IL-10 mediates susceptibility to Leishmania donovani infection

Murphy, Marianne; Wille, Ulrike; Villegas, Eric N.; Hunter, Christopher A.; Farrell, Jay P.

doi:10.1002/1521-4141(2001010)31:10<2848::aid-immu2848>3.3.co;2-k

Cited by 110 publications

(155 citation statements)

References 16 publications

(24 reference statements)

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“…IL-10-deficient C57BL/6 mice or C57BL/6 mice treated with anti-IL-10 receptor Abs achieve sterile cure to L. major infection when inoculated intradermally into the ear dermis (27). In addition, we have shown that IL-10-deficient mice exhibit a dramatic increase in resistance to infection with L. donovani (28). Treatment with anti-IL-10 receptor Ab has also been shown to promote increased resistance to L. donovani (29).…”

Section: Discussionmentioning

confidence: 99%

The Role of Interleukin-10 in Susceptibility of BALB/c Mice to Infection with Leishmania mexicana and Leishmania amazonensis

Padigel

Alexander

Farrell

2003

The Journal of Immunology

106

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Recent studies have demonstrated the critical role of IL-10 in susceptibility to cutaneous and visceral leishmaniasis caused by Leishmania major and Leishmania donovani, respectively. To determine whether IL-10 also plays a similar role in the susceptibility and pathogenesis of cutaneous leishmaniasis caused by the New World species, L. mexicana and L. amazonensis, we analyzed their course of infection in IL-10-deficient BALB/c mice and their wild-type counterparts. Although IL-10-deficient mice infected with either L. mexicana or L. amazonensis failed to control the lesion progression, we did observe consistently lower levels of infection in IL-10−/− mice compared with wild-type BALB/c mice. We also observed increased IFN-γ and NO production and higher levels for IL-12p40 and IL-12Rβ2 mRNA in cells from IL-10−/− mice compared with cells from BALB/c mice. The mRNA levels for IL-4, which increased significantly in both IL-10−/− and BALB/c mice, were comparable. When treated with anti-IL-4 mAb, IL-10−/− mice resolved the infection more effectively and had significantly fewer parasites in their lesions compared with similarly treated BALB/c mice. These findings suggest that IL-10, although not the dominant mediator of susceptibility of BALB/c mice to infection with L. mexicana and L. amazonensis, does play a significant role in regulating the development of a protective Th1-type response. However, effective resolution of infection with these New World parasites requires neutralization of both IL-4 and IL-10.

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Section: Discussionmentioning

confidence: 99%

The Role of Interleukin-10 in Susceptibility of BALB/c Mice to Infection with Leishmania mexicana and Leishmania amazonensis

Padigel

Alexander

Farrell

2003

The Journal of Immunology

106

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“…NO presence has been shown to be very critical in determining the leishmanicidal activity of murine macrophages (54) and has been reported to induce a Th1 response (55). On the other hand, IL-10 is reported to down-regulate NO production (53). ROS, including free radicals, oxygen ions, and peroxides, have also been implicated in cell damage like NO (56,57).…”

Section: Measurement Of No and Ros In Immunized Mice Challenged With mentioning

confidence: 98%

“…Experimental and clinical VL have been reported to be accompanied by the impairment of IL-12 generation (50) and induction of IFN-␥ has been found to be involved in resistance to infection in murine VL (51,52), while IL-10 is reported to correlate with susceptibility (53). Based on the important roles of these cytokines, we checked the functional activity of these cytokines in both pUMVC3-UB-ORFF-and pUMVC3-ORFF-immunized and -infected mice.…”

Section: Proliferation Of Splenocytes and T Cell Immune Response In Mmentioning

confidence: 99%

Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

Sharma

Madhubala

2009

The Journal of Immunology

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Resistance of Leishmania donovani to sodium antimony gluconate has become a critical issue in the current, prolonged epidemic in India. Hence, there is an urgent need for a vaccine that is protective against both antimony-susceptible and -resistant strains of L. donovani. The multigene LD1 locus located on chromosome 35 of Leishmania is amplified in ∼15% of the isolates examined. The open reading frame F (ORFF), a potential vaccine candidate against visceral leishmaniasis, is part of the multigene LD1 locus. ORFF was expressed as a chimeric conjugate of ubiquitin to elicit an Ag-specific cell-mediated immune response. Analysis of the cellular immune responses of ubiquitin-conjugated ORFF (UBQ-ORFF) DNA-immunized, uninfected BALB/c mice demonstrated that the vaccine induced enhanced IFN-γ-producing CD4+ and CD8+ T cells compared with nonubiquitinated ORFF DNA vaccine. Higher levels of IL-12 and IFN-γ and the low levels of IL-4 and IL-10 further indicated that the immune responses with UBQ-ORFF were mediated toward the Th1 rather than Th2 type. Infection of immunized mice with either the antimony-susceptible (AG83) or -resistant (GE1F8R) L. donovani strain showed that UBQ-ORFF DNA vaccine induced higher protection when compared with ORFF DNA. UBQ-ORFF DNA-immunized and -infected mice showed a significant increase in IL-12 and IFN-γ and significant down-regulation of IL-10. High levels of production of nitrite and superoxide, two macrophage-derived oxidants that are critical in controlling Leishmania infection, were observed in protected mice. The feasibility of using ubiquitinated-conjugated ORFF DNA vaccine as a promising immune enhancer for vaccination against both antimony-susceptible and -resistant strains of L. donovani is reported.

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“…It has also been found to be important in susceptibility to visceral leishmaniasis 30,49 . It has been detected in different samples of human visceral leishmaniasis: as mRNA in bone marrow 36 , lymph node 27 , and spleen 38 aspirates and at high levels in serum 1,2,15,40,50,52,63,69 ; for further information see 51 .…”

Section: Immunoactivation In Lymphoid Organsmentioning

confidence: 99%

Immunoactivation and immunopathogeny during active visceral leishmaniasis

Goto

Prianti

2009

Rev. Inst. Med. trop. S. Paulo

101

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SUMMARYVisceral leishmaniasis is caused by protozoan parasites of the Leishmania donovani complex. During active disease in humans, high levels of IFN-g and TNF-a detected in blood serum, and high expression of IFN-g mRNA in samples of the lymphoid organs suggest that the immune system is highly activated. However, studies using peripheral blood mononuclear cells have found immunosuppression specific to Leishmania antigens; this poor immune response probably results from Leishmania antigen-engaged lymphocytes being trapped in the lymphoid organs. To allow the parasites to multiply, deactivating cytokines IL-10 and TGF-b may be acting on macrophages as well as anti-Leishmania antibodies that opsonize amastigotes and induce IL-10 production in macrophages. These high activation and deactivation processes are likely to occur mainly in the spleen and liver and can be confirmed through the examination of organ samples. However, an analysis of sequential data from studies of visceral leishmaniasis in hamsters suggests that factors outside of the immune system are responsible for the early inactivation of inducible nitric oxide synthase, which occurs before the expression of deactivating cytokines. In active visceral leishmaniasis, the immune system actively participates in non-lymphoid organ lesioning. While current views only consider immunocomplex deposition, macrophages, T cells, cytokines, and immunoglobulins by diverse mechanism also play important roles in the pathogenesis. KEYWORDS:Visceral leishmaniasis; Human; Immunosuppression; Immunoactivation; Cytokines; Immunopathogenesis.Visceral leishmaniasis is caused by protozoa of the genus Leishmania that are transmitted to mammalian hosts, including humans, by phlebotomine sandflies. The disease is present in 66 countries in tropical and subtropical regions, and 90% of cases occur in India, Sudan, Bangladesh, Nepal, and Brazil. It is estimated that there are 500,000 new cases a year worldwide 68 , and 3,000 new cases occur each year in Brazil 48 . Until recently, the disease was thought to be caused by three species of the Leishmania donovani complex: Leishmania (Leishmania) donovani, L. (L.) infantum, and Leishmania (L.) chagasi (a species present in Brazil). There is now debate, however, over whether L. (L). infantum and Leishmania (L.) chagasi are the same 44 or different 60 species. In this review, the names of the three species will be used as in the original publications. Leishmania (Leishmania) donovani is present in East Africa, India, and parts of the Middle East, while L. (L.) infantum in Europe, North Africa, and South and Central America. Human infections can be asymptomatic or can manifest as oligosymptomatic and progressive diseases; progressive cases can involve hepatosplenomegaly, fever, pancytopenia, hypergammaglobulinemia, and serious weight loss 4 . During active visceral leishmaniasis, the parasite multiplies within the cells of the mononuclear phagocyte system in the spleen, liver, and bone marrow, and the disease is fatal if untreated.Studies...

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IL-10 mediates susceptibility to Leishmania donovani infection

Cited by 110 publications

References 16 publications

The Role of Interleukin-10 in Susceptibility of BALB/c Mice to Infection with Leishmania mexicana and Leishmania amazonensis

The Role of Interleukin-10 in Susceptibility of BALB/c Mice to Infection with Leishmania mexicana and Leishmania amazonensis

Ubiquitin Conjugation of Open Reading Frame F DNA Vaccine Leads to Enhanced Cell-Mediated Immune Response and Induces Protection against Both Antimony-Susceptible and -Resistant Strains ofLeishmania donovani

Immunoactivation and immunopathogeny during active visceral leishmaniasis

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