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R J North

Publications and source records attributed to R J North.

At least 37 records · Page 2Linked to original sources
PubMed1995

High level monocyte chemoattractant protein-1 expression in transgenic mice increases their susceptibility to intracellular pathogens.

We have constructed transgenic mice in which the mouse mammary tumor virus long terminal repeat controls the expression of murine monocyte chemoattractant protein-1 (MCP-1). Several independently derived lines of transgenic mice constitutively expressed MCP-1 protein in a variety of organs. Protein extracts from these organs had substantial in vitro monocyte chemoattractant activity that was neutralized by an anti-MCP-1 Ab, indicating that transgenic MCP-1 protein is biologically active. However, no transgenic mouse at any age displayed monocyte infiltrates in MCP-1-expressing organs. Two transgenic lines had circulating MCP-1 levels of 13 to 26 ng/ml, which is a concentration sufficient to induce maximal monocyte chemotaxis in vitro. These transgenic lines showed a 1 to 1.5 log greater sensitivity to infection with Listeria monocytogenes and Mycobacterium tuberculosis. A third transgenic line had lower serum levels of MCP-1 and was resistant to L. monocytogenes. The results suggest that this transgenic model is one of monocyte nonresponsiveness to locally produced MCP-1 due to either receptor desensitization or neutralization of a chemoattractant gradient by high systemic concentrations of MCP-1. Regardless of the mechanism, the data indicate that constitutively high levels of MCP-1 expression do not induce monocytic infiltrates, and that MCP-1 is involved in the host response to intracellular pathogens.

Animals↗
PubMed1995

Mycobacterium tuberculosis is strikingly more virulent for mice when given via the respiratory than via the intravenous route.

Fewer Mycobacterium tuberculosis colony-forming units given by aerosol were substantially more virulent for mice than much larger numbers inoculated intravenously (iv), as shown by a faster rate of bacillary growth in the lungs and much shorter survival of the host. Earlier death of mice infected by aerosol was associated with faster development of lung pathology, even though the number of M. tuberculosis given iv resulted in the same number of bacilli initially implanting in the lungs as the number given by aerosol. Mice depleted of CD4 T cells died of infection much sooner than immunocompetent mice but at about the same time after being infected via either route. The results indicate that a small number of M. tuberculosis colony-forming units given by aerosol is less immunogenic than a larger number given iv.

Aerosols↗
PubMed1995

Virulence ranking of some Mycobacterium tuberculosis and Mycobacterium bovis strains according to their ability to multiply in the lungs, induce lung pathology, and cause mortality in mice.

Three virulent strains of Mycobacterium tuberculosis (H37Rv, Erdman, and NYH-27) and two virulent strains of M. bovis (Ravenel and Branch) were compared in terms of their growth rates in the livers and the lungs of mice, their ability to cause lung pathology, and the time taken for them to cause death. In immunocompetent mice, all strains caused an infection that progressed for 20 days or more and then underwent resolution in the liver but not in the lungs. In the lungs, infection persisted and induced progressive pathology. According to host survival time, Ravenel was the most virulent strain, followed, in decreasing order of virulence, by Branch, H37Rv, Erdman, and NYH-27. The much longer survival times of mice infected with M. tuberculosis strains allowed time for lung histopathology to change from a histiocytic alveolitis to a chronic fibroblastic fibrosis that eventually obliterated most of the lung architecture. By contrast, in mice infected with M. bovis strains, the alveolitis that developed during early infection was rapid and expansive enough to cause death before chronic lung pathology became evident. In mice depleted of CD4+ T cells, increased growth of all virulent strains induced necrotic exudative lung lesions that rapidly filled most of the alveolar sacs with inflammatory cells. These mice died much earlier than infected control mice did. Attenuated strains had longer population doubling times in vivo and failed to cause progressive disease or pathology in the lungs or livers of immunocompetent mice.

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PubMed1994

Adoptive immunotherapy of established tumors. Acquisition of radioresistance by tumor-specific T cells after passive transfer into tumor-bearing recipients.

The present study was undertaken to determine the sensitivity to ionizing irradiation of T cells from mice immunized against the Meth-A fibrosarcoma and P815 mastocytoma after the transfer of these cells into tumor-bearing recipients. It was found that T cells from memory-immune donors were destroyed by exposing recipients to 500 rad of gamma irradiation up to 48 hr after transfer of the cells, but not thereafter. In contrast, activated immune cells were resistant to irradiation immediately after transfer. T cells were considered to be actively immune if they were harvested from donors in the process of rejecting their tumor, and were replicating, as evidenced by sensitivity to vinblastine. Memory-immune cells, on the other hand, were T cells that were harvested long after rejection of the immunizing tumor and were vinblastine-resistant. Additional results showed that CD8+ memory T cells were needed to cause regression of Meth-A tumor in recipients, whereas CD4+ memory T cells were needed for P815 tumor regression. These results support the idea that T cells that mediate tumor regression in this model of adoptive immunotherapy are radiosensitive while resting, and radioresistant after becoming activated. This knowledge needs to be taken into account when considering ionizing radiation as an immunomodulating agent for tumor immunotherapy.

Animals↗
PubMed1994

Neutrophils are essential for early anti-Listeria defense in the liver, but not in the spleen or peritoneal cavity, as revealed by a granulocyte-depleting monoclonal antibody.

This study shows that in mice selectively depleted of neutrophils by treatment with a monoclonal antibody, RB6-8C5, listeriosis is severely exacerbated in the liver, but not in the spleen or peritoneal cavity during the crucial first day of infection. At sites of infection in the livers of neutrophil-depleted mice, Listeria monocytogenes grew to large numbers inside hepatocytes. By contrast, in the livers of normal mice neutrophils rapidly accumulated at infectious foci and this was associated with the lysis of infected hepatocytes that served to abort infection in these permissive cells. In the spleen the situation was different, in that depletion of neutrophils did not result in appreciable exacerbation of infection. In this organ intact infected cells, many of which appeared to be fibroblast-like stromal cells, were found at foci of infection in the presence or absence of large numbers of neutrophils. This suggests that neutrophils are less effective at destroying L. monocytogenes-infected target cells in the spleen than in the liver. Consequently, at least during the first day, the organism remained free to multiply intracellularly in the spleen in cells that are permissive for its growth. Presumably, the same situation exists in the peritoneal cavity, because depleting neutrophils did not severely exacerbate infection initiated at this site.

Animals↗
PubMed1994

Elimination of CD4+ T cells in mice bearing an advanced sarcoma augments the antitumor action of interleukin-2.

Experiments were undertaken to determine whether the depletion of CD4+ T cells from mice bearing an advanced immunogenic SA-1 sarcoma would result in an enhanced ability of interleukin-2 (IL-2) to cause tumor regression. The results show that whereas IL-2 therapy given as a 5-day course starting on day 10 of tumor growth caused complete regression of the tumor, it failed to cause regression if started on day 15 of tumor growth. However, in mice depleted of CD4+ T cells by treatment with anti-CD4 monoclonal antibody (mAb), IL-2 therapy started on day 15 resulted in appreciable tumor regression in most animals, and the therapeutic effect was greatly increased if two consecutive courses of anti-CD4 mAb and IL-2 therapy were given. On the other hand, treatment with anti-CD4 mAb alone had no effect on tumor growth. It was shown that the therapeutic action of combination therapy with anti-CD4 mAb and IL-2 was mediated by CD8+ T cells, because the therapeutic effect was completely ablated in mice depleted of CD8+ T cells with anti-CD8 mAb. Taken together these results suggest that, at a late stage of growth of an immunogenic tumor, depletion of CD4+ T cells can enhance the antitumor effect of IL-2 therapy by releasing CD(8+)-T-cell-mediated immunity from T-cell-mediated suppression.

Animals↗
PubMed1994

CD4+ and CD8+ T-cell-dependent and -independent host defense mechanisms can operate to control and resolve primary and secondary Francisella tularensis LVS infection in mice.

Immunity to experimental infection with the facultative intracellular bacterium Francisella tularensis is generally considered an example of T-cell-mediated, macrophage-expressed immunity. However, the results of the present study indicate that T-cell-independent mechanisms are also important in anti-Francisella defense. They show that mice selectively depleted of CD4+, CD8+, or both T-cell populations by treatment with T-cell subset-specific monoclonal antibodies remained capable of controlling and partly resolving a primary sublethal Francisella infection. Similarly, it was found that Francisella-immune mice depleted of either or both subsets of T cells retain a high degree of acquired immunity to reinfection. Together, these findings imply that resistance to primary and secondary tularemia can be mediated by cells other than CD4+ and CD8+ T cells.

Animals↗
PubMed1994

Listeria monocytogenes, but not Salmonella typhimurium, elicits a CD18-independent mechanism of neutrophil extravasation into the murine peritoneal cavity.

This study shows that extravasation of neutrophils into the peritoneal cavities of mice in response to intraperitoneal (i.p.) inoculation of wild-type Listeria monocytogenes requires the participation of leukocyte adhesion molecules that are different from those involved in neutrophil recruitment in response to i.p. inoculation of Salmonella typhimurium. In the case of S. typhimurium, extensive neutrophil influx could be essentially abolished by treating mice with either anti-CD11b or anti-CD18 monoclonal antibodies, whereas the same monoclonal antibodies failed to prevent neutrophil accumulation in the peritoneal cavity in response to inoculation of L. monocytogenes. On the other hand, i.p. inoculation of a listeriolysin-negative strain of L. monocytogenes induced a CD11b-dependent neutrophil influx. The possibility that wild-type L. monocytogenes, by virtue of its ability to inhabit the cytosol of the cells it infects, induces the expression of endothelial cell adhesion molecules in the microvasculature of the peritoneal cavity to which neutrophils adhere via leukocyte adhesion molecules distinct from beta-2 integrins is discussed.

Animals↗
PubMed1994

Neutrophils are critical for host defense against primary infection with the facultative intracellular bacterium Francisella tularensis in mice and participate in defense against reinfection.

It is generally believed that immunity to experimental infection with the facultative intracellular bacterium Francisella tularensis is an example of T-cell-mediated immunity that is expressed by activated macrophages and mediated by Francisella-specific T cells. According to the results presented herein, neutrophils are also essential for defense against primary infection with this organism. It is shown that mice depleted of neutrophils by treatment with the granulocyte-specific monoclonal antibody RB6-8C5 are rendered defenseless against otherwise sublethal doses of F. tularensis LVS inoculated intravenously or intradermally. In neutrophil-depleted mice, the organism grew progressively in the livers, spleens, and lungs to reach lethal numbers, whereas infection was resolved in normal mice. Although neutrophils were found to resistance to reinfection, their participation was less important. The results suggest that neutrophils are needed for defense against primary infection because they serve to restrict the growth of F. tularensis before it reaches numbers capable of overwhelming a developing specific immune response. The exact way that neutrophils achieve this is not clear at this time, although it is probable that they contribute in ways other than by ingesting and killing the bacterium.

Animals↗
PubMed1993

Presence of CD4+ T suppressor cells in mice rendered unresponsive to tumor antigens by intravenous injection of irradiated tumor cells.

We used in vivo and in vitro assays to determine whether suppressor cells are generated in mice rendered unresponsive to tumor-specific antigens by intravenous (i.v.) injection of non-replicating tumor cells. The results show that a single i.v. injection of 2 x 10(7) irradiated P815 tumor cells resulted in the induction of a state of specific unresponsiveness to tumor-associated antigens, as revealed by the inability of the treated mice to achieve immunologically-mediated regression of an intradermal P815 tumor containing C. parvum, or to generate effector T cells capable of causing rejection of a P815 tumor in T-cell-deficient (T x B) test recipients. Failure to respond to tumor antigens was associated with the presence in spleen of CD4+ T cells capable, on passive transfer, of suppressing adoptive T-cell-mediated tumor regression in T x B recipients. However, the same CD4+ suppressor cells failed to inhibit the generation of tumor-specific cytotoxic T lymphocytes (CTL) in vitro. On the contrary, spleen cells from mice made unresponsive by i.v. injection of tumor cells were primed to generate CTL in response to tumor antigens in vitro. Taken together, our results suggest that unresponsiveness induced by i.v. injection of tumor antigens is an active process mediated, at least in part, by CD4+ T suppressor cells, and that these cells coexist in the spleen with antigen-primed effector T cells with a capacity to generate tumor-specific CTL when released from suppression in vitro.

Animals↗
PubMed1993

Mycobacterial virulence. Virulent strains of Mycobacteria tuberculosis have faster in vivo doubling times and are better equipped to resist growth-inhibiting functions of macrophages in the presence and absence of specific immunity.

The kinetics of growth of two virulent strains of mycobacteria (M. tuberculosis Erdman and M. tuberculosis H37Rv) and two attenuated strains (M. tuberculosis H37Ra and M. bovis Bacillus Calmette-Guerin [BCG]) were studied in the lungs, livers, spleens, and kidneys of severe combined immunodeficient (SCID) mice and of their coisogenic CB-17 immunocompetent counterparts. It was found, in keeping with the findings of earlier investigators (Pierce, C. H., R. J. Dubos, and W. B. Schaefer. 1953. J. Exp. Med. 97:189.), that in immunocompetent mice, virulent organisms grew progressively only in the lungs, whereas the growth of attenuated organisms was controlled in all organs. In SCID mice, in contrast, virulent mycobacteria grew rapidly and progressively in all organs, as did BCG, although at a slower rate. However, H37Ra failed to grow progressively in any organs of SCID mice, unless the mice were treated with hydrocortisone. In fact, hydrocortisone treatment enabled virulent, as well as attenuated, organisms to grow strikingly more rapidly in all organs of SCID mice and in all organs of CB-17 mice. A histological study showed that in SCID mice, multiplication of mycobacteria in the liver occurs in the cytoplasm of macrophages in granulomas and presumably in macrophages in other organs. It is suggested, therefore, that the macrophages of SCID mice possess a glucocorticoid-sensitive mycobacterial mechanism that prevents virulent and avirulent mycobacteria from expressing their true minimal doubling times. In the absence of this mechanism in the lungs of hydrocortisone-treated SCID mice, the doubling times of Erdman, H37Rv, BCG, and H37Ra were 17.7, 17.4, 44.6, and 98.6 h, respectively. The possible importance of a rapid multiplication rate for mycobacterial virulence is discussed.

Animals↗
PubMed1993

Minimal effect of advanced aging on susceptibility of mice to infection with Mycobacterium tuberculosis.

Young (3-month-old) and old (> or = 24-month-old) mice of a long-lived strain were compared in terms of their ability to resist infection with Mycobacterium tuberculosis. There was little overall difference in the ability of young and old mice to resist this infection. Mice in both age groups could control infection in their livers and spleens by a mechanism that was predominantly CD4+ T cell-mediated but not in their lungs. Again, old mice were almost as capable as young mice at being immunized by bacille Calmette-Guérin against a challenge infection with M. tuberculosis. The results argue against including M. tuberculosis among infectious agents to which mice become susceptible with advanced age.

Aging↗
PubMed1993

Evidence inconsistent with a role for tumor necrosis factor in tumor allograft rejection.

Since it has been suggested that tumor necrosis factor is involved in organ allograft rejection, experiments were undertaken to determine whether it is involved in the rejection of allogeneic P815 tumor cells growing as ascites in the peritoneal cavities of mice. The results show that biologically active TNF was not detectable in serum or ascites fluid of mice during either growth or vigorous rejection of the tumor. On the other hand, mice in the process of rejecting their ascites tumor displayed a greatly enhanced capacity to produce TNF in the peritoneal cavities and systemically in response to an injection of endotoxin i.p. These results show that the immune response to the tumor was associated with the priming of host cells for increased TNF production both locally and systemically in response to an appropriate stimulus that was not supplied during the generation and expression of immunity. Additional evidence against a role for TNF in ascites tumor allograft rejection is seen in the finding that i.p. administration of anti-TNF antibodies failed to interfere with elimination of allogeneic tumor cells, even though the antibodies were given repeatedly before and during the rejection process. Taken together, these results are inconsistent with the view that TNF is involved in the effector stage of the anti-allograft response, even though cells at the site of rejection are primed to produce large quantities of TNF in response to endotoxin.

Animals↗
PubMed1993

Antibody response to pneumococcal polysaccharide vaccine in young, adult and old mice.

The anti-pneumococcal antibody response was studied in young (5-week-old) and adult (10-week-old) BALB/c and CBA/J mice and in adult (9-10-week-old) and old (12-, 18- and 24-month-old) AB6F1 and B6D2F1 mice after s.c. immunization with a 23-valent pneumococcal polysaccharide vaccine. Both young and adult mice showed a significant IgM antibody response to the vaccine 6 days after immunization with 1-11 micrograms antigen. There were significant immune responses to serotypes 1, 2, 4 and 7F in contrast to small responses to serotypes 14, 19F and 23F after immunization with the vaccine. One month after immunization, there were only marginal differences in IgM anti-pneumococcal antibody levels to the vaccine (anti-PPS) between immunized and unimmunized BALB/c mice, whereas in CBA/J mice the anti-PPS remained higher in immunized than in unimmunized mice. Immunization of old mice induced a significant IgM antibody response 6 days after immunization, but the anti-PPS thereafter decreased rapidly towards preimmunization values in AB6F1 mice. A significant IgG anti-PPS was not detected in any of the mice studied. The IgA anti-PPS tended to vary over time with no consistent pattern. It is important to carefully consider age and strain of the mice used when studying the immune response to pneumococcal polysaccharide antigens.

Aging↗
PubMed1993

Leukocyte-mediated lysis of infected hepatocytes during listeriosis occurs in mice depleted of NK cells or CD4+ CD8+ Thy1.2+ T cells.

An important early component of defense against listeriosis in mice is the lysis of infected hepatocytes by leukocytes that accumulate at foci of infection in the liver. This serves to release Listeria monocytogenes from permissive parenchymal cells for ingestion and inactivation by phagocytic cells. It is shown here that lysis of infected hepatocytes is as extensive in mice depleted of T cells or NK cells as it is in control mice. This supports the original interpretation that hepatocyte lysis is mediated mainly by neutrophils.

Animals↗
PubMed1993

Granuloma formation in severe combined immunodeficient (SCID) mice in response to progressive BCG infection. Tendency not to form granulomas in the lung is associated with faster bacterial growth in this organ.

Intravenous inoculation of Mycobacterium bovis, strain bacillus Calmette-Guerin caused infection in the lungs, livers, and spleens of severe combined immunodeficient (SCID) mice and in the same organs in immunocompetent co-isogenic C.B17 mice. However, whereas infection in the latter mice was stabilized and partly resolved, it was progressive in SCID mice and eventually lethal, with the most rapid bacterial growth occurring in the lungs. Histological examination of infected organs showed that well-developed, compact epithelioid granulomas formed at sites of bacterial multiplication in livers, spleens, and lungs of C.B17 mice. Granulomas also formed in the livers and spleens of SCID mice, despite their inability to generate immunity. However, in the lungs of SCID mice, bacillus Calmette-Guerin was regionally distributed mostly in isolated alveolar macrophages and in aggregates of macrophages resembling small granulomas. The possibility that this tendency not to form granulomas in the lung is the reason for the more rapid growth of bacillus Calmette-Guerin in this organ is discussed.

Animals↗
PubMed1992

Evidence for an alpha/beta T cell-independent mechanism of resistance to mycobacteria. Bacillus-Calmette-Guerin causes progressive infection in severe combined immunodeficient mice, but not in nude mice or in mice depleted of CD4+ and CD8+ T cells.

Depleting thymectomized mice of CD4+ T cells, or CD4+ plus CD8+ T cells, rendered them incapable of resolving Bacillus-Calmette-Guerin (BCG) infection in their lives, spleens, kidneys, and lungs. However, it did not render them incapable of stabilizing infection in the latter three organs after an initial period of BCG growth. Athymic nude mice showed a similar capacity to control BCG growth in these organs after a certain stage of infection. In contrast, congenitally severe combined immunodeficient (SCID) mice appeared to offer no resistance to BCG infection, in that the organism grew progressively in all organs of these mice and was lethal for them beginning on day 55 of infection. The results suggest that, although CD4+ T cells are important for resolving BCG infection, an alpha/beta T cell-independent mechanism of resistance can be acquired at 2-3 wk of infection that is capable of inhibiting further BCG growth in all organs except the lungs. Because this mechanism is absent from SCID mice, it is likely that it depends on the functions of gamma/delta T cells, B cells, or both types of cells. In keeping with this possibility is the additional finding that SCID mice engrafted with lymph node cells depleted of CD4+ or CD8+ T cells were capable of expressing an appreciable level of resistance against BCG infection.

Animals↗