Drastic Reduction of a Filarial Infection in Eosinophilic Interleukin-5 Transgenic Mice

Martin, Coralie; Goff, Laëtitia Le; Ungeheuer, Marie‐Noëlle; Vuong, P. N.; Bain, O.

doi:10.1128/iai.68.6.3651-3656.2000

Cited by 75 publications

(63 citation statements)

References 37 publications

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“…These include L. sigmodontis (44), Nippostrongylus brasiliensis (10), Strongyloides venezuelensis (13), and Strongyloides stercoralis (21). Interestingly, there was no difference between the survival of O. volvulus L3 in IL-5 KO mice and the survival of O. volvulus L3 in wild-type mice, which has also been reported for L. sigmodontis (40).…”

Section: Discussionsupporting

confidence: 53%

Immunoglobulin E and Eosinophil-Dependent Protective Immunity to LarvalOnchocerca volvulusin Mice Immunized with Irradiated Larvae

et al. 2004

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Mice immunized with irradiated Onchocerca volvulus third-stage larvae developed protective immunity. Eosinophil levels were elevated in the parasite microenvironment at the time of larval killing, and measurements of total serum antibody levels revealed an increase in the immunoglobulin E (IgE) level in immunized mice. The goal of the present study was to identify the role of granulocytes and antibodies in the protective immune response to the larval stages of O. volvulus in mice immunized with irradiated larvae. Immunity did not develop in mice if granulocytes, including both neutrophils and eosinophils, were eliminated, nor did it develop if only eosinophils were eliminated. Moreover, larvae were killed in naïve interleukin-5 transgenic mice, and the killing coincided with an increase in the number of eosinophils and the eosinophil peroxidase (EPO) level in the animals. To determine if EPO was required for protective immunity, mice that were genetically deficient in EPO were immunized, and there were no differences in the rates of parasite recovery in EPO-deficient mice and wild-type mice. Two mouse strains were used to study B-cell function; MT mice lacked all mature B cells, and Xid mice had deficiencies in the B-1 cell population. Immunity did not develop in the MT mice but did develop in the Xid mice. Finally, protective immunity was abolished in mice treated to eliminate IgE from the blood. We therefore concluded that IgE and eosinophils are required for adaptive protective immunity to larval O. volvulus in mice.Infection of humans with the filarial worm Onchocerca volvulus results in a spectrum of disease states ranging from mild to hyperreactive disease. In addition, there are individuals who are considered immunologically resistant to the infection, based on the fact that they live in an endemic area and are free of infection and disease. Individual immune responses appear to be responsible for the different disease states, and roles have been attributed to Th1 cells, Th2 cells, antibodies, and granulocytes in the different disease presentations (24). Specific mechanisms of protective immunity have been identified in vitro with human cells and serum, and it has been shown that eosinophils and neutrophils adhere to and kill larval O. volvulus in the presence of serum or complement (9,27,41).O. volvulus has a very limited host range, infecting only humans and chimpanzees; therefore, other animal models have been utilized to study immunity to this infection. It has been observed that cattle immunized with irradiated Onchocerca ochengi third-stage larvae (L3) were protected against challenge infection, based on greatly reduced burdens of adult worms in the immunized animals (1). In order to generate a more practical way to study immunity to the larval stages of O. volvulus, a mouse model was developed. L3 were implanted subcutaneously in diffusion chambers to allow efficient recovery of parasites and to permit analysis of the parasite's microenvironment. Larvae survived and grew at the same rate when they ...

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Section: Discussionsupporting

confidence: 53%

Immunoglobulin E and Eosinophil-Dependent Protective Immunity to LarvalOnchocerca volvulusin Mice Immunized with Irradiated Larvae

et al. 2004

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“…This outcome could reflect a more potent immune response, in the absence for example of suppressive macrophages, although the lack of an increased neutrophil recruitment or increased Th1 cytokines argues against this possibility. Alternatively, as filarial worms show accelerated growth in an IL-5-over-expressing host (67,68), the reduction of IL-5 levels in the IL-4R Ϫ/Ϫ mouse may impact on parasite survival. The fact that only live parasites can induce Foxp3 within the CD4 ϩ population is consistent with both field and laboratory data linking active infection to immune regulation.…”

Section: Discussionmentioning

confidence: 99%

Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

McSorley

Harcus

Murray

et al. 2008

The Journal of Immunology

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Many helminths, including Brugia malayi, are able to establish long-lived infections in immunocompetent hosts. Growing evidence suggests that the immune system’s failure to eliminate parasites is at least partially due to the effects of regulatory T cells (Tregs). To test whether parasites may directly stimulate host regulatory activity, we infected mice with two key stages of B. malayi. Both mosquito-borne infective larvae and mature adults i.p. introduced were found to preferentially expand the proportion of CD25+Foxp3+ cells within the CD4+ T cell population. The induction of Foxp3 was accompanied by raised CD25, CD103, and CTLA-4 expression, and was shown to be an active process, which accompanied the introduction of live, but not dead parasites. CTLA-4 expression was also markedly higher on Foxp3− cells, suggesting anergized effector populations. Peritoneal lavage CD4+CD25+ cells from infected mice showed similar suppressive activity in vitro to normal splenic “natural” Tregs. Both B. malayi larvae and adults were also able to induce Foxp3 expression in adoptively transferred DO11.10 T cells, demonstrating that filarial infection can influence the development of T cells specific to a third party Ag. In addition, we showed that induction was intact in IL-4R-deficient animals, in the absence of a Th2 or alternatively activated macrophage response. We conclude that filarial infections significantly skew the balance of the host immune system toward Treg expansion and activation, in a manner dependent on live parasites but independent of a concomitant Th2 response.

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“…on a 10-mm 3 -thick blood smear stained with Giemsa; (ix) and percentage of mice with blood microfilariae. Protection (%P) was expressed as F/L3 (primary infected Ϫ vaccinated) ϫ 100/(F/L3 primary infected) (23,24,28).…”

Section: Methodsmentioning

confidence: 99%

“…Another approach was to use primary-infected mice overexpressing IL-5 and thus eosinophilic. Filarial mortality in the pleural cavity was faster, occurring by the first half of phase 2 (28).…”

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confidence: 99%

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B-Cell Deficiency Suppresses Vaccine-Induced Protection against Murine Filariasis but Does Not Increase the Recovery Rate for Primary Infection

et al. 2001

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To establish the role of B cells and antibodies in destroying filariae, mice lacking mature B cells and therefore unable to produce antibodies were used. Litomosoides sigmodontis offers a good opportunity for this study because it is the only filarial species that completes its life cycle in mice. Its development was compared in B-cell-deficient mice (BALB/c MT mice) and wild-type BALB/c mice in two different in vivo situations, vaccination with irradiated larvae and primary infection. In all cases, mice were challenged with subcutaneous inoculation of 40 infective larvae. Vaccine-induced protection was suppressed in B-cell-deficient mice. In these mice, eosinophils infiltrated the subcutaneous tissue normally during immunization; however, their morphological state did not change following challenge inoculation, whereas in wild-type mice the percentage of degranulated eosinophils was markedly increased. From this, it may be deduced that the eosinophil-antibody-B-cell complex is the effector mechanism of protection in vaccinated mice and that its action is fast and takes place in the subcutaneous tissue. In primary infection, the filarial survival and growth was not modified by the absence of B cells. However, no female worm had uterine microfilariae, nor did any mice develop a patent infection. In these mice, concentrations of type 1 (gamma interferon) and type 2 (interleukin-4 [IL-4], IL-5 and IL-10) cytokines in serum were lower and pleural neutrophils were more numerous. The effects of the MT mutation therefore differ from those in B1-cell-deficient mice described on the same BALB/c background, which reveal a higher filarial recovery rate and microfilaremia. This outlines B2-cell-dependent mechanisms as favorable to the late maturation of L. sigmodontis.Despite new chemotherapy protocols (30), filariae are still a major cause of serious tropical diseases (9, 35); therefore, it is worthwhile to consider a vaccination approach as a complementary measure. We now have a particularly relevant experimental model at our disposal with the rodent filaria Litomosoides sigmodontis. It is the only filarial species able to regularly develop from the infective larvae to the patent phase in the BALB/c mice (18,32). Therefore, the strength of this model is that is allows us to study and modulate the immune reaction during vaccination as well as during primary infection and thus to describe the immune mechanism critical for parasite control.

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Drastic Reduction of a Filarial Infection in Eosinophilic Interleukin-5 Transgenic Mice

Cited by 75 publications

References 37 publications

Immunoglobulin E and Eosinophil-Dependent Protective Immunity to LarvalOnchocerca volvulusin Mice Immunized with Irradiated Larvae

Immunoglobulin E and Eosinophil-Dependent Protective Immunity to LarvalOnchocerca volvulusin Mice Immunized with Irradiated Larvae

Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

B-Cell Deficiency Suppresses Vaccine-Induced Protection against Murine Filariasis but Does Not Increase the Recovery Rate for Primary Infection

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