Cytokine-mediated host responses during schistosome infections; walking the fine line between immunological control and immunopathology

Hoffmann, Karl F.; Wynn, Thomas A.; Dunne, David W.

doi:10.1016/s0065-308x(02)52014-5

Cited by 114 publications

(90 citation statements)

References 153 publications

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“…In this model, liver toxicity results from both the direct actions of secreted egg Ags and from the indirect effects of the overexuberant and sustained local immune response (41). Consistent with previous findings (13), IL-10 Ϫ/Ϫ mice developed significant increases in both ALT and AST activity relative to WT mice (Fig.…”

Section: T Cells Are Major Il-10 Producers Controlling Egg-induced Mosupporting

confidence: 89%

The Pathogenesis of Schistosomiasis Is Controlled by Cooperating IL-10-Producing Innate Effector and Regulatory T Cells

Hesse

Piccirillo

Belkaid

et al. 2004

The Journal of Immunology

332

309

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IL-10 reduces immunopathology in many persistent infections, yet the contribution of IL-10 from distinct cellular sources remains poorly defined. We generated IL-10/recombination-activating gene (RAG)2-deficient mice and dissected the role of T cell- and non-T cell-derived IL-10 in schistosomiasis by performing adoptive transfers. In this study, we show that IL-10 is generated by both the innate and adaptive immune response following infection, with both sources regulating the development of type-2 immunity, immune-mediated pathology, and survival of the infected host. Importantly, most of the CD4+ T cell-produced IL-10 was confined to a subset of T cells expressing CD25. These cells were isolated from egg-induced granulomas and exhibited potent suppressive activity in vitro. Nevertheless, when naive, naturally occurring CD4+CD25+ cells were depleted in adoptive transfers, recipient IL-10/RAG2-deficient animals were more susceptible than RAG2-deficient mice, confirming an additional host-protective role for non-T cell-derived IL-10. Thus, innate effectors and regulatory T cells producing IL-10 cooperate to reduce morbidity and prolong survival in schistosomiasis.

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Section: T Cells Are Major Il-10 Producers Controlling Egg-induced Mosupporting

confidence: 89%

The Pathogenesis of Schistosomiasis Is Controlled by Cooperating IL-10-Producing Innate Effector and Regulatory T Cells

Hesse

Piccirillo

Belkaid

et al. 2004

The Journal of Immunology

332

309

View full text Add to dashboard Cite

show abstract

“…To model a natural hematopoietic response, we infected mice with the helminthic parasite, S mansoni, and harvested bone marrow during the initial stages of the secondary Th2 response characteristic of this infection. 38,39 By way of the 4-way approach (IL-5 Ϫ/Ϫ uninfected versus wild-type uninfected versus IL-5 Ϫ/Ϫ infected versus wild-type infected), which is the equivalent of 6 pairwise primary comparisons, we subtract out the non-IL-5-dependent effects of S mansoni infection as well as any alterations in bone marrow transcription because of the absence of IL-5 at baseline, in the uninfected state.…”

Section: Discussionmentioning

confidence: 99%

Gene microarray analysis reveals interleukin-5–dependent transcriptional targets in mouse bone marrow

Byström

Wynn

Domachowske

et al. 2004

Blood

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Interleukin-5 (IL-5) is a hematopoietic differentiation factor that promotes the development of mature eosinophils from progenitors in bone marrow. We present a multifactorial microarray study documenting the transcriptional events in bone marrow of wild-type and IL-5-deficient mice at baseline and in response to infection with Schistosoma mansoni. The microarray data were analyzed by a 4-way subtractive algorithm that eliminated con-

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“…Depending on the course of infection and patient symptoms, schistosomiasis mansoni can progress to a severe life-threatening form of disease (2). Indeed, the highest mortality in human schistosomiasis mansoni occurs in the minority of people who develop hepatosplenic schistosomiasis, characterized by periportal fibrosis, portosystemic shunts, and hematemesis (3,4). In the murine model of Schistosoma mansoni infection, adult female worms begin laying eggs 5-6 wk postinfection.…”

mentioning

confidence: 99%

IL-13 receptor α 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis

Mentink‐Kane

Cheever

Thompson

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

124

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An important feature of many chronic parasitic infections is the ability of the invading pathogen and host to establish a compromise, which ensures successful parasitism without killing the infected host. For many helminth infections, down-modulating the immune response is critical because persistent inflammation can become more damaging to the host than the invading pathogen itself. Such is the case with schistosomiasis mansoni, where chronic granulomatous inflammation in the liver causes portal hypertension, porto-pulmonary shunting, bleeding from collateral bypass vessels, and eventual death if not suppressed effectively. CD4 ؉ T helper type 2 cells (Th2) (secreting IL-4, IL-5, and IL-13) characterize the host response after Schistosoma mansoni infection, and recent studies have identified IL-13 as the principal mediator of hepatic fibrosis. Here, we show that the IL-13 receptor ␣ 2 (IL-13R␣2) is a critical mediator of immune down-modulation, identifying the receptor as a life-sustaining off signal for chronic and pernicious inflammation in schistosomiasis.

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Cytokine-mediated host responses during schistosome infections; walking the fine line between immunological control and immunopathology

Cited by 114 publications

References 153 publications

The Pathogenesis of Schistosomiasis Is Controlled by Cooperating IL-10-Producing Innate Effector and Regulatory T Cells

The Pathogenesis of Schistosomiasis Is Controlled by Cooperating IL-10-Producing Innate Effector and Regulatory T Cells

Gene microarray analysis reveals interleukin-5–dependent transcriptional targets in mouse bone marrow

IL-13 receptor α 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis

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