Interleukin‐12‐Dependent Mechanisms in the Clearance of Blood‐Stage Murine Malaria Parasite<i>Plasmodium berghei</i>XAT, an Attenuated Variant of<i>P. berghei</i>NK65

Yoshimoto, Takayuki; Yoneto, Toshihiko; Waki, Seiji; Nariuchi, Hideo

doi:10.1086/515301

Cited by 30 publications

(30 citation statements)

References 32 publications

(4 reference statements)

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“…This IL-12-induced protection is mediated by IFN-␥ and TNF-␣ (15) and requires the presence of NK and CD4 ϩ T cells (15,16). A similar protective effect of IL-12 treatment was also shown in mice infected with a radiation-attenuated variant of Plasmodium berghei (17) or liver-stage Plasmodium yoelli (18). We have also shown that resistant C57BL/6 mice mount a strong IL-12 response within 2-3 days of P. chabaudi AS infection while this response is impaired in susceptible A/J mice.…”

Section: Il-12 Is Required For Antibody-mediated Protective Immunitysupporting

confidence: 78%

“…For murine malaria, a protective effect of IL-12 has also been shown in P. berghei XAT infection in CBA mice (17). Furthermore, studies in P. yoelii-infected BALB/c (30) and P. berghei XAT-infected CBA mice (31) also demonstrate that Th1-associated IgG2a and IgG3 are the major protective Ab subclasses in Ab-mediated immunity against blood-stage malaria.…”

Section: Discussionmentioning

confidence: 93%

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IL-12 Is Required for Antibody-Mediated Protective Immunity Against Blood-StagePlasmodium chabaudiAS Malaria Infection in Mice

Stevenson

2002

The Journal of Immunology

164

142

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In this study, we investigated the role of endogenous IL-12 in protective immunity against blood-stage P. chabaudi AS malaria using IL-12 p40 gene knockout (KO) and wild-type (WT) C57BL/6 mice. Following infection, KO mice developed significantly higher levels of primary parasitemia than WT mice and were unable to rapidly resolve primary infection and control challenge infection. Infected KO mice had severely impaired IFN-γ production in vivo and in vitro by NK cells and splenocytes compared with WT mice. Production of TNF-α and IL-4 was not compromised in infected KO mice. KO mice produced significantly lower levels of Th1-dependent IgG2a and IgG3 but a higher level of Th2-dependent IgG1 than WT mice during primary and challenge infections. Treatment of KO mice with murine rIL-12 during the early stage of primary infection corrected the altered IgG2a, IgG3, and IgG1 responses and restored the ability to rapidly resolve primary and control challenge infections. Transfer of immune serum from WT mice to P. chabaudi AS-infected susceptible A/J mice completely protected the recipients, whereas immune serum from KO mice did not, as evidenced by high levels of parasitemia and 100% mortality in recipient mice. Furthermore, depletion of IgG2a from WT immune serum significantly reduced the protective effect of the serum while IgG1 depletion had no significant effect. Taken together, these results demonstrate the protective role of a Th1-immune response during both acute and chronic phases of blood-stage malaria and extend the immunoregulatory role of IL-12 to Ab-mediated immunity against Plasmodium parasites.

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Section: Il-12 Is Required For Antibody-mediated Protective Immunitysupporting

confidence: 78%

Section: Discussionmentioning

confidence: 93%

IL-12 Is Required for Antibody-Mediated Protective Immunity Against Blood-StagePlasmodium chabaudiAS Malaria Infection in Mice

Stevenson

2002

The Journal of Immunology

164

142

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“…Furthermore, high levels of IL-10 expression were found to protect mice against CM by suppressing proinflammatory cytokines (42,43). Recently, it was shown that IL-12 production was necessary for the development of protective immunity against blood-stage infection with an attenuated P. berghei strain, and that this effect was dependent on IFN-␥ production by CD4 ϩ T cells (44). However, IL-12 production was also shown to induce immune pathology rather than protection using a more virulent P. berghei strain.…”

Section: Discussionmentioning

confidence: 99%

Murine Malaria Is Exacerbated by CTLA-4 Blockade

Jacobs

Graefe

Niknafs

et al. 2002

The Journal of Immunology

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Cytolytic T lymphocyte-associated Ag-4 (CD152) is a negatively regulating molecule, which is primarily expressed on T cells following their activation. In this study, we have examined the role of CTLA-4 expression in experimental blood-stage malaria. Similar to human malaria, CTLA-4 is expressed on CD4+ T cells of C57BL/6 mice after infection with Plasmodium berghei. A kinetic analysis revealed that CTLA-4 expression was increased on day 5 postinfection and reached a peak on day 9 postinfection, when almost 10% of splenic CD4+ T cells expressed CTLA-4. Blockade of CTLA-4 in vivo by a specific mAb and subsequent challenge with P. berghei caused neurological signs reminiscent of murine cerebral malaria and earlier death. Histologic examination of brain sections from anti-CTLA-4-treated mice revealed pathologic changes such as hemorrhages and edema, which were absent in control mice. Furthermore, treatment with anti-CTLA-4 also reversed the extensive loss of CD4+ T cells and the suppressed T cell response occurring during blood-stage malaria. Our data suggest that CTLA-4 expression prevents immune pathology by restricting T cell activation during malaria. They also indicate that the development of cerebral malaria is mediated by a failure to down-regulate T cell activation.

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“…IL-12, composed of two heterologous chains (p35 and p40), is known to confer protection against disease as well as causing host pathogenicity during infection with malaria parasites, which can be explained through the activation of IFN-γ-producing Th1 CD4 + T cells [16][17][18]. These findings were observed in p40-lacking mice deficient in not only IL-12, but also IL-23 (the p40 subunit is shared between IL-12 and IL-23), raising a possibility that the phenomena attributed to IL-12 might in fact be due to IL-23.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, this cytokine restricts the growth of intracellular pathogens in an IL-17-dependent manner [13][14][15]. However, there are only a few reports about whether or not IL-23 plays a protective role against malaria parasites residing in red blood cells (RBCs). IL-12, composed of two heterologous chains (p35 and p40), is known to confer protection against disease as well as causing host pathogenicity during infection with malaria parasites, which can be explained through the activation of IFN-γ-producing Th1 CD4 + T cells [16][17][18]. These findings were observed in p40-lacking mice deficient in not only IL-12, but also IL-23 (the p40 subunit is shared between IL-12 and IL-23), raising a possibility that the phenomena attributed to IL-12 might in fact be due to IL-23.…”

mentioning

confidence: 99%

IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

et al. 2013

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Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites. Keywords: IL-17 · IL-23 · Macrophage · Malaria · Plasmodium bergheiAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMalaria, caused by protozoan parasites of the genus Plasmodium, is still one of the most life-threatening infectious diseases. Two hundred million people are infected annually with malaria paraCorrespondence: Dr. Hajime Hisaeda e-mail: hisa@med.gunma-u.ac.jp sites while about a million people are believed to die every year from the disease [1]. Despite the urgent need for effective vaccines against malaria, progress on vaccine development has been disappointing [2]. A major obstacle for vaccine development is that the immune responses crucial for eradication of malaria * These authors contributed equally to this work. parasites are not fully understood. Another concern is that infection with Plasmodium falciparum, which causes the most severe form of the disease in young children and pregnant women, can lead to pathological inflammation resulting in severe complications, such as cerebral malaria. Thus, to succeed in developing an effective vaccine against malaria, it is crucial that the mechanisms underlying protective immunity as well as those that drive pathogenic responses are better understood.IL-23 is a proinflammatory cytokine that belongs to IL-12 cytokine family. It is a heterodimeric molecule composed of p40 and p19 subunits [3]. The proinflammatory activities of IL-23 are responsible for the onset not only of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis [4,5], but also infection-induced pathological consequences of infection with the pathogens causing Lyme disease and ...

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Interleukin‐12‐Dependent Mechanisms in the Clearance of Blood‐Stage Murine Malaria ParasitePlasmodium bergheiXAT, an Attenuated Variant ofP. bergheiNK65

Cited by 30 publications

References 32 publications

IL-12 Is Required for Antibody-Mediated Protective Immunity Against Blood-StagePlasmodium chabaudiAS Malaria Infection in Mice

IL-12 Is Required for Antibody-Mediated Protective Immunity Against Blood-StagePlasmodium chabaudiAS Malaria Infection in Mice

Murine Malaria Is Exacerbated by CTLA-4 Blockade

IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

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