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The Journal of Immunology, 1998, 160: 5436-5440.
Copyright © 1998 by The American Association of Immunologists

IL-5-Dependent Immunity to Microfilariae Is Independent of IL-4 in a Mouse Model of Onchocerciasis1

Philip J. Hogarth, Mark J. Taylor and Albert E. Bianco2

Division of Molecular Biology and Immunology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Th2 lymphocyte responses under the control of IL-4 and IL-5 are frequently associated with protective responses to parasitic helminths. Studies on the role of these cytokines in acquired resistance to parasitic nematodes indicate that, in the case of gastrointestinal nematodes, immunity is mediated by IL-4, while immunity to tissue-dwelling nematodes is dependent on IL-5. Here we investigate the role of IL-5 and eosinophils in protective immunity to Onchocerca microfilariae in IL-4-deficient mice. In the absence of IL-4, and despite the up-regulation of Th1-type responses, immunity remains dependent on IL-5 and eosinophils. Protection was unaffected by the absence of Ab in B cell-deficient mice, confirming that IL-5 is not acting via either B cell differentiation, Ag presentation, or isotype switching mechanisms. These data demonstrate the dissociation of IL-4 and IL-5 in a functional model of protective immunity to a tissue dwelling nematode and cast doubt on the role of IL-4 in the generation of CD4+ T cell-mediated, IL-5-dependent immunity to Onchocerca microfilariae. Importantly, they also segregate T cell-mediated mechanisms of protective immunity from those characterized in ocular pathologic responses in onchocerciasis, which are dependent on IL-4.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Defining the role of Th1 and Th2 responses in protective immunity and pathology has been a major area of research in a number of parasitic infections (1, 2). Studies on gastrointestinal nematodes have shown an essential role for Th2 responses and IL-4 in protective immunity (3, 4, 5, 6), whereas immunity to tissue-dwelling nematodes has been shown to depend on IL-5 (7, 8, 9). To characterize the protective immune responses to Onchocerca microfilariae (mf)3 in vivo, an experimental model has been developed using Onchocerca lienalis, in which clearance of a primary infection and resistance to reinfection are mediated by CD4+ T cells and are dependent on IL-5 (9, 10, 11). Surprisingly, mice deficient in IL-4 are able to clear a primary infection and express unimpaired resistance to reinfection (12).

The requirement for IL-4 in the generation and regulation of Th2 responses is considered to be of paramount importance (13). We therefore examined the role of IL-4 in the development of IL-5-dependent immunity to Onchocerca mf in vivo. Here we demonstrate that, in the absence of IL-4 and in spite of the up-regulation of Th1 responses, protective immunity remains dependent on IL-5 and eosinophils. These results dissociate IL-4 and IL-5 in a functional model of protective immunity to a tissue-dwelling nematode and question the role of IL-4 in the generation of CD4+ T cell-mediated, IL-5-dependent immunity to Onchocerca mf. They also distinguish between responses conferring protection and those associated with the pathogenesis of experimental ocular keratitis, which is IL-4 dependent (14). Given that ocular disease is caused by immunopathologic reactions to mf, the separation of immunologic pathways leading to protection or pathology is encouraging for the future of immunoprophylaxis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Parasites and Ag

O. lienalis mf were obtained from the skin of British cattle harboring natural infections and prepared as a suspension for inoculation into mice, as described (11). An antigenic extract of Onchocerca adult worms and mf was prepared using fecund O. gutturosa female worms dissected from the nuchal ligaments of cattle. Worms were homogenized in PBS and sonicated on ice for 30-sec cycles until all tissues and uterine mf were disrupted. The preparation was then centrifuged (30,000 x g, 2 h, at 4°C) and the supernatant medium removed. This was stored at -70°C until use.

Animals

IL-4-deficient mice carrying a targeted disruption of the gene encoding IL-4 (15) were obtained from Bantin & Kingman (Hull, U.K.). µMT mice carrying a targeted disruption of the IgM gene, which leads to a failure of B cell precursors to develop into mature Ig-secreting B cells (16), were obtained from the same supplier. Both transgenic strains were obtained on a C57BL/6 background, and normal age-matched C57BL/6 mice were used as wild-type controls. All mice used in this study were males of 8 to 10 wk old at the time of introduction into experiments.

Infection of mice and recovery of parasites

Mice were inoculated s.c. with a standard dose of 5000 mf in the nape of the neck. The recovery of live mf from the ears was used as an index of parasite migration and survival in the skin, as described by Townson and Bianco (17).

In vivo IL-5 neutralization

Mice received i.p. injections of 2 mg of neutralizing anti-IL-5 Ab (TRFK-5, DNAX, Palo Alto, CA), or an equivalent amount of normal rat Ig (NRIg), 4 h before parasite inoculation. Both Ig preparations were purified by ammonium sulfate precipitation.

Spleen cell culture

Spleens were removed aseptically, and a single cell suspension was prepared by passage through a metal gauze (Sigma, Poole, U.K.) into RPMI 1640 medium, supplemented with 10% FCS and antibiotics (100 U/ml penicillin and 100 µg/ml streptomycin; all from Life Technologies, Paisley, Scotland, U.K.). Cells were washed (200 g for 10 min) and erythrocytes lysed with 0.85% ammonium chloride solution. Splenocytes were resuspended in supplemented RPMI 1640 medium at 5 x 106 cells/ml. One ml of cell suspension was cultured with 10 µg/ml Ag for 72 h (37°C/5% CO2). Supernatant medium was harvested for analysis of cytokine content by ELISA.

Detection of Igs

Total IgG. Total serum IgG was measured in µMT mice at various time points to confirm the absence of functional B cells. ELISA plates (Life Technologies) were coated overnight at 4°C with 100 µl/well goat anti-mouse IgG (Dako, High Wycombe, U.K.) diluted 1:1000 in 0.05 M carbonate buffer (pH 9.6). Plates were washed four times with tris-saline-tween (TST) and blocked with 200 µl/well 1% BSA/TST for 1 h at 37°C. Serum samples (100 µl/well) diluted 1:100 in 1% BSA/TST were added for 1 h at 37°C. After washing, 100 µl/well secondary Ab (peroxidase-conjugated rabbit anti-mouse IgG, Dako) was added at a dilution of 1:1000 in 1% BSA/TST. Plates were incubated at 37°C for 1 h and washed. Working substrate 2,2' azinobis(3-ethylbenthiazidine sulfonic acid (ABTS, 100 µl/well; Sigma) was added and the plates were read at 405 nm.

Detection of parasite-specific Ab. This was conducted using the basic ELISA procedure outlined above. For IgG assays, plates were coated with 100 µl/well of Onchocerca Ag at 5 µg/ml in carbonate buffer (0.05 M, pH 9.6) overnight at 4°C. Serum samples (100 µl/well) diluted 1:100 in 1% BSA/TST were added for 1 h at 37°C. For IgE assays, plates were coated with Ag at 20 µg/ml, and serum was used at a dilution of 1:40. Peroxidase-conjugated goat anti-mouse Ig isotype-specific Abs (all from Nordic, Tilberg, The Netherlands) were used at a dilution of 1:1000 in 1% BSA/TST.

Detection of cytokines

IFN-{gamma} and IL-4 were detected in culture supernatants using the Duoset ELISA reagents from Genzyme Diagnostics (West Malling, U.K.) according to manufacturer’s instructions. IL-5 was detected by ELISA as previously described (11).

Eosinophilia

Peripheral eosinophilia was measured by differential counts of at least 200 cells in tail blood smears stained with Neat Stain (Guest Medical, Ederbridge, U.K.) according to manufacturer’s instructions.

Statistical analyses

Differences in the mean and variance of data sets between experimental groups were compared using the Student t test. P values < 0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Parasite clearance and resistance to reinfection is dependent on IL-5 in the absence of IL-4

To examine the role of IL-5 and eosinophils in parasite clearance during primary infection, groups of six IL-4+/+ or IL-4-/- mice were treated with either neutralizing anti-IL-5 Ab or NRIg 4 h before, and 15 days following, infection with 5000 O. lienalis mf. Parasite survival was assessed 32 days after infection. Neutralization of IL-5 in both IL-4+/+ and IL-4-/- mice significantly increased parasite survival, compared with NRIg-treated mice during primary exposure (Fig. 1GoA).



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  		FIGURE 1. Effect of IL-5 neutralization on parasite clearance following primary infection, or reinfection, with O. lienalis mf. A, Primary infection: IL-4-/- mice were treated with TRFK-5 or NRIg before, and 15 days following, infection with 5000 O. lienalis mf. Parasite recoveries 32 days postinfection are shown. B, Resistance to reinfection: IL-4-/- mice were infected with 5000 O. lienalis mf and rested. One hundred days postinfection they were treated with TRFK-5 or NRIg, and, together with a group of challenge control mice, were reinfected with 5000 mf. Parasite recoveries 15 days post reinfection are shown. Bars represent mean (± SE) parasite recoveries (n = 6). * represents p < 0.05 between TRFK-5- and NRIg-treated mice.

 
To examine resistance to reinfection, mice were sensitized with a primary infection of 5000 mf and challenged 100 days later, when it is known from previous work that they will have cleared the initial inoculum and are highly resistant to reinfection (17). Groups of six IL-4+/+ or IL-4-/- "immune" mice (sensitized with a primary infection) were treated with anti-IL-5 Abs or NRIg at the time of challenge with a second dose of 5000 mf. Naive challenge control mice were infected in parallel. Parasite survival was assessed 15 days later. Treatment of immune mice with anti-IL-5 Abs, but not NRIg, ablated the expression of resistance to reinfection in both IL-4+/+ and IL-4-/- animals (Fig. 1GoB).

Measurement of peripheral eosinophil levels confirmed that neutralization of IL-5 ablated the infection-induced eosinophilia observed during primary exposure (Fig. 2GoA) and reinfection (Fig. 2GoB) in both groups of mice.



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  		FIGURE 2. IL-5 neutralization ablates parasite-induced eosinophilia during primary infection and reinfection with O. lienalis mf. Mice were treated as described in Figure 1Go. A, Eosinophilia during primary infection. B, Eosinophilia 15 days following reinfection. Bars represent mean percent eosinophilia (± SE, n = 6). * represents p < 0.05 between TRFK-5- and NRIg-treated mice.

 
Up-regulation of Th1 responses during induction and effector phases of protective immunity to mf in the absence of IL-4

To determine the effect of IL-4 on the development of immune responses following exposure to O. lienalis mf, serum isotype levels (as markers of systemic type 1 or type 2 differentiation) and spleen cell cytokine production (as a measure of Ag-specific responses) were examined in IL-4-/- and IL-4+/+ mice. Exposure to either a primary or secondary infection with mf induced a marked dichotomy of Ag-specific serum isotypes between the two groups of mice, as shown in Figure 3Go. IL-4+/+ mice showed greater increases in the type 2 associated-isotypes IgE and IgG1, while IL-4-/- mice produced more pronounced IgG2a and IgG3 responses, associated with type 1 differentiation. The complete lack of detectable IgE in the sera of IL-4-/- mice demonstrated its dependence on IL-4 in this system.



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  		FIGURE 3. Th1-type Ab isotypes predominate during primary infection and reinfection in IL-4-/- mice. Parasite-specific Ab isotypes were measured in sera of IL-4+/+ (solid bars) and IL-4-/- (open bars) mice during primary infection (A–E), or 15 days following reinfection (F–J) (lightly hatched bars, IL-4+/+ normal mouse sera; densely hatched bars, IL-4-/- normal mouse sera). Values represent mean OD405 readings (± SE, n = 4). * represents p < 0.05 between IL-4+/+ and IL-4-/- mice.

 
Analysis of the Ag-induced splenocyte cytokine production during primary and secondary mf infections confirmed this dichotomy (Fig. 4Go). Spleen cells from IL-4+/+ mice predominantly made IL-4 and IL-5, but IL-4-/- cells produced significantly higher levels of IFN-{gamma} and lower levels of IL-5. Cells from both groups of mice produced equivalent levels of IL-2.



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  		FIGURE 4. Spleen cells from IL-4-deficient mice produce increased IFN-{gamma} during primary and secondary infections. Thirty-two days after primary (A–D), or 15 days after secondary (E–H), infection, spleen cells from infected or naive mice were isolated and cultured for 72 h in the presence of 10 µg/ml Onchocerca Ag. IFN-{gamma}, IL-2, IL-4, and IL-5 levels were measured by ELISA. * represents p < 0.05 between IL-4+/+ and IL-4-/- mice.

 
Parasite clearance and resistance to reinfection is independent of Ab

To investigate the possibility of IL-5 mediating immunity via Ig isotype switching, the role of Ab in protective immunity against mf was examined. Exposure of µMT mice to a primary infection with mf resulted in a profile of parasite clearance equivalent to that seen in wild-type controls (Fig. 5GoA). The expression of resistance to reinfection with mf following sensitization with a primary infection was also similar between µMT and wild-type control mice (Fig. 5GoB). There was no detectable serum IgG in µMT mice, and levels of peripheral eosinophilia were equivalent in both groups of animals (data not shown).



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  		FIGURE 5. Clearance of primary infection and resistance to reinfection are independent of Ab. A, Primary infection: µMT mice and wild-type controls (C57BL/6) received 5000 O. lienalis mf, and parasite recoveries were assessed throughout infection. B, Resistance to reinfection: µMT mice and wild-type controls (C57BL/6) were infected with 5000 O. lienalis mf and reinfected 100 days later with an equivalent inoculum (open bars). Naive mice were infected as challenge controls (solid bars). Parasite recoveries were assessed 15 days following reinfection. Bars represent mean parasite recoveries (± SE, n = 6). * represents p < 0.05 between reinfected and challenge control group recoveries.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These experiments show that CD4+ T cell-mediated, IL-5 dependent immunity to Onchocerca mf occurs independently of IL-4. Neutralization of IL-5 during primary and secondary infections in IL-4-deficient mice depleted eosinophilia and eliminated protective immunity against mf to the same extent as wild-type mice, in spite of an up-regulation in Th1 responses. The demonstration that protective immunity is independent of Ab confirms previous findings (10) and suggests that IL-5 is not exerting its effects via isotype switching mechanisms or other B cell-dependent mechanisms. Together, these data indicate that protective immunity to Onchocerca mf in the absence of IL-4 is not due to alternative Th1 mechanisms, but that IL-5-dependent, eosinophil-mediated immunity is operating independently of IL-4.

The relationship between IL-4 and the development of type 2 immune responses to parasites or parasite Ags has been addressed in several studies. Infection of IL-4-deficient mice with Nippostrongylus brasiliensis (18, 19), Brugia malayi (20), or Schistosoma mansoni (21) results in severely diminished Th2 responses, with an elevation of IFN-{gamma} production. Surprisingly, despite these profound immunologic changes, the expression of immunity to infection was unaffected.

The diminished IL-5 production and eosinophil responses in IL-4-deficient mice reported here may be due to the inhibitory effect of IFN-{gamma} overproduction in the absence of IL-4 down-regulation, rather than the absence of IL-4 per se. Indeed the production of IL-5 and eosinophils in IL-4-deficient mice may be under the regulation of IL-2, in view of the unimpeded IL-2 production observed here and by others (22). This accords with the conclusions of previous studies on the relationship between IL-2 and IL-5, which indicates a mechanism of IL-5 and eosinophil regulation distinct from classical Th1/Th2 polarization (23, 24). Although the source of IL-5 in IL-4-deficient mice was not determined, previous studies in immunocompetent mice showing the requirement for CD4+ T cells in the expression of immunity to mf (10, 11) supports the view that these cells are a likely source of IL-5. An alternative or supplementary origin might be eosinophils. The profound effect of the absence of IL-4 on parasite-specific IgG isotypes, IgE production, and up-regulation of Th1 cytokine responses provides no evidence for the existence of compensatory mechanisms, such as IL-13 or other factors, that can signal through the IL-4 receptor complex and STAT6 transduction pathway.

These observations cast doubt on a protective role for IL-4 in eosinophil-mediated IL-5-dependent immunity to tissue-dwelling mf. Importantly, they segregate T cell-mediated mechanisms of protective immunity from those mediating the development of ocular pathologic responses to Onchocerca Ags in a murine model of experimental keratitis (14). Furthermore, protective responses to mf are distinct from those generated by vaccination with radiation-attenuated infective larvae, which have been shown to require both IL-4 and IL-5 (25).

Perhaps the predominant role of IL-4 in tissue-dwelling parasitic infections is in the regulation of pathologic responses rather than the development of protective immunity, in contrast to gastrointestinal nematodes infections. Indeed, studies on another tissue invasive helminth, S. mansoni, have also highlighted the role of IL-4 in the development of immunopathologic granulomatous responses (26, 27, 28).

In conclusion, this study demonstrates that CD4+ T cell-mediated, IL-5-dependent immunity to a tissue-dwelling nematode occurs in the absence of IL-4 and Ab and dissociates the roles of IL-4 and IL-5 in a functional model of protective immunity.


   Footnotes
 
1 This work was supported by a Medical Research Council (U.K.) Research Studentship to P.J.H. M.J.T. is supported by a Research Career Development Fellowship in Basic Biomedical Science from the Wellcome Trust (047176). Back

2 Address correspondence and reprint requests to Dr. A. E. Bianco, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, United Kingdom. E-mail address: Back

3 Abbreviations used in this paper: mf, microfilariae; TST, tris-saline-tween; NRIg, normal rat Ig. Back

Received for publication December 2, 1997. Accepted for publication January 30, 1998.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Clin. Microbiol. Rev., July 1, 1999; 12(3): 445 - 453.
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