Enhanced Th1 and dampened Th2 responses synergize to inhibit acute granulomatous and fibrotic responses in murine schistosomiasis mansoni.
In murine schistosomiasis mansoni, CD4(+) Th1 and Th2 cells participate in the ovum-induced granulomatous inflammation. Previous studies showed that the interleukin-12 (IL-12)-induced Th1 response strongly suppressed the Th2-cell-mediated pulmonary granuloma development in naive or primed mice. However, liver granulomas were only moderately suppressed in egg-vaccinated, recombinant IL-12 (rIL-12)-treated infected mice. The present study shows that repeated rIL-12 injections given during early granuloma development at 5 to 7 weeks after infection prolonged the Th1 phase and resulted in gamma interferon-mediated suppression of liver granulomas. The timing is crucial: if given at 6 to 8 weeks, during the Th2-dominated phase of florid granuloma growth, the treatment is ineffective. Daily injections of rIL-12 given between 5 and 7.5 weeks during the period of granuloma growth achieved a somewhat-stronger diminution in granuloma growth with less deposition of collagen but caused 60% mortality and liver pathology. In contrast, combined treatment with rIL-12 and anti-IL-4-anti-IL-10 monoclonal antibody (MAb) injections given during the Th2 phase strongly inhibited liver granuloma growth without mortality. The diminished inflammatory response was accompanied by less deposition of collagen in the liver. Moreover, neutralization of endogenous IL-12 by anti-IL-12 MAbs effectively decreased the early Th1 phase (between 5 and 6 weeks after infection) but not the developing Th2 phase (5 to 7 weeks) of granuloma development. These studies indicate that the granulomatous response in infected mice can be manipulated by utilizing the Th1-Th2-subset antagonism with potential salutary results in the amelioration of fibrous pathology. (+info)
Mortality due to schistosomiasis mansoni: a field study in Sudan.
Although schistosomiasis affects 200 million persons, 20 million of whom have advanced disease, little is known about the mortality pattern in areas of endemic schistosomiasis mansoni. In an attempt to assess the mortality rates in an endemic area in Sudan, we conducted two demographic surveys in a village in the Gezira area. Clinical, sonographic, and parasitologic examinations were performed in a randomly selected sample of 25% of the population in 1987 and 1994. One of us asked each head of household about the names, sex, and age of family members. Particularly, we asked about death in the family if any, history of schistosomiasis, abdominal swelling, and hematemesis. Possible causes of death were ascertained by reviewing medical records in the village dispensary and the district hospital. There were 42 deaths in the village. Four males died of hematemesis secondary to portal fibrosis. The crude mortality rate of schistosomiasis was is 51/100,000/year. The overall schistosomiasis fatality rate per year was 1/1,000 infected persons, but was as high as 11/100/infected patients with bleeding varices. These findings showed the impact of schistosomiasis on public health in this economically important region of Sudan. (+info)
Experimental murine schistosomiasis in the absence of B7 costimulatory molecules: reversal of elicited T cell cytokine profile and partial inhibition of egg granuloma formation.
The granulomatous inflammation in infection with the helminth Schistosoma mansoni represents a cellular hypersensitivity reaction mediated by, and dependent upon, MHC class II-restricted CD4+ Th cells sensitized to parasite egg Ags. The current work examines the role and significance of the B7:CD28/CTLA-4 pathway in providing the costimulation necessary for the activation of these pathogenic T cells. In vitro T cell responses in B7-1-/- mice, 7-8 wk postinfection, were no different from wild-type controls, but the absence of B7-2 molecules resulted in a decrease in egg Ag-induced proliferation with increased IFN-gamma production. Both B7-1-/- and B7-2-/- mice exhibited intact granuloma formation. In contrast, CD4+ Th cells from B7-1/2 double-deficient mice displayed a dramatic loss of proliferative capacity upon stimulation with egg Ag. Most strikingly, these T cells secreted only IFN-gamma, but not IL-4 and IL-10, a pattern entirely opposite to that displayed by wild-type controls. Despite these major differences in T cell reactivity, B7-1/2-/- mice had only a limited reduction of granuloma size and fibrosis, without appreciable difference in cellular composition. These results show that substantial granuloma formation can occur under conditions of limited T cell expansion and restricted Th1-type cytokine production. They also support the notion that the combined effect of B7 signaling is not as critical for Th1 cell activation as it is for the development of the Th2 dominant environment characteristic of the evolving schistosome infection in H-2b mice. (+info)
Tolerization of mice to Schistosoma mansoni egg antigens causes elevated type 1 and diminished type 2 cytokine responses and increased mortality in acute infection.
The granuloma that surrounds the Schistosoma mansoni egg is the cause of pathology in murine schistosomiasis, and its formation is driven by egg Ag-stimulated type 1 and type 2 cytokines. To determine the role of egg-driven immune responses during schistosome infection we rendered CBA/Ca mice unresponsive to schistosome eggs by combined cyclophosphamide treatment and thymectomy. In the early acute stages of schistosome infection, egg-tolerized mice suffered high mortalities. Granuloma size and deposition of collagen in the liver were significantly reduced in egg-tolerized mice. Similarly, limited granuloma responses were detected in the intestines of these mice, and this was associated with a >90% reduction in egg excretion. Histologically, egg-tolerized mice had exacerbated hepatocyte damage, with extensive microvesicular steatosis. Elevated plasma transaminase levels confirmed the damage to hepatocytes. Infected egg-tolerized mice had impaired proliferation responses to egg Ag but intact responses to worm Ag. Tolerized mice had diminished Ab responses to egg Ag and had a type 1 cytokine isotype pattern to worm Ag, with elevated IgG2a and diminished IgG1 and IgE. Egg-tolerized mice failed to down-regulate type 1 cytokines that are normally elicited during early schistosome infection. Hepatic granuloma cells from egg-tolerized mice were also type 1 cytokine dominated, with elevated frequencies of Tc1/Th1 and reduced Tc2/Th2 cells. This study demonstrates that mice tolerized to schistosome eggs have elevated type 1 cytokine responses with diminished type 2 responses and reduced anti-egg Ab during schistosome infection, and these effects are detrimental to the host. (+info)
Interleukin-12 as an adjuvant for an antischistosome vaccine consisting of adult worm antigens: protection of rats from cercarial challenge.
Our group previously demonstrated that a detergent extract (fraction S3) prepared from immature (4-week) Schistosoma mansoni parasites can induce partial, serum-transferable immunity to challenge infection in rats when administered as an alum precipitate. In the present study, we examined whether S3 prepared from adult (7-week) worms could similarly induce protection and whether immunity could be positively influenced by treatment with interleukin-12 (IL-12). IL-12 coadministered to Fischer rats and C57BL/6 mice at the time of S3 vaccination altered the prechallenge kinetics of S3-specific antibody titers in both species, ultimately leading to a stable enhancement of titers (relative to those in animals vaccinated without IL-12) in mice but not rats. Immunoblot analysis of prechallenge immune sera demonstrated that IL-12 treatment was associated with changes in the S3 antigen recognition profile in each species. Isotyping of specific antibodies in S3- plus IL-12-vaccinated mice prior to challenge infection revealed a moderate elevation in immunoglobulin G1 (IgG1) responses, strongly enhanced IgG2a and IgG2b responses, as well as diminished total serum IgE responses compared to those in mice given S3 only. In vaccinated rats, IL-12 profoundly suppressed specific IgG1 and enhanced IgG2b responses but did not affect IgG2a responses. S3- plus IL-12-vaccinated rats also produced less total IgE upon challenge infection. Enumeration of worm burdens revealed that vaccination with S3 plus IL-12 conferred 50% protection from cercarial challenge to rats, whereas rats given S3 only were not protected; mice were not protected by S3 vaccination regardless of IL-12 coadministration. The protection observed in S3- plus IL-12-vaccinated rats could not be transferred with serum, suggesting participation of an activated cellular component in the expression of immunity. (+info)
Single-dose mucosal immunization with biodegradable microparticles containing a Schistosoma mansoni antigen.
The purpose of this work was to assess the immunogenicity of a single nasal or oral administration of recombinant 28-kDa glutathione S-transferase of Schistosoma mansoni (rSm28GST) entrapped by poly(lactide-co-glycolide) (PLG)- or polycaprolactone (PCL)-biodegradable microparticles. Whatever the polymer and the route of administration used, the equivalent of 100 microg of entrapped rSm28GST induced a long-lasting and stable antigen-specific serum antibody response, with a peak at 9 to 10 weeks following immunization. Isotype profiles were comparable, with immunoglobulin G1 being the predominant isotype produced. The abilities of specific antisera to neutralize the rSm28GST enzymatic activity have been used as criteria of immune response quality. Pooled 10-week sera from mice receiving PLG microparticles by the nasal or oral route neutralized the rSm28GST enzymatic activity, whereas sera of mice receiving either PCL microparticles, free rSm28GST, or empty microparticles inefficiently neutralized this enzymatic activity. Finally, this study shows that a single administration of these microparticles could provide distinct and timely release pulses of microencapsulated antigen, which might greatly facilitate future vaccine development. (+info)
Cytokine production in acute versus chronic human Schistosomiasis mansoni: the cross-regulatory role of interferon-gamma and interleukin-10 in the responses of peripheral blood mononuclear cells and splenocytes to parasite antigens.
The contribution of interleukin (IL)-10 and interferon (IFN)-gamma to the regulation of type 1 and type 2 cytokine responses was investigated in Brazilians with different clinical forms of schistosomiasis mansoni. Cells from members of a family with acute intestinal schistosomiasis responded to schistosomal soluble egg antigen (SEA) or soluble adult worm antigen preparation (SWAP) with greater amounts of IFN-gamma than did cells from several patients with chronic intestinal schistosomiasis; IL-10 levels were similar. Neutralization of IL-10 had no effect on the SEA-specific IFN-gamma response in patients with acute infection, whereas SWAP-induced IFN-gamma was increased in both groups. Anti-IL-10 also up-regulated SEA-specific IFN-gamma protein and mRNA responses in most splenocyte cultures from hepatosplenic schistosomiasis patients but had no effect on antigen-specific IL-4 or IL-5 production. Neutralization of IFN-gamma resulted in a comparable increase in SWAP-specific IL-10 and IL-5, while IL-4 was not affected. These studies demonstrate that early disease in schistosomiasis is associated with a significant IFN-gamma response and that IL-10 contributes to the suppression of that response during both early and chronic infection. (+info)
The substance P receptor is necessary for a normal granulomatous response in murine schistosomiasis mansoni.
Immune cells within the granulomas of murine schistosomiasis mansoni make the neuropeptide substance P (SP) and express neurokine 1 receptor, which is the specific receptor for substance P (SPr). It was determined if mice with deletion of the SPr (SPr-/-) would develop a normal granulomatous response to schistosome ova during the course of natural infection. Mean liver granuloma size was smaller in SPr-/- mice compared with that of wild-type control animals. Although flow analysis revealed little difference in the cellular composition of the granulomas, both splenocytes and granuloma cells from SPr-/- mice produced much less IFN-gamma and IgG2a and less IgE. The expression of Th2 cytokines (IL-4/IL-5) and IgG1 was comparable to the wild-type control. The mouse with targeted disruption of its SPr had the nonmammalian gene encoding the enzyme beta-galactosidase inserted in exon 1 of the SPr gene. There was beta-galactosidase activity in many mononuclear cells scattered throughout the schistosome granulomas of SPr-/- mice. Also, a granuloma T cell line derived from this transgenic mouse produced beta-galactosidase. These results provide further evidence that in murine schistosomiasis SPr is displayed commonly on granuloma inflammatory cells and is important for granuloma development and expression of IFN-gamma circuitry in this natural infection. (+info)