Schistosomal Granuloma Research Articles

Expression of class II, but not class I, major histocompatibility complex molecules is required for granuloma formation in infection with Schistosoma mansoni.

Previous studies have suggested that granulomatous inflammation in schistosomiasis is mediated by CD4+ T helper lymphocytes sensitized to parasite egg antigens. However, CD8+ T cells have also frequently been associated with the immune response to schistosome eggs. To examine more precisely the role of CD4+ and CD8+ T cells in the pathology of the schistosomal infection, we used mice with targeted mutations in major histocompatibility complex (MHC) class II or class I molecules. These mutations lead, respectively, to the virtual absence of CD4+ and CD8+ T cells. The results clearly show that schistosome-infected MHC class II mutant mice failed to form granulomas around parasite eggs. In contrast, infected MHC class I mutant mice displayed characteristic granulomatous lesions that were comparable to those in wild-type control mice. Moreover, lymphoid cells from MHC class II mutant mice were unable to react to egg antigens with either proliferative or cytokine [interferon-gamma, interleukin (IL)-4, IL-10] responses; nor were they able to present egg antigens to specifically sensitized CD4+ T helper cells from infected syngeneic control mice. By comparison, cells from MHC class I mutant mice exercised all these functions in a manner comparable with those from wild-type controls. These observations clearly demonstrate that schistosomal egg granulomas are mediated by MHC class II-restricted CD4+ T helper cells. They also suggest that CD8+ T cells do not become sensitized to egg antigens and play little role, if any, in the pathogenesis of schistosomiasis.

Effect of slow release IL-12 and IL-10 on inflammation, local macrophage function and the regional lymphoid response during mycobacterial (Th1) and schistosomal (Th2) antigen-elicited pulmonary granuloma formation.

This study examines the local and regional effects of exogenously administered interleukins 10 (IL-10) and 12 (IL-12) on pulmonary granulomas mediated by Th1/type 1-(IFN-gamma) and Th2/type 2-(IL-4, IL-5 cytokines. MATERIALS AND TREATMENTS: Granulomas (GR) were induced in presensitized CBA mice by embolization of beads coated with Mycobacteria tuberculosis or Schistosoma mansoni egg antigens. Before challenge, osmotic pumps distributing IL-10 or IL-12 (50 micrograms/kg/day) were implanted intraperitoneally, then GR and draining lymph nodes were examined 4 days. GR sizes and composition were determined by morphometry and differential analysis. Isolated GR macrophages and draining lymph nodes were assessed for cytokine production by ELISA. IL-10 did not effect GR sizes but reduced neutrophils in type 1 GR. IL-12 minimally reduced type 1 GR but decreased the type 2 lesion by up to 70%, primarily curtailing eosinophils. Type 2 GR macrophages were unaffected but type 1 were impaired by IL-10. Conversely, type GR macrophages were more resistant to IL-12 while type 2 showed enhanced IL-10, IL-12 and TNF, but reduced MCP-I production. In lymph nodes, IL-10 caused paradoxical effects, enhancing IFN-gamma in the type 1 and decreasing Th2 cytokines in the type 2 response. Exogenous IL-12 profoundly augmented IFN-gamma and abrogated type 2 cytokines while inhibiting intrinsic IL-12 production in lymph nodes. These findings provide novel information regarding cytokine regulation and the effects of systemic cytokine therapy.

IL-1 receptor antagonist (IL-1ra) expression, function, and cytokine-mediated regulation during mycobacterial and schistosomal antigen-elicited granuloma formation.

Granulomas (GR) mediated predominantly by Th1/type 1 (IFN-gamma) and Th2/type 2 (IL-4, IL-5, IL-10) cytokines were induced by i.v. injection of sensitized CBA/J mice with carbohydrate beads coated with Mycobacterium tuberculosis or Schistosoma mansoni egg Ags, respectively. GR macrophages (Mphi) from types 1 and 2 GR both produced IL-1ra, but the former showed accelerated IL-1ra-producing capacity, releasing two- to threefold greater amounts on day 4 than those of type 2 GR, as measured by sandwich ELISA. In vivo depletion of IL-1ra exacerbated GR size and augmented regional cytokine production in both types of responses. To determine the critical cytokines mediating IL-Ira expression, oil-elicited peritoneal Mphi were exposed to graded doses (0.1 to 10 ng/ml) of cytokines (IL-1beta, IL-2, IL-4, IL-10, IL-12, IFN-gamma, and TNF-alpha) for 24 h, then stimulated with opsonized zymosan. Of the cytokines tested, IFN-gamma and TNF-alpha were the best costimuli for IL-1ra production in the presence of zymosan, whereas IL-1beta, IL-10, and IL-12 were not active. In vivo depletion of IL-4, IL-10, IL-12, IFN-gamma, or TNF-alpha with 5 mg of cytokine-specific neutralizing rabbit IgG revealed that IFN-gamma and TNF-alpha were required for maximal IL-1ra production by Mphi. Furthermore, the delayed IL-1ra production by type 2 GR Mphi could be related to later TNF-alpha production. Our findings indicate that IL-1ra is a common regulatory product of inflammatory Mphi and is particularly promoted by type 1 cytokines, IFN-gamma, and TNF-alpha.

GM-CSF and IL-3 activities in schistosomal liver granulomas are controlled by stroma-associated heparan sulfate proteoglycans.

Connective tissue cells (myofibroblasts) from liver inflammatory granulomatous reactions to schistosome eggs are able to sustain a long-term proliferation of myeloid cells, both in vivo and in vitro. We have addressed the question of the molecular mechanisms involved in control of this extramedullar stroma-dependent production of inflammatory cells. Heparan sulfate proteoglycans (HSPGs) were purified from granuloma-derived connective tissue cells and bound to plastic or collagen substrate. Their ability to bind recombinant murine granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), to stimulate proliferation of the FDC-P1 myeloid cell lineage, and to modify growth factor activity was monitored. The specificity of this stroma cell-derived glycosaminoglycan interaction with the myeloid growth factors was analyzed by comparing other glycosaminoglycans and sulfated polysaccharides. HSPGs could act as an artificial myelopoietic stroma; they were both required and sufficient for binding and presenting GM-CSF and IL-3 in biologically active form. Moreover, they were able to mediate an increase in the specific growth-promoting activity of GM-CSF and IL-3. This was specific for stroma-derived heparan sulfate and heparin, since heparan sulfate derived from other cells, other glycosaminoglycans and related molecules had no effect. These results indicate that HSPGs can stimulate and control the in situ proliferation of myeloid cells, modifying in both quantitative and qualitative terms the composition of inflammatory cell infiltrates in hepatic granulomas.

Tumoral form of cerebral schistosomiasis mansoni. A report of four cases and a review of the literature

We describe four cases of the tumoral form of cerebral schistosomiasis mansoni. The patients had symptoms of increased intracranial pressure and focal neurological signs that varied according to the site of the lesion. Computerized tomography showed a hyperdense, enhancing lesion located in the cerebellum (2 patients), frontal lobe and thalamus (1 patient), and temporal subdural region (1 patient), with associated mass effects. The lesion was resected in tree patients and a stereotactic biopsy was performed in one. Histopathologic specimens of all four patients revealed multiple schistosomal granulomas in various evolutive phases. Two of these patients differ from previously described cases; one because of the subdural location of the lesion, mimicking a meningioma, and the other one because two lesions were present.

Schistosomiasis: An Unusual Cause of Hematuria in the Ileal Neobladder

Bladder substitution using bowel has improved the quality of life of cystectomy patients. However, late complications are not rare and may include deterioration of the upper tract, malignancy or stricture of the retained urethra, stone formation and spontaneous rupture of the neobladder.' We report a unique complication of severe hematuria due to schistommiasis of the ileal neobladder. CASE REPORT A 39-year-old man underwent radical cystectomy and creation of an orthotopic ileal neobladder in February 1991. Definitive histopathology showed grade 2 TP3aNOMO squamous cell carcinoma. Schistosoma haematobium eggs were present in the cystectomy specimen. The patient had a history of exposure and unknown treatment of schistosomiasis 3 years before cystectomy. At that time he complained of dysuria and terminal hematuria, which improved after antibilharzial treatment. There was no history of exposure to schistosomiasis after that course of treatment and no evaluation for schistosomiasis was performed before or after cystectomy. The patient did well until January 1994, when he complained of gross hematuria. The kidneys and ureters were normal on excretory urography and ultrasonography. UMalysis revealed active S. haematobium eggs and urine culture yielded no growth. Panendoscopy demonstrated a normal urethra and ileo-urethral junction, and extensive submucod hemorrhagic areas with multiple mucosal ulcerations in the ileal neobladder. Biopsy showed partial ulceration of the ileal mucosa with calcified bilharzial ova surrounded by diffuse mononuclear cellular infiltrate (see figure). Anti-bilhanial treatment was given orally (60 mg&. praziquantel in 2 divided doses daily) in conjunction with a total dose of 60 mgkg. oxamniquine given orally in 6 divided doses (twice daily for 3 days). There was dramatic improvement after anti-bilharzial therapy and the patient was free of hematuria 8 months after treatment. Repeat urinalysis was normal. DISCUSSION Schistosomiasis is an endemic dieease that inf man and animals. A total of 1,ooO million people is at risk and approximatelv 200 million are infected throughout the Partial ulceration of ileal muwa with calcified.bilharzial ovum (arrow) surrounded by diiTuse mononuclear cellular mfiltrate. H & E, reduced from X250. In tropical areas intestinal schistmomiasis could be a cause of hematuria in patients with substitution of the bladder by a bowel segment. Patients in these areas should undergo a thorough evaluation for schistosomiasis before surgery. We suggest urinalysis for S. haematobium eggs (characteristic terminal spine) and stool analysis for S. mansoni eggs (characteristic lateral spine). An indirect hemagglutination test must be performed to detect circulating antischistosomal antibodies. All patients in whom stool analysis and indirect hemagglutination testing fail to show the presence of infection should undergo biopsy of the rectal mumsa to reveal any signs of egg deposits or schistosomal granulomas. Infected patients must be treated as described. Repeat urine and stool analyses with indirect hemagglutination testing should prove the resolution of the infection before surgery. F'urthermore, a bowel mucosal biopsy must be obtained intraoperatively and examined for schismmiasis.

Cytokine function during mycobacterial and schistosomal antigen-induced pulmonary granuloma formation. Local and regional participation of IFN-gamma, IL-10, and TNF.

Pulmonary granulomas (GR) with type 1 or type 2 cytokine involvement were induced in presensitized CBA mice by embolization of beads coupled to purified protein derivative (PPD) of Mycobacterium tuberculosis or soluble Ags derived from Schistosoma mansoni eggs (SEA). Using neutralizing Abs against IFN-gamma, IL-10, and TNF-alpha/beta, we examined effects on GR size, GR macrophage function, and regional lymph node (LN) responses. Profoundly different effects were observed in the two models. Anti-IFN decreased PPD-GR size by 20%, but augmented SEA GR by nearly 50%. Anti-TNF abrogated PPD-GR area by 40% and SEA GR by 15% suggesting that TNF contributed more to the former. Anti-IL-10 did not affect GR sizes. Analysis of TNF indicated that IFN was required for maximum production by both PPD GR and SEA GR macrophages. Interestingly, TNF tempered its own expression by SEA GR macrophages. In LN, PPD GR and SEA GR formation was associated with T cell-dependent type 1 (IFN and IL-2) and type 2 (IL-10 and IL-4) cytokine profiles, respectively. In PPD LN, anti-IFN decreased IFN and IL-2 production by 50%. In contrast, anti-IL-10 increased IFN and IL-2 production by two- to fourfold, indicating that IFN and IL-10 had opposing effects on the type 1 response. In SEA LN, anti-IFN decreased IFN production but augmented IL-4 and IL-10 production by 50 and 90%, respectively, supporting the notion that IFN constrains Th2 responses. Conversely, IL-10 promoted the Th2 response. Surprisingly, anti-TNF reduced IL-4 and IL-10 in SEA LN but did not affect PPD LN, suggesting that TNF-alpha or -beta supports Th2 differentiation in LN during the secondary response to schistosomal Ags.

Endomyocardial fibrosis in Egypt: an illustrated review.

The detailed features of right sided endomyocardial fibrosis are described in 15 out of 10,000 consecutive patients who all had infection with Schistosoma mansoni and came from rural Egypt. Laboratory investigations, 12 lead electrocardiography, chest radiography, and Doppler echocardiography were performed in all patients. Cardiac catheterisation and angiography were performed in eight. Endomyocardial biopsy specimens were obtained from the right ventricles of two patients and pericardial biopsy specimens from two. Pericardiocentesis was performed in all patients. All patients were infected with S mansoni and had schistosomal hepatic fibrosis and ascites. Eleven had splenomegaly. All patients had raised cervical venous pressure with prominent Y descent and atrial fibrillation. Eosinophilia was notably absent. Echocardiography showed apical fibrosis in the right ventricle, obliteration of the ventricle, and moderate to massive exudative pericardial effusion in all patients. Calcification and fibrosis extended into the right ventricular outflow tracts in two patients. Huge right atrial thrombi occurred in five patients. Tricuspid regurgitation (grades I-II) was detected in 11 patients by Doppler ultrasonography. Haemodynamic and angiographic data confirmed the pure right sided restrictive pathophysiology. Pericardial biopsy specimens showed perivascular inflammatory infiltrates in two patients and a schistosomal granuloma in one. Endocardial biopsy specimens showed dense fibrosis with many fibroblasts. Endomyocardial fibrosis in Egypt is unique in several aspects. It always affected only the right side of the heart. Calcification and fibrosis extended to the right ventricular outflow tract. Pericardial inflammatory reaction was present. The relation to schistosomiasis and the link to periportal hepatic fibrosis in these patients is intriguing.

Endomyocardial Fibrosis with Unusual Patterns of Endocarditis and Pericarditis

In this report of three patients with EMF, we report the unusual affection of the pericardium with echocardiographic epicardial thickening and pericardial inflammatory reaction, the presence of schistosomal granuloma in the pericardium, echocardiographic evidence of dense extensive fibrotic endocardial lesions, and microscopic evidences of an ongoing fibrotic process.

Macrophages from schistosomal egg granulomas induce unresponsiveness in specific cloned Th-1 lymphocytes in vitro and down-regulate schistosomal granulomatous disease in vivo.

We previously have proposed that accessory cells from individuals infected with schistosomiasis induce unresponsiveness in specific Th-1 lymphocytes resulting in the immunologic down-regulation of egg-induced granulomatous inflammation characteristically seen in this disease. We now show that macrophages isolated from schistosomal egg granulomas (GM) fail to serve as stimulatory APC for cloned, murine schistosomal egg Ag (SEA)-specific, CD4+, Th-1-type lymphocytes, while being able to stimulate Th-2-type responses. Instead, GM render Th-1 cells unresponsive to restimulation. Based on these findings, we tested two approaches to down-regulate the granulomatous inflammation associated with a schistosomal challenge infection. First, active ectopic granuloma induction in response to Schistosoma mansoni eggs, but not to Ascaris lumbricoides eggs, resulted in a significant reduction of granulomatous disease in vivo, as well as in the inhibition of specific proliferation of mesenteric lymph node cells in vitro. Second, passive administration of purified GM, but not of normal peritoneal cells (PC), resulted, similarly, in significant reduction of granuloma size in vivo and specific lympho-proliferation in vitro. Moreover, cytokine analysis of supernatants from stimulated lymph node cells disclosed that the Th-1-derived cytokine IL-2 decreased to undetectable levels, at the same time as the Th-2-derived cytokines IL-4 and IL-10 increased, in animals receiving GM, in contrast to those receiving PC or no cells. These findings are consistent with the interpretation that accessory cells such as GM induce unresponsiveness in specific Th-1 cells that, in turn, results in the down-regulation of granulomatous schistosomal disease and its in vitro correlates.

Role of fat-storing cells in schistosomal hepatic fibrosis of mice.

The involvement of fat-storing cells (FSC) in hepatic schistosomal granuloma was investigated in mice infected with Schistosoma mansoni cercariae. After infection, 24 animals were treated with s.c. injections of vitamin A in a total dose of 210,000 IU given twice a week for 3 weeks. Two other groups of 24 animals each were: a) non-infected vitamin A-treated animals and (b) untreated infected controls. Animals from all groups were killed at weekly intervals from the 5th through the 10th week following infection. Pieces of liver were examined by light microscopy and transmission electron microscopy. In all vitamin A-treated animals, FSC disclosed prominent cytoplasmic fat droplets, which permitted their prompt identification in the light and in the electron microscope. They were found in large numbers as a constituent of periovular granulomas. In infected controls, FSC were not identified in granulomas, possibly because lipid droplets disappeared during differentiation to the fibroblastic phenotype. FSC also appeared within areas of septal fibrosis. These data suggest that FSC play an important part in focal portohepatic fibrosis during granuloma formation around S. mansoni eggs in the liver of mice.

Experimental pulmonary schistosomiasis: lack of morphological evidence of modulation in schistosomal pulmonary granulomas.

Numerous pulmonary schistosome egg granulomas were present in mice submitted to partial portal vein ligation (Warren's model). The granulomas were characterized by cellular aggregations formed within alveolar tissue. Main cellular types were macrophages (epithelioid cells), eosinophils, plasma cells and lymphocytes. These cells were supported by scanty fibrous stroma and exhibited close membrane contact points amongst themselves, but without forming specialized adhesion apparatus. When granulomas involved arterial structures, proliferation of endothelial and smooth muscle cells occurred and fibrosis associated with angiogenesis became more evident. Granulomas formed around mature eggs in the pulmonary alveolar tissue presented approximately the same size and morphology regardless of the time of infection, the latter being 10, 18 and 25 weeks after cercarial exposure. This persistence of morphological appearance suggests that pulmonary granulomas do not undergo immunological modulation, as is the case with the granulomas in the liver and, to a lesser extent, in the intestines. Probably, besides general immunological factors, local (stromal) factors play an important role in schistosomal granuloma modulation.

Role of IL-10 on antigen-presenting cell function for schistosomal egg-specific monoclonal T helper cell responses in vitro and in vivo.

Egg Ag-stimulated lymphoid cell culture supernatants from schistosome-infected mice significantly inhibited Ag-specific, MHC-restricted proliferative responses of cloned schistosomal egg Ag-specific CD4+, Th-1-type lymphocytes. The inhibitory molecule in the supernatants was found to be the cytokine IL-10. Maximal IL-10 was produced by cells from mice carrying 8-wk schistosome infections, and none by cells from normal mice. IL-10 exerted its biologic activity on APC, and not directly on the cloned lymphocytes, resulting in the inhibition of Th-1 lymphocyte proliferation, whereas Th-2 responses were not affected. Most significantly, IL-10 also affected Th-1 clone activity in vivo, as measured by the inhibition of schistosomal egg Ag-specific local delayed-type hypersensitivity reactions. IL-10 produced in schistosome-infected individuals may play a role in the generation of APC, such as macrophages in schistosomal egg granulomas, unable to efficiently stimulate, but capable of inducing a state of anergy/unresponsiveness in Th-1 lymphocytes. We believe that this state of Th-1 cell anergy translates into the down-regulation of granulomatous hypersensitivity (immunomodulation) characteristically observed in the evolving schistosomal disease.

Fibroblast-stimulating factor 1, a novel lymphokine produced in schistosomal egg granulomas, stimulates liver fat-storing cells in vitro.

We report that the novel lymphokine fibroblast-stimulating factor 1, produced within hepatic schistosomal egg granulomas, stimulates liver fat-storing cells (FSC) in vitro to proliferate and express fibronectin genes. Because FSC are critical in hepatic fibrogenesis generally, we propose that in vivo stimulation of FSC by fibroblast-stimulating factor 1 may be an important step in schistosomal liver fibrosis.

Fibroblast stimulation in schistosomiasis. XII. Identification of CD4+ lymphocytes within schistosomal egg granulomas as a source of an apparently novel fibroblast growth factor (FsF-1).

Granulomas that form around Schistosoma mansoni eggs deposited in the liver secrete a variety of fibrogenic factors that may provide a molecular link between chronic inflammation and hepatic fibrogenesis in schistosomiasis. We recently isolated from conditioned medium of egg granuloma cultures a approximately equal to 60-kDa heparin-binding growth factor for fibroblasts. Because this protein is distinct from other defined heparin-binding growth factors, we designated it "fibroblast stimulating factor-1" (FsF-1). We now report that FsF-1 is a lymphokine. We prepared IgG antibody against purified FsF-1 and determined that it did not cross-react with a variety of growth factors or recombinant interleukins. Using two-color flow cytometry of dissociated granuloma cell suspensions, we observed that approximately 20% to 25% of granuloma CD4+ lymphocytes express surface FsF-1. We isolated CD4+ granuloma lymphocytes by FACS and observed that these cells spontaneously secrete into culture supernatant a fibroblast mitogen that is neutralized by anti-FsF-1 antibody. Furthermore, anti-FsF-1 can specifically immunoprecipitate a metabolically labeled protein produced by the granuloma CD4+ lymphocytes. The labeled protein has the same apparent molecular mass (approximately equal to 60 kDa) as FsF-1 purified from granuloma culture supernatants. These findings define CD4+ lymphocytes as a source of FsF-1. Because FsF-1 has biologic and chemical features distinct from most other defined lymphokines and from other heparin-binding growth factors, FsF-1 appears to be a novel lymphokine.

Dynamics of fibrosis production and resorption in intestinal schistosomiasis of mice

A histological, morphometric and immunocytochemical study of schistosomal periovular granulomas in the liver and intestines of mice revealed that intestinal granulomas are smaller and contain less collagen than those in the liver. After curative treatment intestinal granulomas undergo a relatively more rapid resorption, although the general pattern of collagen degradation apparently does not differ from that observed in the liver. Tendency to form scattered, usually isolated granulomas that are only mildly fibrogenic, coupled with a well-balanced process of resorption appear as the explanation why intestinal fibrosis is not an outstanding feature of schistosomiasis as it is in the liver.

Membrane-associated and secreted proteoglycans from a continuous cell line derived from fibrotic schistosomal granulomas

Proteoglycans were isolated from a continuous murine cell line (GRX) established from fibrotic granulomas induced in mouse liver by schistosomal infection, representative of liver connective tissue cells. The proteoglycans were labelled with 35SO 4, extracted by guanidine-HCl + Triton X-100 in the presence of proteinase inhibitors, and purified by anion-exchange, gel-filtration and affinity-column chromatography. The major fractions of cell-associated and secreted proteoglycans are heparan sulfate proteoglycans. Gel-filtration chromatography on Sephacryl S-400 revealed K av values of 0.20 and 0.30 for the cell-associated and secreted heparan sulfate proteoglycans, respectively. About 50% of the cell-associated heparan sulfate proteoglycans contained hydrophobic regions, as evidenced by their ability to bind to octyl-Sepharose, while only about 20% of secreted proteoglycans bound to this resin. In addition, no proteoglycan was competitively displaced from the cell surface by heparin. Taken together with other reports on proteoglycan synthesis by a variety of cell types in culture, these observations suggest that cell-surface heparan sulfate proteoglycans possibly contain a hydrophobic domain that functions as a membrane anchor in their attachment to cells. Addition of ß- d-xyloside to the cultures greatly enhanced the release of 35S-dermatan sulfate to the medium. Interestingly, dermatan sulfate is the major glycosaminoglycan found in the schistosoma-induced granuloma, from which the GRX cell line is derived. These studies provide the first biochemical description of the proteoglycans produced by a liver connective tissue cell line derived from schistosomal granulomas.

Experimental murine schistosomiasis mansoni: establishment of the chronic phase of the disease.

After the acute hyperergic phase of schistosomal infection, the chronic phase of the disease corresponds to the establishment of a relative equilibrium between the host and the parasite. This involves: (1) A shift from the predominance of the TH2 response observed in the acute phase, to the predominance of the TH1 response in the chronic phase of the disease, with modification of lymphokine and immunoglobulin secretions patterns. (2) Redistribution of hosts responses to parasite, with predominance of systemic controls in the acute phase, and a shift towards local tissue responses in the chronic phase. This redistribution relieves the hyperergic response involving the whole body of the host, and delimits cellular and molecular reactions to parasites to only those tissues that are directly involved by the adult parasites and their eggs. Mobilization of eosinophil granulocytes in schistosomal periovular granulomas is one of examples of this redistribution.

Alterations in influence of granuloma-derived cytokines on fibrogenesis in the course of murine Schistosoma mansoni infection

Schistosomiasis is the main cause of hepatic fibrosis worldwide, yet its pathogenesis remains unknown. We previously reported that conditioned medium from cultures of hepatic egg granulomas (isolated from mice acutely infected with Schistosoma mansoni) can stimulate fibroblast proliferation and matrix production in vitro. We have proposed that initiation of hepatic fibrosis in this infection might be under the control of granuloma-derived cytokines. We now report that conditioned medium from cultures of schistosomal egg granulomas isolated from liver of chronically infected mice has reduced fibrogenic activity compared with medium from cultures of granulomas obtained from more acutely infected mice. In related studies, we adoptively transferred splenocytes from infected mice and examined the fibrogenic activity in culture supernatants of hepatic egg granulomas isolated from the recipients. Those prepared from recipients of splenocytes from chronically infected mice contained substantially less fibrogenic activity than did those from recipients of splenocytes of acutely infected mice. These findings suggest that the fibrogenic influence of schistosomal egg granuloma products decreases during the course of chronic murine S. mansoni infection. Furthermore, our preliminary findings suggest that immunoregulatory cells may be responsible for the down-regulation of this influence. Previous observations indicating that in murine schistosomiasis hepatic collagen and hyaluronate synthesis and deposition are elevated in acute but not chronic infection might be explained on the basis of our observations.

Alterations in influence of granuloma-derived cytokines on fibrogenesis in the course of murine Schistosoma mansoni infection

Schistosomiasis is the main cause of hepatic fibrosis worldwide, yet its pathogenesis remains unknown. We previously reported that conditioned medium from cultures of hepatic egg granulomas (isolated from mice acutely infected with Schistosoma mansoni) can stimulate fibroblast proliferation and matrix production in vitro. We have proposed that initiation of hepatic fibrosis in this infection might be under the control of granuloma-derived cytokines. We now report that conditioned medium from cultures of schistosomal egg granulomas isolated from liver of chronically infected mice has reduced fibrogenic activity compared with medium from cultures of granulomas obtained from more acutely infected mice. In related studies, we adoptively transferred splenocytes from infected mice and examined the fibrogenic activity in culture supernatants of hepatic egg granulomas isolated from the recipients. Those prepared from recipients of splenocytes from chronically infected mice contained substantially less fibrogenic activity than did those from recipients of splenocytes of acutely infected mice. These findings suggest that the fibrogenic influence of schistosomal egg granuloma products decreases during the course of chronic murine S. mansoni infection. Furthermore, our preliminary findings suggest that immunoregulatory cells may be responsible for the down-regulation of this influence. Previous observations indicating that in murine schistosomiasis hepatic collagen and hyaluronate synthesis and deposition are elevated in acute but not chronic infection might be explained on the basis of our observations.