The work presented in this thesis is an investigation of the immune responses induced by chronic schistosomiasis in Gabonese schoolchildren. By investigating concurrently various aspects of the... Show moreThe work presented in this thesis is an investigation of the immune responses induced by chronic schistosomiasis in Gabonese schoolchildren. By investigating concurrently various aspects of the immune response, including innate, adaptive and regulatory responses, we are able to gain a more in-depth understanding of the dynamic changes brought about by infection. Through a number of cross-sectional and longitudinal studies we show that S. haematobium infection induces increased frequencies of regulatory B (Breg) and T (Treg) cell subsets which are associated with increased levels of IL-10 and adaptive immune hypo-responsiveness. Anti-schistosome treatment results in the reduction of regulatory subsets, an increase in effector T cells and alleviation of suppressed antigen immune responses. By showing that Treg cells are linked to effector responses and that schistosomes can induce Breg cells, the scene is set for future studies to determine antigen specificity of these cells as well as ways to control their activity. As regulatory responses have been shown to be not only important in chronic infectious disease, but also in chronic inflammatory diseases the knowledge gained here may be of substantial value to the health of those living in both low- to middle-income countries as well as high-income countries. Show less
This thesis is focusing on cell-mediated induction of immune tolerance and consists of two parts. The studies described in Part I report the development of strategies for possible treatment of... Show moreThis thesis is focusing on cell-mediated induction of immune tolerance and consists of two parts. The studies described in Part I report the development of strategies for possible treatment of Inflammatory Bowel Diseases (IBD). Induction of immune tolerance, in IBD mouse model, with the use of regulatory T (Treg) cells generated in vitro by specific activation of naive T cells was achieved. Additionally Treg cells were also shown to be induced in vivo and restore intestinal immune tolerance with the use of adeno-associated virus (AAV) vector-based gene delivery. In relation to the use of AAV vector, Part II of this thesis is addressing the possibilities of tolerance induction to AAV capsid or transgene specific immune responses which can develop after AAV-based therapy Show less
Helminth parasites are able to induce immune regulation in their host. Suppression of the host immune system is beneficial for both the parasite, by inhibiting anti-parasite immunity, and for the... Show moreHelminth parasites are able to induce immune regulation in their host. Suppression of the host immune system is beneficial for both the parasite, by inhibiting anti-parasite immunity, and for the host, by preventing tissue damage due to excessive inflammation. There are indications that in countries where parasites have been eliminated the immune regulatory network is impaired, leading to inflammatory diseases such as allergies and asthma. An important player in immune regulation is the regulatory T cell (Treg). We have shown that the number and/or function of Tregs were indeed enhanced in several helminth and also malaria infections in humans. Tregs were not only involved in suppression of anti-parasite responses, but also of responses to other infections or vaccines. We further investigated the effect of helminth elimination in a randomized placebo-controlled trial. Treatment of helminths led to a strong increase in __mainly pro-inflammatory__ immune responses, which confirms the importance of immune regulation during infection. Furthermore, the prevalence of malaria was transiently increased and allergy was slightly on the rise in treated school children. These results further endorse the possible beneficial effects of helminthic therapy, which is currently being tested in a number of clinical trials. Show less
