Interleukin-10 (IL-10) in Experimental Visceral Leishmaniasis and IL-10 Receptor Blockade as Immunotherapy

Murray, Henry W.; Lu, Christina M.; Mauze, Smita; Freeman, Sherry; Moreira, André L.; Kaplan, Gilla; Coffman, Robert L.

doi:10.1128/iai.70.11.6284-6293.2002

Cited by 212 publications

(243 citation statements)

References 63 publications

(89 reference statements)

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“…A progressive increase in IL-10 mRNA level in tissues during infection suggested a role in susceptibility (17). In addition, the control of parasite growth in inner organs in BALB/c IL-10 -/-mice and in normal mice with IL-10 receptor blockade by antibodies confirmed the role of IL-10 in susceptibility (18,19). Since IL-10 receptor blockade increased serum IFN-γ levels, a protective effect was initially attributed to the non-suppressed leishmanicidal effect of IFN-γ.…”

Section: Role Of Cytokinesmentioning

confidence: 59%

Immunity and immunosuppression in experimental visceral leishmaniasis

Goto

Lindoso

2004

Braz J Med Biol Res

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Leishmaniasis is a disease caused by protozoa of the genus Leishmania, and visceral leishmaniasis is a form in which the inner organs are affected. Since knowledge about immunity in experimental visceral leishmaniasis is poor, we present here a review on immunity and immunosuppression in experimental visceral leishmaniasis in mouse and hamster models. We show the complexity of the mechanisms involved and differences when compared with the cutaneous form of leishmaniasis. Resistance in visceral leishmaniasis involves both CD4 + and CD8 + T cells, and interleukin (IL)-2, interferon (IFN)-γ, and IL-12, the latter in a mechanism independent of IFN-γ and linked to transforming growth factor (TGF)-ß production. Susceptibility involves IL-10 but not IL-4, and B cells. In immune animals, upon reinfection, the elements involved in resistance are different, i.e., CD8 + T cells and IL-2. Since one of the immunopathological consequences of active visceral leishmaniasis in humans is suppression of T-cell responses, many studies have been conducted using experimental models. Immunosuppression is mainly Leishmania antigen specific, and T cells, Th2 cells and adherent antigen-presenting cells have been shown to be involved. Interactions of the co-stimulatory molecule family B7-CTLA-4 leading to increased level of TGF-ß as well as apoptosis of CD4 + T cells and inhibition of macrophage apoptosis by Leishmania infection are other components participating in immunosuppression. A better understanding of this complex immune response and the mechanisms of immunosuppression in experimental visceral leishmaniasis will contribute to the study of human disease and to vaccine development.

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Section: Role Of Cytokinesmentioning

confidence: 59%

Immunity and immunosuppression in experimental visceral leishmaniasis

Goto

Lindoso

2004

Braz J Med Biol Res

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“…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). In the present study, we examined whether a deficiency in IL-10 production has a similar effect on infections with L. mexicana and L. amazonensis.…”

Section: Discussionmentioning

confidence: 96%

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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“…Our initial results using the anti-IL-10 mAb (clone JES5-A) indicated that IL-10 production was not efficiently neutralized by this Ab in vivo (data not shown). Therefore, we explored IL-10 neutralization by weekly injections of an mAb to the IL-10R (clone 1B1.3a) (16), which has recently been shown to promote sterile cure following healing in L. major-infected C57BL/6 mice (18) and in L. donovani-infected mice (19). Six weeks following infection, the number of LV39 pms per milligram of tissue was decreased ϳ600-fold in the anti-IL-10R-treated BALB/c mice, although four of the six treated mice still harbored Ͼ10 4 /mg of tissue (Fig.…”

Section: Susceptibility Of Il-4r␣ ϫ/ϫ Mice To L Major Substrain Lv39mentioning

confidence: 99%

The Relative Contribution of IL-4 Receptor Signaling and IL-10 to Susceptibility toLeishmania major

Noben-Trauth

Lira²,

Nagase

et al. 2003

The Journal of Immunology

111

101

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The roles of IL-10 and IL-4 receptor signaling were evaluated in a murine model of Leishmania major infection. In previous studies the L. major substrain LV39 caused progressive, nonhealing lesions in BALB/c mice deficient for IL-4R α-chain (IL-4Rα), while substrain IR173 was highly controlled. To explore whether IL-10 is responsible for inducing susceptibility to LV39, wild-type and IL-4Rα−/− mice were treated with anti-IL-10R mAb, and in a genetic approach, the IL-4Rα−/− mice were crossed with BALB/c IL-10−/− mice. In contrast to the lack of resistance conferred by IL-4Rα gene deletion, partial resistance to LV39 was conferred by IL-10 gene deletion or treatment of BALB/c mice with anti-IL-10R mAb. Lesion sizes and LV39 parasite numbers were further and dramatically reduced in both anti-IL-10R-treated IL-4Rα−/− mice and IL-4Rα × IL-10 double knockouts. Anti-IL-10R mAb treatment further suppressed parasite growth in IL-4Rα−/− mice infected with L. major IR173. Production of IFN-γ was only increased relative to wild-type or littermate controls in IL-4Rα−/− mice with complementary defects in IL-10. Comparisons of IFN-γ-treated infected macrophages in vitro indicated that LV39 required 25- to 500-fold greater concentrations of IFN-γ than IR173-infected macrophages to achieve a similar efficiency of parasite killing. These studies suggest that regardless of parasite substrain, IL-10 is as important as IL-4/IL-13 in promoting susceptibility to L. major and even more so for those substrains that are relatively resistant to IFN-γ mediated killing.

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Interleukin-10 (IL-10) in Experimental Visceral Leishmaniasis and IL-10 Receptor Blockade as Immunotherapy

Cited by 212 publications

References 63 publications

Immunity and immunosuppression in experimental visceral leishmaniasis

Immunity and immunosuppression in experimental visceral leishmaniasis

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

The Relative Contribution of IL-4 Receptor Signaling and IL-10 to Susceptibility toLeishmania major

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