Immunolocalization of intercellular adhesion molecule-1 and leukocyte functional associated antigen-1 in schistosomal soluble egg antigen-induced granulomatous hyporesponsiveness.

In this work, the changes in expression of the adhesion molecules ICAM-1/LFA-1 on inflammatory cells of the liver were studied by immunohistochemistry. Mice sensitized with SEA and infected with S. mansoni and S. mansoni-infected controls were examined from day 35 to day 56 postinfection. A significant upregulation of ICAM-1 and LFA-1 in both the SEA group and the infected control group started shortly after egg deposition at day 35 and persisted up to day 56 p.i. Notably, both ICAM-1 and LFA-1 expression peaks were shifted earlier to day 38 p.i. in the SEA group compared to day 40 in the infected control group. The distribution of ICAM-1 and LFA-1 in both groups was comparable. At the early phase of infection before granuloma formation, both ICAM-1 and LFA-1 were detected along the sinusoidal wall of small blood vessels. At the acute cellular granuloma phase, they were homogeneously distributed all over the inflammatory cells, while at the chronic fibrocellular stage a non-homogeneous staining of granuloma cells at the periphery of the granuloma was apparent. The present data suggest that adhesion molecules play a role in the initiation and maintenance of granuloma formation. Thus, the granulomatous hyporesponsiveness induced by sensitization with SEA was associated with reduced expression of adhesion molecules.

Immunolocalization of macrophage adhesion molecule-1 and macrophage inflammatory protein-1 in schistosomal soluble egg antigen-induced granulomatous hyporesponsiveness.

This work studied the histopathological changes and the changes in the expression of macrophage adhesion molecule-1 (Mac-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) in a murine model of soluble egg antigen (SEA) - induced granulomatous hyporesponsiveness. Histopathological results of hepatic sections in an SEA group showed early acceleration of ova destruction and markedly diminished granuloma cellularity with eosinophils and macrophages still being the predominant cells. Later, giant cells and pigmented macrophages that were scattered among granuloma cells and in intimate contact with the deposited eggs were more predominant in the SEA group than in the infected control group. Concurrently, the counts of Mac-1 positive cells were significantly increased in liver sections of the SEA group than the infected control group during the course of infection. MIP-1alpha showed early higher counts followed by lower counts in the later stages of infection on granuloma cells in the SEA group than the infected control group. During the course of infection, similar distribution of Mac-1 and MIP-1alpha was present in both groups. This study suggests that sensitization with SEA probably leads to enhancement of phagocytic activity of macrophages via increasing expression of Mac-1 and hence engulfment of ic3b coated schistosomal products such as ova. It leads to rapid destruction of ova and hence decreases the host inflammatory response to infection and amelioration of hepatic pathology which would be a promising approach in reduction of host morbidity and mortality.

Induction of hepatic egg granuloma hyporesponsiveness in murine schistosomiasis mansoni by intravenous injection of small doses of soluble egg antigen.

This work was designed to test whether hyporesponsiveness to schistosomal egg antigen (SEA) was associated with reduction in size of hepatic granulomas. Multiple small doses of SEA (10 micrograms x 4) were injected intravenously (i.v.) into C57B1/6 mice either at 7 or 30 days prior to cercarial exposure. Eight weeks postinfection, hepatic histopathology and granuloma diameter were studied. SEA-induced lympho-proliferative response, splenic cytokines (IL-2, IL-4 and IL-5) and serum antischistosomal IgG were assessed. Worm burden and tissue egg load were counted. Compared to infected controls, the SEA-treated groups showed decrease in granuloma diameter, remarkable increase in the percentage of degenerated ova within hepatic granulomas and amelioration of histopathological changes. SEA lymphoproliferative response, and levels of Il-2 and IL-4, were lower in SEA-treated groups than infected controls. The levels of IL-5 and antishistosomal IgG were comparable to the infected controls. The intensity of infection was not influenced by i.v. injection of SEA. The present data show that i.v. administration of multiple small doses of SEA induced granulomatous hyporesponsiveness with amelioration of hepatic pathology and acceleration of egg destruction.

Efficacy of an antipathology vaccine in murine schistosomiasis administered with and without chemotherapy.

This study was undertaken to study the efficacy of praziquantel (PZQ) in potentially tolerized Schistosoma mansoni infected, egg-injected C57BL/6 mice, receiving multiple administrations of soluble egg antigen (SEA) intravenously (i.v.). Four animal groups were studied. Experimental group I received four injections of SEA (10 micrograms) intravenously on days -7, -5, -3 and -2 before infection and PZQ orally (500 mg/kg over two consecutive days 7 weeks post-infection. Three control groups received the following treatment: group II received the same tolerizing dose of SEA without PZQ, group III received PZQ in the same dose and at the same timing. Group IV received S. mansoni infection and egg injection 8 weeks post-infection and served as an infected, egg-injected control. Egg injection was conducted 8 weeks post-infection using viable S. mansoni eggs via the tail vein. Animals were killed 16 days post-egg injection, i.e. 10 weeks post-infection. After sacrifice, lungs and livers were removed for histopathological study and measurement of granuloma diameters. Spleens and serum were collected for the assay of lymphoproliferative response to SEA and antischistosomal immunoglobulins. The worm and egg burdens were also studied. Compared to infected, egg-injected untreated controls, repeated i.v. administrations of SEA down-regulated egg-injected (pulmonary) and egg-deposited (hepatic) granulomas and the lymphoproliferative response to SEA. Antischistosomal IgG level was increased. Susceptibility to S. mansoni infection was not found to be different from that in the infected, egg-injected controls. PZQ in the dose used caused complete eradication of worms, disappearance of immature egg stages, decrease in the number of mature eggs and an increase in the number of dead eggs. Hepatic granuloma diameter, lymphoproliferative response to SEA and IgG level were reduced. In mice receiving a combined regimen of multiple SEA administrations and PZQ with down-regulated granuloma and reduced lymphoproliferative response to SEA, the efficacy of PZQ was the same as in mice receiving PZQ alone. This was shown by comparable grades of worm and egg reduction. The histopathological examination of liver and lung sections in the different treated groups revealed moderate to small-sized hypocellular granulomas. Although no statistically significant difference was recorded between the mean granuloma diameters of the experimental group receiving both the tolerizing dose of SEA and PZQ compared to the group receiving the tolerizing dose of SEA without chemotherapy, this experimental group showed the least associated histopathological parenchymal changes. It appears from this work that combined SEA and PZQ provided many complementary goals; a reduction of egg-induced pathology, minimal parenchymal changes and the eradication of worms.