Effect of praziquantel treatment against schistosoma mansoni during pregnancy on anti-schistosome immune responses in pregnant women and their babies
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Chemotherapy with praziquantel against schistosomiasis acts in synergy with the immune responses against the schistosomes. Praziquantel acts by disruption of the integrity of the surface membranes of schistosomes and this exposes the antigens that are targets of immune attack; this leads to immunologically mediated killing of the worms and a boosting of anti-schistosome responses. Until 2002, treatment of schistosomiasis during pregnancy and lactation had not been recommended, simply because praziquantel had not been tested in pregnant women. As a result of the previous policy, there has, until now, been no information on the immunological effects in mothers and infants associated with praziquantel treatment in pregnancy. Immune responses during pregnancy are suppressed, and this could have impact on the immune mediated action of praziquantel; at the same time praziquantel treatment during pregnancy could cause immune alterations of the baby. To bridge the gap of lack of adequate information on schistosomiasis and its treatment during pregnancy, a randomised placebo controlled trials of praziquantel during pregnancy was conducted in Entebbe Hospital involving women from Entebbe and Katabi communities, endemic with S. mansoni. The main aims were to elucidate the effect on the treatment during pregnancy on maternal anti-schistosome immune responses and on in-utero sensitisation of the baby with four major specific objectives. (1) To determine alterations of maternal anti-schistosome immune responses with progression of pregnancy among women infected with S. mansoni. (2) To determine the effect of praziquantel treatment of S. mansoni on maternal anti-schistosome immune responses in infected women treated during pregnancy or after delivery. (3) To determin the impact of pregnancy on the effect of praziquantel treatment against S. mansoni during pregnancy. (4) To determine the effect of praziquantel treatment against S. mansoni during pregnancy on in-utero sensitisation of the fetus to S. mansoni through assessment of responses in cord blood. Alterations of maternal anti-schistosome immune responses during pregnancy were examined by measuring whole blood culture cytokine responses (IFNγ, IL-2, IL-4, IL-5, IL-13 and IL-10) to SWA and SEA as well as antibody levels (IgG1, IgG2, IgG3, IgG4, IgE and IgM against SWA and IgG1, IgG2, IgG3, IgG4 and IgE against SEA) among the women who did not receive praziquantel treatment at enrolment (the placebo group) in this study. Cytokine responses to SWA and SEA as well as levels of antibodies against the worm and egg antigens declined with progression of pregnancy. The cytokine responses and antibodies were suppressed during pregnancy when compared to the responses after delivery. The effect of praziquantel treatment of S. mansoni during pregnancy on maternal anti-schistosome immune responses were examined by measuring whole blood culture cytokine responses to SWA and SEA as well as levels of antibodies against SWA and SEA at six weeks after treatment. In spite being suppressed during pregnancy, cytokine responses and levels of antibodies against SWA and to a less extent SEA were boosted at six weeks following praziquantel treatment. The impact of pregnancy on the effects of praziquantel treatment of S. mansoni on immune responses observed at six weeks following treatment were examined by comparing cytokine responses and antibody levels to SWA and SEA following treatment during pregnancy with the cytokine responses and antibody levels following treatment after delivery. Cytokine responses to SWA and SEA and levels of antibodies against SWA and SEA at six weeks post-treatment were lower following treatment during pregnancy than those following treatment after delivery. In spite of the lower boost of immune responses following praziquantel during pregnancy than after delivery, the cure rates following praziquantel treatment during pregnancy or after delivery were not significantly different. The effects of praziquantel treatment against S. mansoni during pregnancy on in-utero sensitisation of the foetus to S. mansoni antigens were examined by whole cord blood culture cytokine responses to SWA and SEA and levels of IgE and IgM in cord blood. Praziquantel treatment reduced sensitisation to SEA, an effect that was prominent for type one cytokines. On the other hand praziquantel treatment did not significantly affect the level of in-utero sensitisation to SWA with a possible exception of IL-4 where praziquantel treatment showed an increase of IL-4 responders to SWA in cord blood. The effects of praziquantel treatment during pregnancy on immune responses to non-schistosome antigens were explored by examining effects on antibody isotypes against P falciparum schizont extract antigen (PflSE), total IgG against tetanus toxoid and cytokine responses to culture filtrate of Mycobacterium tuberculosis (CFP-Tb). Praziquantel treatment during pregnancy did not significantly influence the antibody levels against PflSE and tetanus toxoid. The effect of praziquantel treatment during pregnancy on cytokine responses to CFP-Tb became apparent at six weeks after delivery as an increase in the responses to CFP-Tb. In conclusion, this study showed the beneficial effects of the treatment to the women in as far as cure rate was concerned, which supports the recommendations to treat pregnant women in national schistosomiasis control programs such as those ongoing in Uganda. However, the beneficial or negative effects of the treatment to the babies remain to be ellucidated. Therefore further research on praziquantel treatment during pregnancy as recommended by WHO (2006), should seriously consider long term follow up of babies born to women treated during pregnancy, up to the age where the children have a high risk of exposure and start becoming infected with schistosomes.