Lack of Involvement of Nitric Oxide in the Macrophage-Mediated Inhibition of Spleen Cell Proliferation during Experimental Cryptococcosis

Rossi, Gabriela R.; Cervi, Laura; Sastre, Darío; Masih, Diana T.

doi:10.1006/clin.1997.4459

Cited by 13 publications

(20 citation statements)

References 49 publications

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“…This contrasts with the high levels NOS2 expressed at 14 days of infection that we previously observed in association with an almost 2 log 10 -fold reduction in fungal burden (see Table 1 and Fig. 2 production by peritoneal macrophages after 14 days of infection in rats infected systemically with C. neoformans (23). We also observed regional differences in NOS2 expression among granulomas of long-term infection, suggesting that NOS2 expression is regulated on a local level.…”

Section: Discussioncontrasting

confidence: 99%

PersistentCryptococcus neoformansPulmonary Infection in the Rat Is Associated with Intracellular Parasitism, Decreased Inducible Nitric Oxide Synthase Expression, and Altered Antibody Responsiveness to Cryptococcal Polysaccharide

Goldman

Lee²,

Mednick³

et al. 2000

Infect Immun

149

122

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Fungal pathogens are notorious for causing chronic and latent infections, but the mechanism by which they evade the immune response is poorly understood. A major limitation in the study of chronic fungal infection has been the lack of suitable animal models where the infection is controlled and yet persists. Pulmonary Cryptococcus neoformans infection in rats results in a diffuse pneumonitis that resolves without dissemination or scarring except for the persistence of interstitial and subpleural granulomas that harbor viable cryptococci inside macrophages and epithelioid cells. Infected rats are asymptomatic but remain infected for as long as 18 months after inoculation with C. neoformans. Containment of infection is associated with granuloma formation that can be partially abrogated by glucocorticoid administration. Using this model, we identified several features associated with persistent infection in the rat lung, including (i) localization of C. neoformans to discrete, well-organized granulomas; (ii) intracellular persistence of C. neoformans within macrophages and epithelioid cells; (iii) reduced inducible nitric oxide synthase expression by granulomas harboring C. neoformans; and (iv) reduced antibody responses to cryptococcal polysaccharide. The results show that maintenance of persistent infection is associated with downregulation of both cellular and humoral immune responses.Cryptococcus neoformans is a fungal pathogen that causes meningoencephalitis in immunocompromised individuals. Infection is believed to be acquired through the respiratory tract, although the precise relationship between pulmonary and central nervous system infection is not understood. Several lines of evidence suggest that C. neoformans causes persistent, primary lung infection in immunocompetent individuals that is similar to infections caused by Mycobacterium tuberculosis and Histoplasma capsulatum. Primary cryptococcal infection is likely to be associated with few or minimal symptoms, but it may disseminate in the context of an acquired immunodeficiency, such as AIDS, or corticosteroid therapy. Persistent, pulmonary cryptococcosis has been described in humans. In one study, approximately 47% of individuals with pulmonary cryptococcosis had abnormal radiographic findings for at least 3 months before diagnosis, and an additional 17% of patients had radiographic findings for more than 18 months before diagnosis (2). Primary cryptococcal pneumonia has also been described as an incidental finding of autopsy studies of immunocompetent individuals. In these cases, infection was associated with small subpleural granulomas containing C. neoformans (16). A primary cryptococcal complex consisting of circumscribed granulomas with hilar lymphadenitis without calcifications has also been described (24).Current animal models are inadequate for studying the pathogenesis of persistent cryptococcosis. The two species that have been most extensively studied are mice and rabbits. Mice are extremely susceptible to pulmonary infection, which is inva...

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Section: Discussioncontrasting

confidence: 99%

PersistentCryptococcus neoformansPulmonary Infection in the Rat Is Associated with Intracellular Parasitism, Decreased Inducible Nitric Oxide Synthase Expression, and Altered Antibody Responsiveness to Cryptococcal Polysaccharide

Goldman

Lee²,

Mednick³

et al. 2000

Infect Immun

149

122

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show abstract

“…On the other hand, we observed killing of C. neoformans by an NADPH oxidase-dependent mechanism (27). We have recently demonstrated that the proliferative response to mitogens of spleen mononuclear (Spm) cells from C. neoformans-infected rats dramatically decreased in the suppressor period postinfection (28). Furthermore, nitric oxide production was a protecting mechanism during experimental cryptococcosis, but this molecule was not involved in the antiproliferative response (28,29).…”

Section: Introductionmentioning

confidence: 88%

“…Furthermore, nitric oxide production was a protecting mechanism during experimental cryptococcosis, but this molecule was not involved in the antiproliferative response (28,29). Lymphocyte proliferation was partially restored when the cultures were made in the presence of exogenous IL-2 (28). These results would suggest that cytokines could be involved in the impaired lymphocyte response; however, the mechanisms underlying this immunosuppression remain unclear.…”

Section: Introductionmentioning

confidence: 97%

“…We have recently demonstrated that the proliferative response to mitogens of spleen mononuclear (Spm) cells from C. neoformans-infected rats dramatically decreased in the suppressor period postinfection (28). Furthermore, nitric oxide production was a protecting mechanism during experimental cryptococcosis, but this molecule was not involved in the antiproliferative response (28,29). Lymphocyte proliferation was partially restored when the cultures were made in the presence of exogenous IL-2 (28).…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms for Induction of Immunosuppression during Experimental Cryptococcosis: Role of Glucuronoxylomannan

Chiapello

Iribarren

Cervi

et al. 2001

Clinical Immunology

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“…After incubation, nonadherent cells were removed by extensive washing with X-vivo medium. The resulting APCs were used in T-cell proliferation and cytokine-production assays, 29 and they consisted of more than 95% CD11b ϩ cells and 95% CD3 Ϫ cells as determined by FACS analysis. Enriched T cells (10 5 cells/well) were cultured with APCs (5 ϫ 10 4 cells/well) and serial dilutions of fVIII in X-vivo medium for 4 days in 96-well flat-bottom plates.…”

Section: Splenic T-cell Proliferation and Cytokine Assaysmentioning

confidence: 99%

Long-term induction of immune tolerance after blockade of CD40-CD40L interaction in a mouse model of hemophilia A

Rossi

Sarkar

Scandella

2001

Blood

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A factor VIII-deficient knockout mouse was used as a model for severe hemophilia A to characterize the immune response to recombinant human factor VIII (fVIII) and to study new approaches for induction of immune tolerance to fVIII. Mice initially received periodic injections of fVIII in doses similar to those used for the treatment of human hemophilia A. To induce immune tolerance, a hamster monoclonal antibody specific for murine CD40 ligand (CD40L or CD154) was injected with fVIII. Control mice received fVIII alone or fVIII and hamster immunoglobulin G. After treatment, humoral and cellular immune responses were evaluated. Ninety-five percent of anti-CD40L-treated mice had lower titers of anti-fVIII antibody (less than 1 g/mL) compared with fVIII-injected control mice (mean, 18 g/mL). To determine whether anti-CD40L treatment induces long-term immune tolerance, mice were rechallenged 3 times with fVIII alone. At 150 days after treatment, 12 of 22 anti-CD40L-treated mice remained tolerant to fVIII (anti-fVIII antibody titers less than 1 g/mL). However, tolerant mice immunized with tetanus toxoid (TT) developed high anti-TT antibody, demonstrating that tolerance is fVIII specific. T cells from tolerant mice showed impaired proliferative responses after stimulation with fVIII in vitro and lack of production of the cytokines interleukin-2 (IL-2), IL-4, interferon ␥, and IL-10. These results demonstrate that long-term immune tolerance to fVIII was effectively induced after early blockade of CD40-CD40L interaction. In addition, the lack of tolerance in this model was associated with the expression of a Th2 phenotype.

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Lack of Involvement of Nitric Oxide in the Macrophage-Mediated Inhibition of Spleen Cell Proliferation during Experimental Cryptococcosis

Cited by 13 publications

References 49 publications

PersistentCryptococcus neoformansPulmonary Infection in the Rat Is Associated with Intracellular Parasitism, Decreased Inducible Nitric Oxide Synthase Expression, and Altered Antibody Responsiveness to Cryptococcal Polysaccharide

PersistentCryptococcus neoformansPulmonary Infection in the Rat Is Associated with Intracellular Parasitism, Decreased Inducible Nitric Oxide Synthase Expression, and Altered Antibody Responsiveness to Cryptococcal Polysaccharide

Mechanisms for Induction of Immunosuppression during Experimental Cryptococcosis: Role of Glucuronoxylomannan

Long-term induction of immune tolerance after blockade of CD40-CD40L interaction in a mouse model of hemophilia A

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