Interleukin 5 is required for the blood and tissue eosinophilia but not granuloma formation induced by infection with Schistosoma mansoni.

Abstract

Eosinophils are thought to play a major role in the immunobiology of schistosomiasis. To investigate the immunologic basis of the eosinophil response and directly assess the function of eosinophils in egg-induced pathology, mice infected with Schistosoma mansoni were injected with a monoclonal antibody produced against interleukin 5 (IL-5), a cytokine previously shown to stimulate eosinophil differentiation in vitro. This treatment suppressed the generation of eosinophil myelocyte precursors in the bone marrow and reduced to background levels the numbers of mature eosinophils in the marrow, in circulation, and within acute schistosome egg granulomas. Nevertheless, granulomas in the anti-IL-5-treated/eosinophil-depleted mice at 8 weeks of infection were only marginally smaller than those in animals injected with control monoclonal antibody, and hepatic fibrosis was comparable in the two groups. Additional parameters such as worm burden, egg output, and serum IgE levels were unaltered by the anti-IL-5 treatment. In contrast, infected animals injected with monoclonal antibody against y interferon (IFN-y) displayed circulating eosinophil levels that were elevated with respect to control mice, possibly because ofan enhanced release of mature eosinophils from the marrow, and developed egg granulomas that were indistinguishable in size and cellular composition from those in control animals. Immunologic assays revealed that lymphocytes from acutely infected mice produce large quantities of IL-5 but minimal IFN-y when stimulated with either egg antigen or mitogen. Taken together, these results indicate that neither IL-5 nor eosinophils are essential for egg-induced pathology but suggest that lymphocytes that belong to the IL-S-producing TH2 subset predominate during acute infection and may induce granuloma formation by the production of other cytokines.

Experimental models of Schistosoma mansoni infection

“…Anti-IL-5 treated mice lacked eosinophils but granuloma size and hepatic fibrosis were virtually unaffected in both acute (Sher et al 1990) and chronic (Cheever et al 1992c) infections and the pathology was not greatly changed in IL-5 ko mice (Rosa Brunet et al 1999a). Rumbley et al (1999), however, note that eosinophils form the majority of cytokine producing cells in the granuloma and are the dominant source of IL-4.…”

“…1: Czaja et al (1989a, b); 2: (Sher et al 1990, Cheever et al 1992c; 3: SCID mice, Amiri et al (1992); chronically infected mice, Joseph & Boros (1993); 4: Joseph & Boros (1993); 5: Mathew et al (1990);6: Cheever et al (1992); 7: Yamashita & Boros (1992); 8: Yamashita & Boros (1992), Cheever et al (1994); 9: acute (Sher et al 1990), chronic (Cheever et al 1992c); 10: IL-10/Fc fusion protein, competes with IL-10 (Flores- , also see Verwaerde et al 1999); 11: 12: (IP Oswald et al unpublished) IL-12 was generally ineffective in reversing the Th2 response in S. mansoni-infected mice once infection has begun; 13: ; 14: Prostaglandin E 1 (Chensue et al 1986); 15: Prostaglandin F 2α (Chensue et al 1986); 16: antagonist for NK-1 receptor (for substance P & other tachykinins), (Blum et al 1993); 17: (Blum et al 1992, Mansy et al 98), mice were treated with octreotide, a somatostatin (SOM) analogue which competes with SOM; 18: antihistamines, Cimetidine blocks H 1 receptors and diphenhydramine H 2 receptors (Weinstock et al 1983 The use of T cell lines and clones would seem to be a definitive way of resolving the relative importance of Th1 and Th2 cells. However granulomas are induced by transfer of Th0, Th1 and Th2 cells specific for SEA (Chickunguwo et al 1991, Zhu et al 1994.…”

“…This effect is dependent on IFN-γ, IL-12 and TNF-α (Hoffmann et al 1999) and mediated through nitric oxide synthase-2 (Hesse et al 2000). Treatment with IFN-γ resulted in a marked decrease in hepatic fibrosis (Czaja et al 1989a) but anti-IFN-γ had no effect on granuloma size or hepatic fibrosis in infected mice (Sher et al 1990). SEA given without adjuvant intravenously or intraperitoneally before infection also affected granuloma size (Botros et al 1997) and fibrosis (uncorrected for egg number, Pancré et al 1999).…”

Systemic modulation of peripheral eosinophilia (air pouch model) in Schistosoma mansoni infection

“…Even present in high number, the eosinophil is not a sine qua non condition for granuloma development (Sher et al 1990). The acute eosinophil cellular response to eggs, and its contribution to the granuloma formation is not a well studied field.…”

“…Not withstanding from the ability to kill helminths to the destructive actions in asthma, eosinophil is a complex and mysterious cell. In parasitic diseases, as in schistosomiasis mansoni, eosinophilia is dependent on antigens secreted by eggs through the pores of the egg shell (SEA) (Race et al 1969, Sher et al 1990). The bone marrow and the blood eosinophilia peak, respectively, by the fifth and seventh week after the infection, and have been attributed to the en-pivotal role in these mechanisms (Stadecker 1994).…”