Tumour necrosis factor α restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice

Abstract

Schistosomiasis (bilharzia) is a parasitic disease caused by several species of schistosome worms (blood flukes). The key pathogenic event in this disease is the formation of granulomas around schistosome eggs trapped in portal venules of the liver. Granulomas are a distinctive form of chronic inflammation characterized by localized aggregation of activated macrophages around an inciting stimulus. Each granuloma evolves to form a fibrous scar; in schistosomiasis, the result is widespread hepatic fibrosis and portal hypertension. To identify the specific immune signal molecules necessary for granuloma formation, we studied schistosome infections in severe combined immunodeficient (SCID) mice, which have normal macrophages but lack functional B or T lymphocytes. Here we report that the immunoregulatory cytokine tumour necrosis factor alpha is necessary and sufficient to reconstitute granuloma formation in schistosome-infected SCID mice. Moreover, we find that the parasitic worms require tumour necrosis factor alpha for egg-laying and for excretion of eggs from the host. The implication of this latter result is that the parasite has adapted so successfully to its host that it uses a host-derived immunoregulatory protein as a signal for replication and transmission.

Lack of antigen-specific Th1 response alters granuloma formation and composition inSchistosoma mansoni-infected MyD88-/- mice

“…Indeed, granulomas fail to develop in SCID mice [24] or in the absence of either MHC class II molecules or CD4 + T cells. In these models the SEA-specific recall responses by T cells were either absent or diminished [14,25], implying a clear link between granuloma formation, T cells, cytokines and the recognition of schistosomosal antigens.…”

Experimental models of Schistosoma mansoni infection

“…1a : Viera & Moraes-Santos (1987); 2: Cheever et al (1987); 2a: Biozzi high (HIII) and low (LIII) responder mice (Blum & Cioli 1978, Catapani et al 1994; 3a: nude athymic mice lacking T cells ; 3b: mice with severe combined immunodeficiency lacking T & B cells (Amiri et al 1992; 3c: mast cell deficient mice (Cheever et al 1987); 3d: Cheever et al (1987); 3e: Gaubert et al (1999); 5a: Yap et al (1977); 5b: β-2 microglobulin deficient mice , Hernandez et al1997b; 5c: mice unable to process class 1 antigens (Yap et al 1977); 5d: receptor for macrophage Inflammatory Protein-1α [CCR-III] (Gao et al 1997); 5e: mice lacking both TNF-α receptors (Yap et al unpublished); 5f: µ-MT mice , Ferru et al 1998) JHD B-less mice had normal granulomas at 8 wk (Hernandez et al 1997a); 5g: Jankovic et al (1997); 5h: Jankovic et al (1998); 5i: IL-4 ko mice from cross of 129J and C57BL/6 mice ; 5j: IL-4 ko mice bred back to the C57BL/6 background (Rosa Brunet et al 1997); 5k: IL-4 ko mice formed using C57BL/6 germline only (Metwali et al 1996);5l: Rosa Brunet et al (1999a); 5m: Wynn et al (1998);5n: Wynn et al (1998);5o: Amiri et al (1994, Yap et al unpublished);5p: (Akihani et al 1996, Rezende et al 1997a, Oliveira et al 2000; 5q: ; 5r: 5 lipoxegenase, 12-lipoxygenase (Secor et al 1998 ↓ / ↓ ? ↑, ↓: increase, decrease or no change; ?…”

“…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.…”

“…SCID mice show almost no reaction to S. mansoni eggs but after injection with recombinant TNF-α formed granulomas around S. mansoni eggs (Amiri et al 1992) and infected, immunologically intact mice treated with anti-TNF-α formed granulomas reduced in size (Joseph & Boros 1993). Administration of recombinant murine TNF-α to mice with chronic S. mansoni infection restored granuloma size to that seen in acutely infected animals (Joseph & Boros 1993).…”

Role of cytokines in the formation and downregulation of hepatic circumoval granulomas and hepatic fibrosis in Schistosoma mansoni-infected mice

“…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).…”