interleukin-8 and Schistosomiasis-mansoni

We have found that infection with the large extracellular parasite S. mansoni leads to the development of a type 1 CD8+ T cell response. While there are many poorly understood aspects of this immune response, our working hypothesis is that it functions primarily to regulate the parasite egg-antigen induced Th2 response, which itself is responsible for circumoval granunuloma formation. This view of the activity of CD8+ cells mirrors Bloom and colleagues' postulate that type 2 CD8+ cells function to regulate Th1 responses. Since it is well recognized that Th1 and Th2 cells can cross regulate each other, why should a type 1 CD8+ rather than a Th1 response be used for the regulation of the Th2 response during schistosomiasis? The answer to this may in part lie in the apparent dependence of the type 1 CD8+ cells on IL-4. Because of this, there is little likelihood for the over-production of IFN-gamma (a potentially dangerous proinflammatory cytokine) and "suppression" is provided only when needed. Th1 cells have no such dependence on IL-4 for IFN-gamma production. Current work in the laboratory is directed towards testing the various hypotheses put forward here.

Topics: Animals; CD8-Positive T-Lymphocytes; Host-Parasite Interactions; Humans; Interferon-gamma; Interleukin-8; Schistosoma mansoni; Schistosomiasis mansoni; Th1 Cells; Th2 Cells

Schistosome infections are renowned for their ability to induce regulatory networks such as regulatory T cells (Treg) that control immune responses against homologous and heterologous antigens such as allergies. However, in the case of co-infections with hepatitis C virus (HCV), schistosomes accentuate disease progression and we hypothesized that expanding schistosome-induced Treg populations change their phenotype and could thereby suppress beneficial anti-HCV responses. We therefore analysed effector T cells and n/iTreg subsets applying the markers Granzyme B (GrzB) and Helios in Egyptian cohorts of HCV mono-infected (HCV), schistosome-co-infected (Sm/HCV) and infection-free individuals. Interestingly, viral load and liver transaminases were significantly elevated in Sm/HCV individuals when compared to HCV patients. Moreover, overall Treg frequencies and Helios(pos) Treg were not elevated in Sm/HCV individuals, but frequencies of GrzB(+) Treg were significantly increased. Simultaneously, GrzB(+) CD8(+) T cells were not suppressed in co-infected individuals. This study demonstrates that in Sm/HCV co-infected cohorts, liver disease is aggravated with enhanced virus replication and Treg do not expand but rather change their phenotype with GrzB possibly being a more reliable marker than Helios for iTreg. Therefore, curing concurrent schistosome disease could be an important prerequisite for successful HCV treatment as co-infected individuals respond poorly to interferon therapy.

Topics: Adult; Animals; Coinfection; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interleukin-8; Liver; Male; Middle Aged; Schistosoma mansoni; Schistosomiasis mansoni; T-Lymphocytes, Regulatory; Viral Load

Schistosomiasis is the most common worldwide cause of pulmonary arterial hypertension. The anti-schistosome drug praziquantel has been shown to reverse the liver fibrosis associated with Schistosoma mansoni in mice.. We sought to determine whether praziquantel reverses established pulmonary vascular remodeling and pulmonary hypertension in a mouse model of S. mansoni.. Mice were infected percutaneously with S. mansoni. At 17 weeks after infection mice were either killed or received two doses of praziquantel or vehicle by oral gavage. Treated mice were studied at 25 weeks after infection.. Vehicle-treated mice demonstrated significant increases in right ventricular systolic pressures (RVSP) and right ventricular hypertrophy (RVH) at 25 weeks, accompanied by pulmonary vascular remodeling. The degree of vascular remodeling correlated with proximity to granulomas. The elevation of RVSP and RVH at 25 weeks was dependent on the presence of eggs in the lung. Praziquantel eliminated the production of eggs in feces and led to clearance of eggs from the lung and to a lesser extent from liver. Praziquantel prevented the rise in RVSP and RVH seen in vehicle-treated mice and reversed established pulmonary vascular remodeling. Praziquantel significantly reduced lung mRNA expression of IL-13, IL-8, and IL-4, but did not reduce serum cytokine levels.. The development of pulmonary hypertension associated with S. mansoni infection can be prevented by praziquantel, and established vascular remodeling can be reversed. The mechanism involves clearance of lung eggs and reduced local expression of lung cytokines.

Topics: Animals; Anthelmintics; Blood Pressure; Blood Vessels; Cytokines; Down-Regulation; Female; Granuloma; Heart Ventricles; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Inflammation Mediators; Interleukin-13; Interleukin-4; Interleukin-8; Liver; Lung; Mice; Mice, Inbred C57BL; Ovum; Praziquantel; RNA, Messenger; Schistosoma mansoni; Schistosomiasis mansoni

Peripheral blood mononuclear cells (PBMN) from individuals with active or former intestinal schistosomiasis mansoni or splenocytes from patients with the hepatosplenic form of the disease were evaluated for their ability to generate chemotactic factors for neutrophils in response to schistosomal antigenic preparations derived from adult worms (SWAP), eggs (SEA), or phytohemagglutinin (PHA). When supernatants from cultures of stimulated PBMN from normal donors were assayed, only those obtained from cells which had been cultured in presence of PHA displayed chemotactic activity for neutrophils. In contrast, supernatants from cultures of SWAP or SEA stimulated PBMN from patients with intestinal or hepatosplenic schistosomiasis were shown to contain chemotactic activity for neutrophils from normal individuals. PBMN from persons who previously had been infected with Schistosoma mansoni but had received chemotherapy years before presented a pattern of response to SWAP or SEA similar to those from patients with active infections. The response of splenocytes from patients with hepatosplenic schistosomiasis was considerably different from PBMN from individuals with active or with treated schistosomiasis. Splenocytes from most of those patients with hepatosplenic disease failed to produce chemotactic factors for neutrophils in response to stimulation with at least 1 of the schistosome antigens tested. These results indicate that the lymphocytes from schistosomiasis mansoni patients are able to recognize and are stimulated by adult worm and egg antigens to produce chemotactic substances for neutrophils, and that this ability persists for many years after chemotherapy with schistosomicidal drugs. At the hepatosplenic stage, immunoregulatory mechanisms, which may prevent the production of chemotactic factors by splenocytes and/or their activity upon neutrophils in vitro, seem to occur.

Topics: Adult; Brazil; Chemotactic Factors; Chemotaxis, Leukocyte; Fluorescent Antibody Technique; Humans; Interleukin-8; Leukocytes, Mononuclear; Neutrophils; Schistosomiasis mansoni; Spleen