Proc. Nail. Acad. Sci. USA Vol. 88, pp. 5513-5517, July 1991 Immunology 4 is important in protective immunity to a gastrointestinal nematode infection in mice (interleukin 4/interleukin 5/IgE//HeLigmosomoides polygyrus) JOSEPH F. URBAN, JR.*t, ILDY M. KATONAt§, WILLIAM E. PAUL¶, AND FRED D. FINKELMAN§ *Helminthic Diseases Laboratory, Livestock and Poultry Sciences Institute, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705-2350; Departments of tPediatrics and §Medicine, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 208884799; and 1Laboratory of Immunology, National Institute of and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 Contributed by William E. Paul, March 28, 1991

ABSTRACT Parasitic helminths typically induce compo- with the nematode Nippostrongylus brasiliensis (20) and nents of immediate-type hypersensitivity, including elevated from liver granulomas induced by eggs of the trematode serum IgE, eosinophilia, and mucosal mast cells. These re- Schistosoma mansoni, without affecting lesion size (15). sponses are T-cell-dependent and associated with rapid expul- However, neutralization of endogenously produced IL-4 or sion of parasitic worms from a sensitized host; existing exper- IL-5 fails to measurably compromise host immunity in mice imental systems have failed to derme the precise role of infected with S. mansoni (21) or N. brasiliensis (ref. 20; in these responses. We report here that anti- J.F.U., I.M.K., and F.D.F., unpublished data). interleukin 4 or anti-interleukin 4 receptor antibodies block the The absence of a definitive role for IL-4 and IL-5 in host polyclonal IgE response to a parasitic nematode, Heligmo- responses to these parasites prompted the study of a nema- somoides polygyrus, and abrogate protective immunity to the tode parasite with a completely enteric and more chronic infection. In contrast, anti-interleukin 5 antibody prevented H. infection than N. brasiliensis to determine whether mucosal polygyrus-induced eosinophilia but did not prevent protection. elements important in protective immunity were regulated by These data provide evidence that a specific affects the IL-4 or IL-5. Parasitic third-stage larvae ofHeligmosomoides physiology and survival of a parasitic nematode in the host. polygyrus (Hp) invade the intestinal mucosa after oral inoc- ulation and molt twice within 8 days before emerging into the Resolution of gastrointestinal helminthiasis is a T-cell- intestinal lumen as adults that persist for several weeks (22). dependent process. Parasite expulsion mechanisms do not The results of the studies reported here show that antibodies function in congenitally athymic nude mice or in mice that against IL-4 or the IL-4 receptor (IL-4R), but not antibodies have been depleted of T cells (1-3). Host responses that against IL-5, block host protective mechanisms that normally modulate parasite physiology, such as worm fecundity, are limit parasite egg production and reduce the development of also known to be T-cell-dependent (4, 5). Because there is no new worms inoculated into previously infected mice. evidence that T cells directly kill nematode worms, immune and inflammatory responses that combine to eliminate par- MATERIALS AND METHODS asites or impair their activity might result from T-cell-derived cytokines. Interleukin 4 (IL-4) and interleukin 5 (IL-5) are Animals. Female BALB/c mice were obtained from the two cytokines that could potentially affect immunity to Small Animal Division of the National Cancer Institute helminths. (Frederick, MD) and were used for experimentation at 8-12 IL-4 has multiple immunoregulatory functions, including weeks ofage. All experiments were conducted with five mice autocrine T- factor activity, regulation of B-cell per group. Blood samples were obtained from the orbital IgE isotype expression, and stimulation ofthe growth and/or plexus. Serum was separated from clotted blood by centrif- differentiation of , hematopoietic cells, and ugation and stored at -80'C until used. An anthelminthic mast cells (6-12). The complexing of IgE receptors on drug, pyrantel pamoate (Strongid T, Pfizer Diagnostics), was mucosal mast cells with IgE antibody specific for parasite- administered orally at a dose of 1-2 mg per mouse to some derived antigens is postulated to be important in protective parasite-infected mice to remove adult worms from a primary immunity because of the subsequent release of mediators of infection. that could adversely affect parasite survival Parasitological Parameters. Infective, ensheathed third- (13). IL-5 regulates the generation of eosinophil myelocyte stage larvae of Hp (specimens on file at the U. S. National precursors in bone marrow and the development of mature Parasite Collection, U. S. National Museum Helmintholog- after helminth infection (14, 15), and there is ical Collection no. 81930, Beltsville, MD) were propagated evidence that eosinophils and IgE may constitute an impor- and stored at 40C until used (23). Mice were inoculated orally tant defense mechanism in rats infected with schistosomes with 200 larvae by using a ball-tipped feeding tube. Adult (16) or the nematode Trichinella spiralis (17). Treatment of worms and total parasite eggs in the intestinal contents were mice with monoclonal antibody (mAb) against IL4 (llB11) determined at necropsy (23). Worm fecundity was expressed in vivo completely suppresses polyclonal IgE responses (18, by dividing the total number of eggs recovered from each 19) and limits the expansion of mucosal mast cells (K. B. mouse by the total number of female worms. Madden, J.F.U., H. J. Ziltener, J. W. Schrader, F.D.F., and Antibodies. The preparation and specificity testing of the I.M.K., unpublished work). Anti-IL-5 (TRFK-5) suppresses following antibodies have been previously described: affini- eosinophilia and eliminates eosinophils from the cellular ty-puriflied rabbit anti-mouse IgG1 (24) and anti-mouse IgE infiltrates responding to larvae in the lungs of mice infected Abbreviations: IL-4, interleukin 4; IL-5, interleukin 5; IL-4R, inter- The publication costs of this article were defrayed in part by page charge leukin 4 receptor; mAb, monoclonal antibody; Hp, Heligmo- payment. This article must therefore be hereby marked "advertisement" somoides polygyrus. in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed.

5513 Downloaded by guest on September 23, 2021 5514 Immunology: Urban et al. Proc. Natl. Acad. Sci. USA 88 (1991) (25); monoclonal rat IgG2b anti-mouse CD4 (GK1.5) (26); monoclonal rat IgG2a anti-mouse IgE (EM95) (27); mono- Hp + uNP clonal mouse IgE anti-dinitrophenyl (SPE-iv-7) (28); mono- N Secondary Infection clonal rat IgGl anti-mouse IL-4 (ilB11) (29) (Verax, Leba- Hp + AIL-4/5 * Primary Infection non, NH); monoclonal rat IgG2a anti-mouse IL-4R (ml) (30); monoclonal rat IgG1 anti-4-hydroxy-3-nitrophenylacetyl Hp + rAL-5 (J4-1) (31); monoclonal rat IgGl anti-mouse IL-5 (TRFK-5) (20); alkaline phosphatase-conjugated goat anti-rabbit immu- noglobulin (APGaRIg) (32). Hp + ct IL-4 Quantitation of Serum Immunoglobulin. Serum levels of mouse IgGl were determined by radial immunodiffusion with Hp -I02 standards and materials purchased from Hazelton Laborato- ries (Rockville, MD). Serum IgE levels were determined by Uninfected a micro ELISA (33). Peripheral Blood Analysis. Eosinophils were counted from 0 11000 2000 fresh blood samples by using the Unopette Test (Becton Eosinophils/mm3 Dickinson). Total peripheral blood leukocyte counts of ci- trated blood collected at were FIG. 2. Combined effects ofanti-IL-4 and anti-IL-5 on eosinophil the same time determined by responses to Hp. Mice were the same as those described for Fig. 1. using a ZM Coulter Counter. Eosinophils were counted from fresh blood samples and expressed as arithmetic means and SEs on day 21 after primary inoculation RESULTS (broad peak response between day 7 and 21) and day 11 after secondary inoculation (peak response between day 7 and 12). Total The kinetics of the serum IgE response to parasite infection peripheral blood leukocyte counts of citrated blood collected con- was followed to evaluate mAb treatment in vivo (Fig. 1). currently were similar among all groups at times examined. aNP, Serum IgE levels rose 4100-fold in response to a primary Hp anti-4hydroxy-3-nitrophenylacetyl. infection in mice treated with anti-IL-5 mAb, control mAb, or no antibody; a second inoculation with Hp produced a further The role ofIL-4 and IL-5 in protective immunity to Hp was 5-fold increase in serum IgE levels in these mice. Treatment evaluated by measuring adult worm survival and fecundity of Hp-infected mice with anti-IL-4 or a combination of (eggs per female worm) in mice cleared ofa primary infection anti-IL4 and anti-IL-5 mAb inhibited the Hp-induced rise in with an anthelminthic drug and then reinoculated with Hp serum IgE by a factor of 100 (Fig. 1). (Fig. 3). Previously uninfected mice had an average of 131 Although anti-IL-4 blocked the IgE response to infection, adult worms at necropsy 17 days after inoculation with Hp, it did not inhibit all T-dependent antibody responses to Hp whereas previously infected mice given a secondary infection because the IgG1 response was not blocked (34). Anti-IL-5 alone or after treatment with anti-IL-5 or control mAb mAb, which totally blocked eosinophilia (Fig. 2), had no averaged <10 adult worms. Mice infected similarly but given effect on either IgG1 or IgE responses (34). Interestingly, anti-IL-4 or anti-IL-4 plus anti-IL-5 averaged 46 and 54 adult anti-IL4 treatment considerably enhanced the eosinophil worms, respectively. Anti-IL-4 suppression ofthe protective response to Hp, especially after a secondary challenge in- immunity resulted in increased worm fecundity as well as fection (Fig. 2). Peripheral blood leukocyte levels were not adult worm survival in the challenge infection. However, different among the treatment groups at the times sampled, interpretation of this experiment was complicated by the indicating a preferential expansion of eosinophils (data not relatively low level of fecundity observed in control mice shown). inoculated only once with Hp, as compared with most of our other experiments (compare Figs. 3 and 4). Drug Treatment ofmice with both a mAb that blocks the binding Treatment Hp of IL-4 to the IL-4 receptor (ml) and anti-IL-4 mAb more 1000 fully suppressed protective immunity in a second Hp infec- tion than did anti-IL-4 mAb alone. Mice with a primary Hp E 100 ,aNP+ infection were injected with anti-IL-4R once weekly starting at day 30 after inoculation and also were injected with anti-IL-4 antibody concurrently at the time of anthelminthic treatment and throughout a secondary challenge infection. - -H + Protective immune responses in these mice were completely E~~~~~~~~~xiL-+i4 blocked in that total adult worms, total eggs per mouse, and 01 worm fecundity levels were comparable to previously unin- fected mice given an initial Hp infection (Fig. 4). Initiating 7 14 21 28 35 42 anti-IL-4R antibody treatment at the time of reinfection also Days After Initial Inoculation proved effective in blocking protective immunity. In this experiment, mice were inoculated with Hp, treated with FIG. 1. Anti-IL-4, but not anti-IL-5, suppresses both primary and anthelminthic on day 21 after inoculation, given a second Hp secondary IgE responses to Hp. Mice (five pergroup) were inoculated inoculation on day 36, and sacrificed 17 days later. The worm twice orally with 200 Hp larvae (day 0 and day 31) and either received burden of reinoculated mice averaged <2, whereas nonim- no further treatment or were injected weekly i.p. starting on day 0 with mune mice inoculated similarly averaged 30 adults. Injection anti-IL4 mAb (llB11; 10 mg per mouse), i.v. with anti-IL-5 mAb of immune mice with various doses of anti-IL-4R mAb at the (TRFK-5; 2 mg per mouse), or with a combination of anti-IL4 and time of reinoculation and 1 week later inhibited protective anti-IL-S. Hp-infected control mice were injected similarly with an isotype-matched anti4hydroxy-3-nitrophenylacetyl mAb (J4-1; 10 immunity in dose-dependent fashion. Mice administered 0.2, mg per mouse i.p. and 2 mg per mouse i.v.). Additional controls 0.8, or 3.0 mg ofanti-IL-4R per week had, respectively, 33%, included uninfected mice and mice inoculated with Hp only on day 31. 66%, and >100o the worms of control mice inoculated with All mice were anthelminthic treated to remove adult worms from the Hp for the first time. primary infection and then challenge-inoculated with 200 Hp larvae. An experimental model that uses anthelminthic removal of aNP, anti4hydroxy-3-nitrophenylacetyl. a primary parasite infection followed by a secondary chal- Downloaded by guest on September 23, 2021 Immunology: Urban et al. Proc. NatL Acad. Sci. USA 88 (1991) 5515

1f Hp t Hp ? Hp + aNP 2°?Hp +aoL-4 2 Hp + alL-5 2'Hp + alL-4 + alL-5 0 50 100 150 Worms/Mouse

I 1HH+2PH

20 Hp+ aNP -FI4' x/,%/ .-m/X/lX/O 2° Hp + aIL-4 - r ,]~ 'V'go'g./IME V//, Allen 20 Hp + rfIL-5 1.0111"i !4. 1 1 2° Hp + axlL-4 + '40.. cxIL-5_fax - 0 1000 2000 3000 4000 5000 6000 0 50 100 150 200 250 Eggs/Mouse Fecundity FIG. 3. Effects of anti-IL-4 and anti-IL-S on worm survival and fecundity in mice reinoculated (20) with Hp. Mice were the same as those described for Fig. 1 and were sacrificed on day 48 of the experiment 17 days after challenge-inoculation. Worm fecundity was calculated by determining total number ofeggs present in small intestine, large intestines, and cecum over total female worms recovered. Proportion of males to females was not different among treatment groups. 10, primary infection in previously uninfected mice.

lenge, although clinically relevant, may not represent the mAb (GL117), or no antibody, and their adult worm burdens normal host response to repeated parasite infection. To were determined on day 35. An additional three groups of address this issue, three groups ofmice were inoculated three mice were inoculated only once on days 0, 14, or 21 to times with Hp on days 0, 14, and 21 of the experiment but determine the number of worms that would establish from a were not given anthelminthic drug treatment. These mice single infection. Mice inoculated at all three time points and were injected once weekly with either anti-IL-4R, control treated with control mAb or no antibody had no more worms

2°Hp+ alL4R

?Hp+Rat IgG Wt

tHp

12 Hp

Untreated

0 100 200 Hp Fecundity (Eggs/Worm)

2 Hp + aIL-4R 2 Hp+ aIL-4R

2 Hp + Rat IgG 2 Hp + Rat IgG

2 Hp 2 Hp

1f Hp f Hp

Untreated Untreated

2000 4000 6000 0 20 40 60 80 Eggs/Mouse Adult Worms/Mouse

FIG. 4. Effect ofcombined treatment with anti-IL-4 and anti-IL-4R mAb on worm survival and fecundity in mice reinoculated with Hp. Mice were inoculated with Hp on day 0 and reinoculated on day 65 (20), 7 days after anthelminthic treatment. All mice were necropsied on day 81 after primary inoculation. Anti-IL-4R or control mAb (GL117, anti-f-galactosidase) was given i.v. on days 30, 37,44, 58, 65, and 72 after primary inoculation; anti-IL-4 or control mAb (J4-1) was given i.p. on days 58, 65, and 72 after primary inoculation. Proportion of males to females was not different among treatment groups. 10, Primary infection in previously uninfected mice. Downloaded by guest on September 23, 2021 5516 Immunology: Urban et A Proc. Natl. Acad. Sci. USA 88 (1991) at the end of the experiment than did mice inoculated only fecundity in Hp-infected mice. However, preliminary studies once on day 0. However, treatment with anti-IL-4R mAb indicate that treatment of Hp-infected mice with an anti- during repeated infections blocked protective immunity in mouse IgE mAb, which neutralizes secreted IgE, fails to that increased numbers of worms were seen in the intestines inhibit protective immunity, whereas doses of anti-IL-4R of anti-IL-4R-treated mice (Fig. 5). In separate experiments, mAb that inhibit IgE secretion incompletely have a consid- anti-CD4 or anti-IL-4R mAb treatment given during a pri- erable blocking effect on protective immunity (I.M.K., K. B. mary Hp infection failed to significantly increase the intes- Madden, F.D.F., and J.F.U., unpublished data). These stud- tinal worm burdens (ref. 23, data not shown). Thus, the ies are incomplete in that they have not yet evaluated IgE increased worm burden of triple-infected, anti-IL-4R mAb- levels at the site of Hp infection in the gut or the role of treated mice results from blocking of a protective immune parasite-specific IgE antibodies; however, they do suggest response that normally inhibits maturation and survival of that other effects regulated by IL-4, such as its stimulation of new worms in the intestines during a challenge infection, T cells and mucosal growth (8), and, possibly, rather than an increase in the longevity of worms that activation of cytotoxic T cells (37), may contribute to the matured during an initial infection. protective immune response to Hp. Although inhibition of IL-4 effectively blocked protective immunity in mice given a second Hp infection, neutralization DISCUSSION of a second cytokine that is associated with worm infections, Our studies demonstrate that the cytokine IL-4 contributes to IL-5, did not affect worm survival or fecundity, even though the immune mechanisms that limit adult worm survival and it totally blocked Hp-induced eosinophilia. Prevention of fecundity in mice reinoculated with the nematode parasite eosinophilia, but not protective immunity, by treatment of Hp. Neutralization of IL-4 activity during a primary infection mice with anti-IL-5 was similar to that reported for mice did not consistently affect parasite egg production (J.F.U., infected with S. mansoni or N. brasiliensis (15, 20) and I.M.K., and F.D.F., unpublished results) in contrast with appears to lead to a similar conclusion-i.e., eosinophils are what had been observed in mice treated with anti-CD4 mAb not critical in murine immunity to these helminths, despite (23). This result suggests that the role of IL-4 in protective the fact that studies with S. mansoni and T. spiralis in a rat immunity during a primary infection may not be all-inclusive. model have suggested a prominent role for this cell type in However, treatment with either anti-IL-4 or anti-IL-4R mAb protective immunity (16, 17). Interestingly, in our studies, or with both mAbs substantially increased adult worm bur- IL-4 antagonist therapy has caused eosinophil levels in dens and fecundity in mice inoculated a second time. Con- Hp-infected mice to rise substantially, possibly because the siderable inhibition of protective immunity was observed, increased worm and egg burden that resulted from this regardless of whether the antagonistic IL-4 treatment was treatment acted to further stimulate eosinophil production. initiated at the first Hp infection, at the second Hp infection, Nevertheless, neutralization of IL-4 suppressed protective or at some point in between. Although anthelminthic therapy responses to infection in the presence of high eosinophilia, was used in most experiments to cure the initial infection and this suppression was not augmented by treatment with before a second inoculation and to demonstrate protective anti-IL-5 in combination with anti-IL-4. immunity, inhibition of protective immunity was also clearly The demonstration that IL-4 is important to protective demonstrated in one experiment in which mice were serially immunity in Hp-infected mice sharply contrasts with evi- inoculated three times with Hp without intervening drug dence that endogenous production of the same cytokine therapy. Anti-IL-4R mAb appeared more effective then anti- strongly inhibits protective immunity in mice infected with IL-4 mAb at inhibiting protective immunity; however, use of the protozoan parasite Leishmania major (38, 39). This either antibody gave qualitatively similar results, and varia- dichotomy between protective immunity in the L. major and tions between different experiments and lack of mAb dose- Hp systems is strengthened by recent studies that show that response studies make it impossible to draw any strong y, which contributes to protective immunity in L. conclusions about apparent quantitative differences. major-infected mice (39), inhibits protective immunity in The mechanism by which endogenously produced IL-4 mice infected with nematode parasites (J.F.U., K. B. Mad- contributes to protective immunity is uncertain. One attrac- den, A. Cheever, P. Trotta, I.M.K., and F.D.F., unpublished tive possibility is that the Hp-induced IgE response, which is work). Thus, a single cytokine response pattern can be totally IL-4 dependent (35, 36), limits worm survival and protective or maladaptive, depending upon the infectious agent involved. Because CD4' T cells, which contribute to H. DolVgyrus INOCULATION ANTIBODY protective immunity in both protozoan and nematode sys- tems, can differentiate either into cells that secrete large Day 0 quantities ofIL-4 with little or no interferon yor into cells that Day 14 have the opposite cytokine secretory pattern (40), the mech- Day 21 anisms that regulate the T cells of an infected host to make the appropriate cytokine response must contribute impor- Days 0, 14, 21 tantly to host survival. Days 0, 14, 21 af>-Gal Days 0, 14, 21 aIL-4R We thank C. Rafter, A. Jones, S. Kang, and J. Holmes for their technical assistance; R. Coffman, T. Mosmann, and the DNAX Worms/Mouse Research Institute for TRFK-5 mAb; and K. Grabstein, M. P. Beckmann, and the Immunex Corporation for ml mAb. This work FIG. 5. Anti-IL-4R mAb blocks protective immunity in mice was supported, in part, by the U. S. Department of Agriculture given serial infections with Hp. Mice (five per group) were inoculated (CRIS 1265-34000-009), the Uniformed Services University of the orally with 200 Hp larvae at the initiation of the experiment and/or Health Sciences Research (protocol nos. R08308 and R086AB), and 14 and 21 days later. Some mice received 3 mg of anti-IL-4R or an National Institutes of Health Grant AI-26150. isotype-matched control [anti-,B-galactosidase (af3-Gal)] mAb weekly, starting at the initiation of the experiment. Mice were 1. Jacobson, R. H. & Reed, N. D. (1974) Proc. Soc. Exp. Biol. necropsied 35 days after the initiation of the experiment, and adult Med. 147, 667-670. worm burdens were determined. Data are expressed as arithmetic 2. Mitchell, G. F. (1980) Prog. Immunol. Proc. Int. Congr. Im- means and SEs. munol. 4th (1980), Vol. 2, pp. 794-808. Downloaded by guest on September 23, 2021 Immunology: Urban et al. Proc. Natl. Acad. Sci. USA 88 (1991) 5517 3. Katona, I. M., Urban, J. F., Jr., & Finkelman, F. D. (1988) J. 23. Urban, J. 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