Regulation of immune responses by the L3 of Brugia pahangi

Gillan, Victoria Ann (2004) Regulation of immune responses by the L3 of Brugia pahangi. PhD thesis, University of Glasgow.

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Abstract

Lymphatic filarial worms are mosquito borne parasites which cause chronic disease in humans. Infection is characterized by proliferative suppression of T cells in the host and a skewing of the immune response, away from an IFN-gamma producing Th1 response, towards a Th2 or regulatory phenotype, with production of IL-4 and IL-10. In this study, a mouse model was used to investigate the role of the infective form of the parasite (the third stage larvae, L3) in regulating immune responses. BALB/c mice were infected by the subcutaneous route to mimic the natural transmission of the parasite, and immune responses generated by the L3 were analysed. Experiments carried out in the intact BALB/c mouse showed that infection with L3 results in increased IL-4, IL-10 and IL-5 with no IL-2 or IFN-gamma, a similar situation to that observed in infected humans. In order to investigate the key components in this skewing of the immune response, experiments were carried out using IL-4-/- mice. IL-4 was shown to have a role in down-regulating Th1 responses in wild type mice, as knock-out animals produced elevated levels of IL-2 and IFN-gamma. However these mice still had the capacity to produce IL-5, IL-13 and IL-10, suggesting that although IL-4 is an important Th2 cytokine, it may be dispensable in the initiation of such a response. In addition, reduced levels of proliferation of CD4+ and B220+ cells were observed in infected IL-4-/- mice. Despite elevated levels of IFN-gamma, this reduction in proliferation was not associated with increased production of NO, and neutralizing IFN-gamma itself did not restore proliferative responses. Addition of rIL-4 to cultures of splenocytes from these mice had a mild effect but did not result in a significant increase in proliferation. Treatment of splenocytes from intact mice with anti-IL-10 MAb in vitro resulted in increased levels of IL-2 and IFN-gamma, but no significant effect on Ag-specific proliferation was observed. However, when mice were treated with an anti-IL-10R MAb the opposite effect was seen, with a significant increase in levels of proliferation and no alteration in cytokines. When examined by FACS it was shown that CD4+ cells were the major population which expanded during IL-10R blockade. In addition, CD4+ cells were found to be the major source of IL-10 post-infection with L3, suggesting these cells may modulate their own proliferation, or perhaps these cells were of a regulatory nature. Experiments were also carried out to determine the effect of natural transmission on host immune responses. L3 were administered via syringe inoculation or via mosquito transmission. Splenocytes from mice infected via syringe inoculation had an increased capacity to produce cytokines and displayed higher levels of proliferation. Further experiments demonstrated that cytokine and proliferative responses were not dose- dependant therefore there may be factors within mosquito saliva which down-regulate immune responses in the mouse model.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Eileen Devaney
Keywords: Immunology, Parasitology
Date of Award: 2004
Depositing User: Enlighten Team
Unique ID: glathesis:2004-70990
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 09 May 2019 14:28
Last Modified: 09 May 2019 14:28
URI: http://theses.gla.ac.uk/id/eprint/70990

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