Genetically Determined Resistance to Murine Cytomegalovirus: A Role for Lymphocytostatic Macrophages

Price, Patricia; Winter, Jörn; Shellam, Geoffrey

doi:10.1099/0022-1317-68-12-2997

Cited by 15 publications

(25 citation statements)

References 24 publications

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“…We have reported previously that the resident peritoneal macrophages of CBA mice show high levels of lymphocytostasis and colloidal gold uptake and that these parameters decline rapidly after infection, concurrent with a 60-80% drop in the total number of cells recoverable from this site [ 18]. This suggests a loss of activated macrophages, which is unlikely to be due to cell death as relatively few of the cells were infected (Table 1) and dead cells were not observed in the preparations.…”

Section: Discussionmentioning

confidence: 82%

“…These are low density, adherent cells, most evident in the spleen 7-8 days p.i. (Table 7), but are also demonstrable in peritoneal preparations following adherence fractionation [ 18].…”

Section: Discussionmentioning

confidence: 93%

“…Resistance to MCMV-infection has also been correlated with changes in the macrophage populations at the site of intraperitoneal infection with MCMV [18]. Susceptible BALB/c mice showed a 25% decline in peritoneal cell (PC) numbers 4 days after infection, and thereafter accumulated mature activated macrophages at this site.…”

Section: Introductionmentioning

confidence: 97%

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Inflammatory and immunological responses to murine cytomegalovirus in resistant CBA mice

Price

Winter

Eddy

et al. 1989

Archives of Virology

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The resistance of CBA mice to MCMV is associated with the resistance of H-2k cells to infection in vitro, high NK and virus-specific DTH responses, and minimal accumulation of cytostatic peritoneal macrophages. This study investigates the functional capacity of lymphoid cells from infected CBA mice, using this strain as a model for successful control of CMV. Splenic viral replication was high 1-3 days p.i. and cell numbers were depressed, but T and B cells frequencies were maintained. The remaining spleen cells were hyporesponsive in culture and accessory cell function was marginally deficient. By 7 days p.i., virus titres declined, responsiveness increased and the residual defect was associated with cytostatic macrophages. The lymph nodes did not atrophy, exhibited low levels of viral replication and proliferative capacity was retained. The beige mutation did not affect the local response to intraperitoneal infection, but spleen cell numbers and responsiveness declined progressively. The results suggest the spleen may contribute to CMV disease by the replication of virus in susceptible cells until the NK response reduces virus titres and hence limits acute virus-induced immunosuppression. Macrophage-mediated suppression persisted in the spleen during recovery so clonal expansion of protective virus-primed T cells may occur predominantly in the lymph nodes.

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Section: Discussionmentioning

confidence: 82%

“…These are low density, adherent cells, most evident in the spleen 7-8 days p.i. (Table 7), but are also demonstrable in peritoneal preparations following adherence fractionation [ 18].…”

Section: Discussionmentioning

confidence: 93%

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Inflammatory and immunological responses to murine cytomegalovirus in resistant CBA mice

Price

Winter

Eddy

et al. 1989

Archives of Virology

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“…The H-2 k phenotype confers resistance relative to H-2 d or H-2 b in vitro and in vivo but CBA (H-2 k) mice are more resistant in vivo than BALB.K. This non-H-2 component of susceptibility to MCMV may be influenced by the nature of the local inflammatory macrophage response to MCMV infection, as cytostatic macrophages are induced at high levels in BALB/c mice [19]. The concept that macrophage-mediated immunosuppression may limit resistance to a number of infectious agents has been discussed widely [15], and suppressive macrophages have been described in studies of blood leukocytes from CMV patients [4] and murine splenocyte cultures treated with MCMV in vitro [12].…”

Section: Introductionmentioning

confidence: 94%

“…In our earlier study [19], BALB/c mice showed a slight decline in peritoneal cell (PC) numbers immediately after infection, with an increase to three times normal levels by day 7. This population yielded large numbers of activated phagocytic macrophages, which were cytostatic when cultured with lymphocytes from normal mice.…”

Section: Introductionmentioning

confidence: 97%

The inflammatory macrophage response to murine cytomegalovirus in genetically susceptible mice

Price

Winter

Shellam

1989

Archives of Virology

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Adherent suppressor cells have often been implicated in the depression of immunocompetence following CMV infections. We have reported that high levels of cytostatic macrophages in the peritoneal cavities of infected mice correlate with genetically-based sensitivity to CMV disease, suggesting they may modulate protective immune responses. This study investigates the properties and kinetics of such cells. Genetically-susceptible BALB/c mice infected with MCMV accumulated activated peritoneal macrophages, 7 days post-infection. These cells suppressed 3H-thymidine-incorporation and lymphokine production in syngeneic lymphocyte cultures and hence appeared to have depressed accessory cell function, although interleukin-1 production and the capacity to take up colloidal gold were enhanced. The cytostatic activity was located in a low density fraction (1.05 g/ml), which was expanded by MCMV infection. The lowest density cells had higher frequencies of infection but the proportion of cells releasing virus (less than 0.2%) was below the proportion activated, as shown by the shift in the density profile or enhanced colloidal gold uptake. A comparable accumulation of cytostatic activated peritoneal macrophages occurred in mice treated with cyclosporine A, but nude mice showed macrophage activation without cytostasis, so the role of T cells is not resolved. The spleens of infected mice maintaining high levels of virus in this organ atrophied, and the remaining cells were unable to proliferate in culture. In contrast, mice clearing the virus developed splenomegaly and restricted responsiveness, which may be governed by cytostatic cells equivalent to those in the peritoneal cavity. The spread of virus to the lymph nodes was limited and MCMV-primed cells were readily demonstrable.

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Influence of a Cytomegalovirus Infection on Functions and Arachidonic Acid Metabolism of Rat Peritoneal Macrophages

Engels

Grauls

Lemmens

et al. 1989

Journal of Leukocyte Biology

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An intraperitoneal (rat) cytomegalovirus (RCMV) infection in the rat caused an influx of mononuclear cells, which have been altered in functions and arachidonic acid (AA) metabolism. Phagocytosis has been increased considerably 3 days postinfection (p.i.), whereas the release of prostacyclin, thromboxane A2, 12-hydroxyheptadecatrienoic acid (HHT), 5-hydroxyeicosatetraenoic acid (5-HETE), and leukotriene B4 (LTB4) was inhibited for more than 80%. The release of superoxide anions and the chemiluminescence response (CL) upon opsonized zymosan stimulation did not differ from those observed in resident peritoneal macrophages. Additionally, the levels of cyclic nucleotides (cAMP and cGMP) were low in both resident and influx macrophages (day 3 p.i.). In contrast, peritoneal macrophages harvested on day 10 p.i. still showed a high level of phagocytosis. However, the intracellular level of cyclic AMP had decreased fivefold, whereas CL response and superoxide anion release were inhibited significantly. Moreover, the production of prostacyclin, LTB4, and 5-HETE was still suppressed in contrast to thromboxane synthesis, which has selectively been restored in these macrophages. A direct regulatory role of AA metabolites in changes in macrophage functions that were due to a RCMV infection could not be demonstrated.

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Genetically Determined Resistance to Murine Cytomegalovirus: A Role for Lymphocytostatic Macrophages

Cited by 15 publications

References 24 publications

Inflammatory and immunological responses to murine cytomegalovirus in resistant CBA mice

Inflammatory and immunological responses to murine cytomegalovirus in resistant CBA mice

The inflammatory macrophage response to murine cytomegalovirus in genetically susceptible mice

Influence of a Cytomegalovirus Infection on Functions and Arachidonic Acid Metabolism of Rat Peritoneal Macrophages

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