Chronic Schistosoma japonicum infection reduces immune response to vaccine against hepatitis B in mice.

BACKGROUND: Hepatitis B and schistosomiasis are most prevalent in Africa and Asia, and co-infections of both are frequent in these areas. The immunomodulation reported to be induced by schistosome infections might restrict immune control of hepatitis B virus (HBV) leading to more severe viral infection. Vaccination is the most effective measure to control and prevent HBV infection, but there is evidence for a reduced immune response to the vaccine in patients with chronic schistosomiasis japonica. METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we demonstrate in a mouse model that a chronic Schistosoma japonicum infection can inhibit the immune response to hepatitis B vaccine (HBV vaccine) and lead to lower production of anti-HBs antibodies, interferon-γ (IFN-γ) and interleukin-2 (IL-2). After deworming with Praziquantel (PZQ), the level of anti-HBs antibodies gradually increased and the Th2-biased profile slowly tapered. At 16 weeks after deworming, the levels of anti-HBs antibodies and Th1/Th2 cytokines returned to the normal levels. CONCLUSIONS/SIGNIFICANCE: The results suggest that the preexisting Th2-dominated immune profile in the host infected with the parasite may down-regulate levels of anti-HBs antibodies and Th1 cytokines. To improve the efficacy of HBV vaccination in schistosome infected humans it may be valuable to treat them with praziquantel (PZQ) some time prior to HBV vaccination.

Tim-2 up-regulation and galectin-9-Tim-3 pathway activation in Th2-biased response in Schistosoma japonicum infection in mice.

T cell immunoglobulin domain and mucin domain (Tim) family, a new gene that expresses on the surface of T cells, plays a critical role in regulation of T cells response. Previous data have shown that Tim-3 expressed on Th1 cells promotes itself apoptosis. Tim-2 is preferentially up-regulated during Th2 differentiation and functions as a potent costimulatory molecule for T-cell immunity. The present study aims to learn whether Tims are responsible for Th2-biased response evoked by Schistosoma japonicum infection. The expressions of Tim-2 and Tim-3 in spleen lymphocytes from S. japonicum-infected mice were examined, and the possible role of galectin-9-Tim-3 pathway in Th2-biased response triggered by schistosome infection was discussed. Our results showed that Tim-2 mRNAs were up-regulated in the spleen of schistosome-infected mice, which coincided with elevated IL-4 gene expression. Administration of galectin-9 significantly induced apoptosis of naïve spleen lymphocytes with down-regulation IFN-γexpression in vitro. Additionally, Tim-3-Fc fusion protein notably enhanced Th1 cells and decreased Th2 cells in vitro. Thus, we concluded that pro-apoptotic effects on Th1 population through galectin-9-Tim-3 pathway and the up-regulation of Tim-2 on Th2 cells might be critical to Th2-biased response of host with schistosomiasis japonica.

The effects of interleukin (IL)-12 and IL-4 deficiency on worm development and granuloma formation in Schistosoma japonicum-infected mice.

CD4(+) T-helper (Th) cell is widely recognized to be capable of influencing worm development and egg granuloma formation after schistosome infection. Interleukin (IL)-12 and IL-4 play key roles in regulation of Th cell differentiation. In the present study, we subcutaneously inoculated mice with hybridoma cells secreting monoclonal antibodies to neutralize IL-12 and IL-4 and explored the effects of IL-12 and IL-4 deficiency on the worm development and granuloma formation in mice infected with cercariae of Schistosoma japonicum. It was found that deficiency of host IL-12 and IL-4 supported normal parasite survival and fecundity. However, worm development (length and female fecundity) was significantly enhanced in anti-IL-12-treated mice. Mean length of worms in anti-IL-12-treated group was significantly greater than that of intact controls on day 28 after infection (females, 11.84 ± 1.20 mm vs. 9.45 ± 1.34; males, 9.35 ± 1.21 mm vs. 8.10 ± 0.85 mm, p < 0.05). Liver egg load per pair of worms (1,770.12 ± 470.67 vs. 806.08 ± 232.37, p < 0.05) and uterine egg load of ovigerous females (93.08 ± 27.85 vs. 46.05 ± 34.24, p < 0.05) in anti-IL-12-treated mice were significantly higher than those in intact control 28 days postinfection. But these effects diminished 42 days postinfection (p > 0.05). Granuloma size in anti-IL-12-treated mice was significantly larger than that in intact mice 42 days postinfection (398.3 ± 80.7 µm vs. 294.4 ± 72.2 µm, p < 0.05). Granuloma fibrosis dramatically intensified in anti-IL-12-treated mice but diminished in anti-IL-4-treated mice. The results suggest that IL-12 may play an impeditive role in the development of S. japonicum and in granuloma formation as well as fibrosis. IL-4 may promote granuloma formation but have no effect on worm development.

[Effects of signal transducers and activators of transcription 4 and 6 on development of worms and granuloma formation in mice infected with Schistosoma japonicum].

OBJECTIVE: To explore the effects of STAT4 and STAT6 on the development of worms and granuloma formation in mice infected with Schistosoma japonicum. METHODS: All the intact BALB/cJ mice and STAT4(-/-), STAT6(-/-) mice with the same genetic background were infected with 25 S. japonicum cercariae. All the mice were sacrificed on the 42nd day after infection and the worms were collected. The total number of worms and the mean number of worm pairs were counted. The liver of each mouse was removed for the count of eggs, the histological examination and the determination of the size of single-egg granulomas in the liver. RESULTS: No significant differences were found in the total number of worms, the number of worm pairs and the number of eggs per pair of worms in the liver among STAT4(-/-), STAT6(-/-) and BALB/cJ mice. The size of single-egg granulomas in the liver of STAT6(-/-) mice (213.3 +/- 68.6) microm was significantly smaller than that in the liver of normal BALB/cJ mice (319.5 +/- 71.9) microm (P < 0.05). The liver granulomas were not well formed and the liver fibrosis decreased in STAT6(-/-) mice. CONCLUSIONS: STAT4 or STAT6 deficiency has no conspicuous effect on the development and fecundity of S. japonicum. STAT6 plays an important role for the granuloma formation and liver fibrosis.

Synthesis and cytotoxic activities of novel phenacylimidazolium bromides.

A series of novel phenacylimidazolium derivatives, bearing an aryl or alkyl substituent at position-1 and a phenacyl substituent at position-3 of the imidazole ring, has been prepared and evaluated in vitro against a panel of human tumor cell lines. Phenacylimidazolium bromides bearing a highly sterically hindered aryl group at position-1 and an electron-rich phenacyl or naphthylacyl substituent at position-3 of imidazole ring proved to be more active than imidazolium bromides with other substituted groups. In particular, compound 5j was found to be the most potent compounds with IC(50) values lower than 5.0 microM against 8 strains human tumor cell lines and more active than cisplatin (DDP).

The effects of T cell deficiency on the development of worms and granuloma formation in mice infected with Schistosoma japonicum.

It is widely accepted that the immune response of the host attacks the parasite and the parasite appears to develop strategies to evade the assault. However, there is increasing evidence that the development of a parasite may be also positively influenced by the immune response of host. In this paper, we explore the effects of T cell deficiency on the development of the worms and granuloma formation in mice infected with cercariae of Schistosoma japonicum. T cell-deficient (nude) mice supported normal parasite survival and fecundity, but compared to normal mice delayed the worms' development (length and female fecundity) until 28 days after infection. However, these differences equaled out at 35 and 42 days. The nude mice apparently suppressed the size of granuloma in the livers around the eggs of S. japonicum. The granulomas were composed predominantly of neutrophils but with significantly fewer eosinophils in nude compared to normal mice. In addition, hepatocyte necrosis occurred in the vicinity of granulomas in nude but not normal mice. This is consistent with egg-granuloma formation in the host being dependent on T-lymphocyte functions and shows that the effect of T cell deficiency on the development of the worms is transitory in S. japonicum.

[Impact of chronic schistosomiasis japonica on the protective immunity induced by vaccine against hepatitis B virus].

OBJECTIVE: To study the impact of chronic schistosomiasis on the protective immunity induced by vaccine against hepatitis B virus. METHODS: 24 patients with chronic or advanced schistosomiasis (experimental group) and 26 healthy volunteers (control group) all without hepatitis B virus infection were selected for the study. Sera of the subjects in the two groups were collected before inoculation and on the 35th day after inoculation with yeast-derived recombinant hepatitis B vaccine. The level of anti-Hbs, IL-2 and TNF-alpha in sera was examined by ELISA respectively. RESULTS: Anti-Hbs in both groups were negative before inoculation, with an average absorbance (A value) of 0.134 and 0.150 respectively. After inoculation, positive rate of anti-Hbs was 17% (4/24, average A value 0.145 ) in experimental group and 92% (24/26, average A value was 1.210) in control group. The vaccine against hepatitis B induced significantly higher level of anti-Hbs in healthy volunteers compared with that in schistosomiasis patients (P < 0.01). The level of IL-2 and TNF-alpha increased in both groups after inoculation without significant difference compared with the level before inoculation. CONCLUSION: The results suggest that the protective immunity of patients with chronic schistosomiasis is deficient to the stimulation of hepatitis B virus and it may involve in a higher incidence of hepatitis B among schistosomiasis patients.

[Microarray DNA chip in analyzing the association between HLA-DRB and advanced hepatosplenic schistosomiasis].

OBJECTIVE: To explore possible associations between host polymorphism of HLA class II genotypes and advanced hepatosplenic schistosomiasis japonica. METHODS: 45 advanced schistosomiasis patients (experimental group) and 44 age- and sex-matched patients with chronic schistosomiasis (control group) from the same area were investigated for their HLA class II gene DRB genotypes by genotyping the alleles using microarray DNA chip. The correlation of allele frequencies to advanced hepatosplenic schistosomiasis was compared for the two groups. RESULTS: HLA-DRB1*04x exhibited markedly higher frequency in advanced patients than that in control group (P < 0.01, RR = 3.928). In contrast, the frequency of HLA-DRB1*15x in advanced patients was much lower when compared with that in control group (P < 0.01, RR = 0.050). Besides, the significant allele HLA-DRB1*15x displayed concurrence with allele DRB5*010x/020x. The linked gene haplotype DRB1*15x-DRB5*010x/020x showed significantly higher incidence in control group than in experimental group (P < 0.01). CONCLUSION: Allele HLA-DRB1*04x is positively, while HLA-DRB1*15x is negatively, correlated with advanced hepatosplenic schistosomiasis.