with Vb-sensitive, CD4+ T cells from a tumour-bearing donor. These and other results are in keeping with the interpretation that Vb-induced regression of the L5178Y lymphoma depends on the ability of the drug to eliminate CD4+ suppressor T cells that are replicating, and to spare non-replicating CD8+ effector cells. It is suggested that at an advanced stage of growth of the L5178Y lymphoma the host possesses an acquired population of antigen-primed CD8+ effector T cells that are unable to become activated in response to abundant tumour antigen because of the dominant influence of CD4+ suppressor cells. Activation of these CD8+ T cells was indicated by the finding that they were rapidly converted from being cyclophosphamide (Cy) resistant to being highly Cy sensitive within 48 hr of giving Vb.

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PubMed1989

Glucocorticoid-mediated inhibition of endotoxin-induced intratumor tumor necrosis factor production and tumor hemorrhagic necrosis and regression.

Intravenous injection of 25 micrograms of bacterial endotoxin on day 9 of growth of the SA1 sarcoma results in extensive necrosis of the core of this tumor and in its subsequent complete regression. Tumor hemorrhagic necrosis and regression failed to occur in mice that were given a subcutaneous injection of cortisone acetate or dexamethasone 12 h before being giving endotoxin. Inhibition of tumor hemorrhagic necrosis and regression by glucocorticoids was associated with inhibition of endotoxin-induced intratumor TNF production that normally takes place several h after endotoxin is given. In contrast, glucocorticoids had no effect on the ability of intravenously injected rTNF to cause tumor hemorrhagic necrosis and regression. The results lend further support to the belief that TNF is the predominant mediator of endotoxin-induced hemorrhagic necrosis of established murine tumors, and that hemorrhagic necrosis is a prerequisite for the immunologically mediated regression that follows.

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PubMed1989

Exacerbation of murine listeriosis by a monoclonal antibody specific for the type 3 complement receptor of myelomonocytic cells. Absence of monocytes at infective foci allows Listeria to multiply in nonphagocytic cells.

Treatment of mice with a rat mAb (5C6) specific for an epitope of the type 3 complement receptor of myelomonocytic cells severely interfered with the ability of the mice to resist infection with Listeria monocytogenes. Consequently, a sublethal infection was rapidly converted to a lethal one that resulted in death in 5 d. However, infection was only exacerbated if 5C6 was given earlier in infection, before mononuclear phagocytes populated sites of Listeria implantation in the liver and spleen. If given after day 3 of infection, 5C6 caused only a temporary increase in bacterial multiplication. The infection-enhancing effect of 5C6 was associated with failure of mice to focus mononuclear phagocytes at sites of bacterial multiplication of Listeria in liver hepatocytes and extracellulary in the spleen. This resulted in unrestricted multiplication of Listeria in hepatocytes and extracellularly in the spleen. The results are in keeping with the ability of 5C6 to inhibit the accumulation of myelomonocytic cells in peritoneal inflammatory exudates, as revealed by a previous study.

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PubMed1989

Elimination of CD4+ suppressor T cells from susceptible BALB/c mice releases CD8+ T lymphocytes to mediate protective immunity against Leishmania.

This study examined the capacity of BALB/c mice that had been depleted of T cell subpopulations to generate a protective immune response to Leishmania major. Thymectomized mice were depleted of either L3T4+ (CD4+) T lymphocytes, Ly2+ (CD8+) T lymphocytes, or both, by treatment with appropriate mAbs. It was found that susceptible mice were rendered resistant to Leishmania by an intravenous infusion of anti-L3T4 mAb. These mice generated an immune response that destroyed the parasite in the primary lesion and in visceral metastatic foci. CD4+ cell-depleted mice also acquired a capacity to mount a sustained delayed-type hypersensitivity (DTH) response to parasite antigens, indicating that DTH, per se, is not a disease-promoting mechanism in the susceptible murine host as has been suggested. Depleting BALB/c mice of CD8+, as well as CD4+ T cells, left them highly susceptible to Leishmania infection, thereby indicating that CD8+ lymphocytes are key protective cells. Our results can be interpreted as showing that the susceptibility of BALB/c mice is due to the generation of CD4+ cells that suppress either the generation or expression of CD8+ T cell-mediated antiLeishmania immunity.

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