Kai Zwingenberger

Determinants of the immune response in visceral leishmaniasis: evidence for predominance of endogenous interleukin 4 over interferon-γ production.

Accumulating evidence points toward an antagonism between TH1 and TH2 focused immune responses decisive for the outcome of parasitic infections with leishmaniae. Interferon-gamma (IFN-gamma) and interleukin 4 (IL4), the principal cytokines involved in these pathways, as well as IgE and the IgG subclasses differentially modulated by these cytokines, were therefore assessed in 18 Brazilian patients with visceral leishmaniasis. The results are compared to those of a local control group. IL4 was detected in all patient sera but in only one control. Low concentrations of IFN-gamma where detectable in 50% of the Brazilian controls but in only two patients. While group medians of mitogen-induced in vitro synthesis of IL4 and IFN-gamma were similar, release of these lymphokines correlated inversely in patients (Spearmans rho = -0.84). Elevations of serum IgE complement the lymphokine data to indicate prominent TH2 type responses in clinical infections with Leishmania donovani.

Release of Interleukin 2 and Gamma Interferon by Peripheral Mononuclear Cells in Human Schistosoma mansoni Infection Normalizes after Chemotherapy

Interleukin 2(IL‐2) and gamma interferon (IFN‐γ) were determined in supernatantsof mitogen and antigen‐driven cell cultures from patients with hepatosplenic or intestinal schistosomiasis. Skin reactivity was tested using a panel of eight recall antigens. Results were compared with those of uninfected local controls. In both schistosomiasis groups, IL‐2 activity was reduced before treatment. In less than one third of the patients, schistosomal antigens elicited detectable IL‐2 activity. IFN‐γ production was reduced more severely in hapatosplenic cases, in particular after stimulation by anti‐CD3 monoclonal antibodies. After anti‐schistosomal therapy with praziquantel, mitogen‐induced IL‐2 and IFN‐γ activities became normal within 3 months in intestinal schistosomiasis, and within 6 months in the hepatosplenic patient group. Results of in vivo delayed‐type hypersensitivity tests paralleled those of in vitro lymphokine production. In conclusion, evidence is presented for severe, antigen‐unspecific suppression of lymphokine production and skin reactivity against recall antigens. Anti‐parasitic chemotherapy is shown to reverse the impairment of cell‐mediated immune responses at the cytokine level.

Praziquantel in the treatment of hepatosplenic schistosomiasis: Biochemical disease markers indicate deceleration of fibrogenesis and diminution of portal flow obstruction

Serological indicators for disease activity and portal vein obstruction and/or deviation were assessed in 23 patients with hepatosplenic schistosomiasis before, and up to 18 months after, praziquantel treatment, as well as in 25 matched local controls. Cessation of egg-induced immunopathology was reflected by the return to normal of serum procollagen-III-propeptide and neopterin concentrations. Reversibility of portal vein pathology was indicated by normal clearance of cholylglycine in cases without signs of decompensating portal hypertension. In most patients with a history of ascites and/or haemorrhage, serum cholylglycine concentration remained pathological. The results provide evidence that the fibrogenic process ceases after specific chemotherapy, and that portal vein pathology regresses in a substantial proportion of hepatosplenic schistosomiasis cases.

Liver involvement in human schistosomiasis mansoni. Assessment by immunological and biochemical markers

In 20 patients with hepatic or hepatosplenic schistosomiasis and 82 individuals infected with S. mansoni, but without liver enlargement, serum parameters reflecting the fibrotic process and hemodynamic alterations as well as immunomodulation were examined. Included as controls were 35 age- and sex-matched healthy individuals from the study region in Northeast Brazil. Peripheral blood cholylglycine levels in patients with hepatomegaly, reflecting the spillover of portal blood into the systemic circulation, were elevated 12-fold over values of patients without liver involvement. Procollagen-III-peptide, a cleavage product of collagen synthesis, was elevated in patients with hepatomegaly (P<0.001) but normal in uncomplicated cases. Immunomodulation was assessed by in vivo delayed hypersensitivity to recall antigens and by serum Β 2-microglobulin and neopterin, substances released in the context of lymphocyte activation. Neopterin, predominantly a macrophage product, was elevated most strikingly in hepatomegalic cases (P< 0.001). The possible interrelation between altered immune responses and excess fibrogenesis is discussed.

Altered generation of interleukin 1 in chronic human schistosomiasis mansoni.

Chronic schistosomiasis mansoni is associated with impaired cell‐mediated immune responsiveness (CMI). To assess co‐stimulatory factors essential in the induction phase of CMI, interleukin 1 (IL‐1) concentration was determined in the sera and cell culture supernatants of Schistosoma mansoni‐infected patients, and circulating monocytes were phenotyped, labelling membrane IL‐1 and HLA‐DP. In addition, adherent cell oxidative‐burst capacity was investigated. Since involvement of IL‐1β in the pathogenesis of severe granulomatous lesions could not be ruled out, 17 patients with intestinal schistosomiasis and 17 patients with hepatosplenic schistosomiasis were matched for intensity of infection and monitored 3–6 months after praziquantel therapy. Seventeen age‐ and sex‐matched uninfected residents ofthe study area in Alagoas, Brazil, acted as controls. Whereas schistosomiasis patients and controls did not differ in the expression of monoeyte surface antigens and the capacity of adherent cells to generate H2O2, IL‐1β release by monocytes in vitro was significantly reduced in both intestinal and hepatosplenic patients. Low concentrations of circulating IL‐1β were detected in comparable frequencies in untreated patients and controls. Three months after therapy, IL‐Iβ was detectable in serum in an increased proportion of intestinal schistosomiasis patients. IL‐1 release in vitro gradually increased in all patients and reached control values 6 months after therapy.

T Cell Phenotype Alterations in Hepatosplenic Schistosomiasis mansoni Normalize after Chemotherapy

Peripheral blood T cell phenotypes, CD3-induced mitogenesis and soluble IL 2 receptor and CD8 in sera were studied in intestinal and hepatosplenic Schistosomiasis mansoni before and three to six months after therapy with praziquantel. Fifteen pairs matched for intensity of infection were analyzed and compared with local, non-infected age-matched controls. CD3+ cell counts were lower in untreated hepatosplenic schistosomiasis (median 1040 cells/microliters; 95% confidence interval 608-1269) compared to controls (1534; 1264-1620). This difference was largely accounted for by immature CD1+/CD3-cells circulating in these patients (median 388/microliters, 252-474). The frequency of CD1+ T cells in circulation decreased drastically after chemotherapy. Similar, but less marked, alterations were seen in intestinal schistosomiasis. Lymphocyte proliferation initiated by agonistic anti-CD3 monoclonal antibody was severely impaired in hepatosplenic patients, who had suffered haemorrhagic complications, but not in the cases of incipient hepatomegaly. Soluble CD8 antigen circulated in increased amounts in hepatosplenic schistosomiasis. Remarkably, a negative correlation between CD3-induced mitogenesis and circulating levels of CD8 was noted in these patients. Whereas CD3-induced mitogenesis in hepatosplenic schistosomiasis normalized after therapy, circulating IL 2R and CD8 antigen in hepatosplenic patients still exceeded control levels. The results demonstrate disturbances of CD3 and CD8 expression and/or T cell maturation in hepatosplenic schistosomiasis. Imbalanced CD4/CD8 ratios and an increased IL 2R/CD8 turnover may reflect an inhibitory circuit within the T cell compartment.