Mem Inst Oswaldo Cruz, Rio de Janeiro, 93 (Suppl.I) October 1998
Original Article

Role of Cytokines in the Formation and Downregulation of Hepatic Circumoval Granulomas and Hepatic Fibrosis in Schistosoma mansoni-Infected Mice

Allen W Cheever+, Dragana Jankovic, George S Yap, Marika C Kullberg, Alan Sher, Thomas A Wynn

Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD 20892-0425 & Biomedical Research Institute, Rockville, MD, USA

Page: 25-32
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Schistosoma mansoniu00a0infections are associated with a strong Th2 cytokine response. Treatment of mice with IL-12 or anti-IL-2 or anti-IL-4 beforeu00a0i.v. injectionu00a0of eggs increased IFN-g production and downregulated Th2 responses and pulmonary granuloma size. Conversely, anti-IFN-g antibody treatment increased Th2 responses and granuloma size. Similar manipulation produced less dramatic results inu00a0infected mice. However, sensitization of mice with eggs + IL-12 before infection augmented the Th1 response and decreased Th2 cytokines, granuloma size and fibrosis. Antisera to IFN-g, TNF-a or IL-12 during IL-12-egg immunization partly restored granuloma size and fibrosis following infection.


Variations in the size of granulomas in acute (8 week) infections may be influenced primarily by the number and state of activation of T cells. In chronic (12-16 week) infections immunologic downmodulation proceeded normally in mice without functional CD8+ cells and in IFN-g KO mice but not in B cell KO (mMT) mice or in mice deficient in FcR expression in spite of the fact that these mice downregulated their T cell and cytokine responses. It is evident that the participation of cytokines in granuloma formation and regulation is complicated and that the mechanisms controlling both these phenomena are likely to involve both T cells and antibody/FcR interactions.

The granulomas around Schistosoma mansoni eggs cause most of the pathology of S. mansoni infections in immunologically competent animals. CD4+ lymphocytes are central in orchestrating the formation and growth of the granulomas and secretion of cytokines, and the resulting cascade of adhesins, chemokines etc. direct the cellular interactions which take place around the schistosome egg (Weinstock 1992, Chensue et al. 1994a, Jankovic & Sher 1996). Chesney et al. (1998) have recently suggested that circulating fibrocytes entering the granulomas may be important in attracting CD4+ lymphocytes.

Most evidence concerning the role of cytokines in circumoval granuloma formation has been obtained either from infected mice or from mice given intravenous eggs or antigen on beads with subsequent examination of the granulomas formed in the lungs (the "lung model"). The lung model obviously provides excellent opportunities to examine immune responses initiated with a synchronous pulse of antigen (Chensue et al. 1992, Wynn et al. 1993), but the immune response and immunopathology in the lung model sometimes do not coincide with those seen in infected mice.

Th1- vs Th2-like responses affect granuloma formation and schistosomal hepatic fibrosis - Th1 responses are accompanied by secretion of IFN-g and IL-2 and are traditionally associated with delayed type hypersensitivity (DTH) reactions while Th2 responses are accompanied by the secretion of IL-4 (necessary for IgE production), IL-5 (vital for eosinopoiesis) and IL-10. Schistosome infections are associated with high levels of serum IgE and the presence of blood and tissue eosinophilia which indicate a predominantly Th2-type reaction. Several recent reviews deal with the relation of cytokines to pathology in schistosome infections (Lukacs & Boros 1993, Wynn & Cheever 1995, Cheever & Yap 1997, Cheever et al. 1998).

Treatment of mice with cytokines and antibodies to cytokines generally supports the importance of Th2-type reactions for the formation and maintenance of large granulomas (Tables III). Antibodies neutralizing IL-2 (thus inhibiting expansion of CD4+ lymphocytes) or IL-4 (blocking differentiation and expansion of Th2 cells) diminished granuloma size and hepatic fibrosis (Cheever et al. 1992, 1994).

Immunization of mice with schistosome eggs together with IL-12 led to an augmented Th1-type response, a diminished Th2 response and a decrease in granuloma size and hepatic fibrosis when the mice were later infected (Wynn et al. 1995). Treatment during immunization with anti-IL-12, anti-IFN-g or anti-TNF-a largely abrogated the effect of IL-12-egg immunization when mice were later infected (Wynn et al., unpublished).

We have seen at least two exceptions to the phenomenon of decreased immunopathology with an increase in Th1 response. S. mansoni-infected IL-10 KO mice demonstrated increased IFN-g responses with markedly increased granuloma size (Wynn et al. 1998). Infected IL-4 KO mice on a BALB/c background also showed very high 
IFN-g levels and greatly enlarged granulomas (Jankovic et al. unpublished). In both instances, total hepatic fibrosis was, surprisingly, unaffected. Overall, S. mansoni infections in various kinds of IL-4 KO mice elicit a bewildering diversity of responses (Table III). The genetic background of the mice, and perhaps local factors in various laboratories, profoundly affects the interaction of the murine host with the schistosome infection. This initially puzzling result opens new opportunities to determine the immunopathological consequences of the different approaches mice use in dealing with the infection.

Mice with severe combined immunodeficiency (scid mice) have a minimal reaction to S. mansoni eggs but when given exogenous tumor necrosis factor (TNF-a) infected scid mice formed substantial circumoval granulomas (Amiri et al. 1992). Treatment of S. mansoni-infected mice with polyclonal anti-TNF-a diminished the size of hepatic granulomas (Joseph & Boros 1993). Monoclonal anti-TNF-a had little effect on granulomas in the lung model (Chensue et al. 1994b) or infected mice (Cheever et al., unpublished). Mice lacking both p55 and p75 chains of the TNF-a receptor formed normal circumoval granulomas 8 weeks after infection (Yap et al. unpublished). The extent and mechanism of the participation of 
TNF-a need further clarification.

Are there different types/mechanisms of immunologic regulation in S. mansoni-infected mice? - Downregulation of the immunologic responses of CD4+ T cells, mediated by CD8+ T cells, was long thought to be the mechanism of downmodulation of granulomatous responses to S. mansoni eggs (Chensue & Boros 1979, Green & Colley 1981). More recently B cells have been shown to be necessary for this downregulation through a process requiring functional Fc receptors in addition to modulation of the T cell response (Jankovic et al. 1998).

One may also ask, as discussed below, whether the mechanisms of downregulation are the same in acute and chronic infections and whether the mechanisms are the same in the liver as compared to other organs (Weinstock & Boros 1981, Souza Vidal et al. 1993). The regulation of fibrosis in the liver may differ from the regulation of granuloma size (Olds et al. 1989, Phillips et al. 1996, Cheever 1997). In addition, the absence of regulatory idiotypes correlated with the development of pipestem portal fibrosis (a qualitative microscopic assessment) in mice but not with altered regulation of granuloma size (Henderson et al. 1993). Splenocytes of these mice were unresponsive to schistosome egg antigens (Bosshardt et al. 1997). Although total hepatic collagen was higher in mice with pipestem fibrosis, more eggs were present and collagen was not increased in relation to egg numbers (quantitative assessments) (Adewusi et al. 1996).

Immunologic downregulation of granuloma size in the livers of chronically-infected mice - Downregulation of the size of S. mansoni-induced circumoval granulomas was first described in chronically-infected mice (Andrade & Warren 1964) and downregulation has generally been studied comparing mice with infections of 8 weeks duration to those with infections of >16 weeks duration. Downregulation has generally been associated with the activity of CD8+ suppressor cells (Chensue & Boros 1979, Green & Colley 1981). However, mice in which CD8+ cell function was genetically deleted formed normal granulomas (Hernandez et al. 1997b, Yap et al. 1997) and several varieties of such mice [CD-8 knockout (KO) mice, ß-2 microglobulin KO mice and TAP-1 KO mice] downregulated granuloma size normally and showed fibrosis equivalent to that in intact mice (Yap et al. 1997). IFN-g might be expected to be a key mediator of downregulatory responses, but IFN-g KO mice also downregulated granuloma size normally (Yap et al. 1997).

Passive transfer of antibody from chronically-infected mice to immunologically intact mice at 6 weeks of infection did not result in downregulation of lesions at 8-weeks (Colley 1976). However, mice rendered deficient in B cells by anti-m antiserum (Cheever et al. 1985) and chronically-infected B cell ko mice (mMT mice, Jankovic et al. 1998) failed to downregulate granuloma size and showed increased hepatic fibrosis. T cell responses in mMT mice, measured as proliferation and by cytokine production, were downregulated as in the wild type-infected mice. In the mMT mice granuloma size was decreased by the passive transfer of serum from chronically infected mice (Jankovic et al. 1998). Antibody apparently acts via the Fc receptors on cells as KO mice (on a C57BL/6 background) deficient in FcR had abundant antibody but did not downregulate granuloma size (Jankovic et al. 1998). These findings are consistent with the reported effects of immune complexes on the formation of in vitro granulomas (Goes et al. 1991, Rezende et al 1997a,b).

Granulomas in FCeR1 KO mice (on a BALB/c background) were larger at 8 weeks than granulomas in wild type mice (Jankovic et al. 1997). This, and the very large granulomas seen at 8 weeks of infection in BALB/c IL-4 KO mice, suggest that IgE, mast cells, non-B, non-T cells and basophils may be involved in regulating granuloma size in BALB/c mice while in C57BL/6 mice other mechanisms might be more important. Chronic infections have not yet been examined in FceR1 KO mice.

Downregulation in chronically infected mice was partially or completely abrogated by treatment with IL-2 (Mathew et al. 1990), IL-4 (Yamashita & Boros 1992) or TNF-a (Joseph & Boros 1993) suggesting that all of these cytokines are involved in the downregulatory process.

Downmodulation of granuloma size in the liver may differ from regulation of granuloma size in the gut (Weinstock & Boros 1981) or lungs (Souza Vidal et al. 1993) of infected mice and regulation of hepatic fibrosis frequently differs from that of hepatic granuloma size (Olds et al. 1989, Cheever 1997).

Immunologic regulation of granuloma size in acutely-infected mice - The presence of immune regulation during acute infection was first suggested by Hood and Boros (1980) who found that mice splenectomized 6 weeks after infection showed an increase in granuloma size 2 weeks later when compared to sham-operated mice, an effect attributed to the removal of CD8+ cells by splenectomy. Cimetidine or cyclophosphamide treatment of mice beginning at 6 weeks of infection also led to an increase in granuloma size (Weinstock & Boros 1981, Weinstock et al. 1983) which was attributed to the removal of regulatory T cells. Increased granuloma size and hepatic fibrosis was noted by 8 weeks of infection in mMT B cell KO mice (Jankovic et al. 1998) although in another B cell KO mouse (JHD) granulomas were the same size as those in control mice (Hernandez et al. 1997a). Chronic infections were not examined in JHD mice. FcR KO mice also showed large granulomas 8 weeks after infection (Jankovic et al. 1998).

Stadecker (1992) has proposed that downregulation is caused by IL-10 mediated T cell anergy and he and his colleagues showed downmodulation of anti-egg immune response and granuloma size in acute infection by IL-10 (Villanueva et al. 1994, Flores-Villanueva et al. 1996). In agreement with this, Wynn et al. (1998) found very large granulomas at 8 weeks of infection in IL-10 KO mice, but these mice downregulated granuloma size in chronic infections suggesting that other mechanisms may be more important. Bosshardt et al. (1997) reported low IL-10 levels in chronically-infected mice which lacked regulatory idiotypes and developed pipestem fibrosis.

It seems that granuloma size in acute S. mansoni infections is determined primarily by T cell reactivity and is therefore sensitive to IL-10 (Flores-Villanueva et al. 1996, Wynn et al. 1998), cimetidine and cyclophosphamide (Weinstock & Boros 1981) while antibody has a minor effect (Jankovic et al. 1998). Downregulation of granuloma size in chronic infections requires antibody and downmodulated T cells (Jankovic et al. 1998).

In S. japonicum-infected mice early downregu-lation of granuloma size was predominantly T cell mediated while in chronic infections downregu-lation was almost exclusively via regulatory cross-reactive idiotypes (Olds & Stavitsky 1986, Kresina & Olds 1986). Immunoregulatory idiotypes are also important in S. mansoni-infected mice (Montesano et al. 1997) but have not been reported to affect granuloma size, and T cell responses to S. mansoni egg antigen were virtually absent in mice lacking the regulatory idiotypes (Bosshardt et al. 1997).

Comparison of granulomas around injected eggs in the lung model with granulomas in infected mice - We were impressed with the dramatic effect of anti-IL-4 treatment on granulomas around eggs injected into the lungs compared to a slight effect on the size of hepatic granulomas in the same infected mice (Cheever et. al 1994, Eltoum et al. 1995). When a shunt was produced surgically to divert eggs laid by the worms to the lungs, the effect of anti-IL-4 on the granulomas was slight, as in the liver. Conversely, when eggs were injected into the portal veins of uninfected mice, anti-IL-4 treatment dramatically reduced the size of the resulting hepatic granulomas (Eltoum et al. 1995). It was clear that the site of the reaction, i.e. lung vs liver, was relatively unimportant. The state of host sensitization was also not of fundamental importance as granulomas around injected eggs were smaller after IL-4 treatment of both infected and uninfected mice. Instead the quality of the eggs seemed vital, i.e. eggs arriving in the tissues directly from the worms may be much more antigenic than eggs recovered from the livers of infected mice and then injected.

Although the lung model has been an extremely useful tool in the study of immune downregulation (Domingo & Warren 1968), Souza Vidal et al. (1993) found that pulmonary granulomas in mice with portacaval shunts did not modulate while hepatic granulomas in the same mice downregulated in size.

Infection, of course, results in much more than merely the delivery of higher quality eggs to the tissues. Once the Th2 reaction has begun, IL-4 and IL-10 inhibit the production of IFN-g. This cross-regulatory effect makes a switch in cytokine patterns particularly difficult. It is thus not surprising that treatment with anti-cytokine antibodies or with cytokines are much more easily demonstrated in the lung model than in infected mice (Table IV). However, the reverse effect is sometimes seen, i.e. mMT mice formed normal sized granulomas in the lung model (Epstein et al. 1995) but augmented granulomas in infected mice (Jankovic et al. 1998) and IL-10 KO mice formed small granulomas using the lung model (Wynn et al. 1997) but very large granulomas in the livers of 8 week infected mice (Wynn et al. 1998). This suggests a fundamental difference in immunoregulatory mechanisms although the questions of site versus egg injection or infection remain unanswered.

There are numerous reasons to think that intrinsic differences between the reactions of the liver and lung to S. mansoni eggs might exist. Miracidia in eggs injected into the tail vein are destroyed more rapidly than those injected into the portal vein (Feldman et al. 1990) and Leptak and McKerrow (1997) found a much more vigorous reaction to eggs injected into the lung than those injected into the liver. Other investigators have not noted a difference in the response to injected eggs at the two sites (Edungbola & Schiller 1979, Raso et al. 1983, Eltoum et al. 1995) and the reasons for the discrepancy are not evident.

Relevance of murine infections for immunopathology in S. mansoni infected humans - The granulomas in mice and humans are similar histologically and the factors regulating their formation and downmodulation are likely to be fundamentally similar. Judging from the apparent differences in granuloma regulation in different anatomic sites and in different mouse strains, our understanding of the process remains somewhat less than fundamental. This is not to say that the experimental findings are not useful for planning studies in humans and even for understanding human disease. In fact, the different responses of varied mouse strains to infection may all have relevance to the spectrum of human responses to schistosome infections. Different FcgR allotypes are known to be clinically important in human responses to infectious diseases (Deo et al. 1997).

We also lack a clear understanding of the relation of granuloma formation to the development of Symmers' portal fibrosis of the liver. One particularly bright spot on this horizon is the association of similar defects in regulatory idiotypes in Symmers' portal fibrosis in humans (Montesano et al. 1990) and mice (Henderson et al. 1993, Montesano et al. 1997). However, the connection between this idiotypic regulation of portal fibrosis and early or late downregulation of T cells, granuloma size or overall hepatic fibrosis is not evident. This association of deficient immunoregulation with disease leads one to believe that the continued elucidation of mechanisms of immune regulation in experimental animals and man is important.



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+Corresponding author. Fax: +301-770.4756 or 301-402.0890. E-mail:u00a0achever@atlas.niaid.nih.govu00a0


Received 4 May 1998


Accepted 31 August 1998

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