Dissection of the mechanisms of action of ES-62 in inflammatory disease

Kean, Dorothy Elizabeth (2006) Dissection of the mechanisms of action of ES-62 in inflammatory disease. PhD thesis, University of Glasgow.

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Filarial nematode parasite infections are endemic in developing countries of the Tropics. Collectively known as filariasis, these helminth parasite infections can occasionally induce gross inflammatory pathology in the infected host, however, more commonly, the host exhibits a somewhat suppressed non-inflammatory immune response to the parasite, permitting longevity of infection. Improved sanitation, increased use of antibiotics and vaccination has all but eradicated parasite infection in developed. Western society. Coincident with this improvement in hygiene, however, inflammatory autoimmune (e.g. rheumatoid arthritis) and allergic disease (e.g. asthma) has become more prevalent in these countries; a trend not observed in parasite-endemic countries. The hygiene hypothesis controversially proposes that these trends are directly associated, by predicting that insufficient exposure to pathogens in childhood results in development of an aberrant immune system that responds inappropriately to non-pathogenic stimuli as is manifested by allergy and/or autoimmunity. Thus, conversely, it has been proposed that exposure to parasite infection may prevent development of autoimmune and/or allergic diseases. Filarial nematodes secrete immunomodulatory excretory-secretory (ES) products into the host bloodstream, which act to modulate inflammatory host immune responses and thus, protect the parasite from elimination. ES-62, an immunomodulatory glycoprotein product of rodent filarial nematode, Acanthocheilonema viteae, has previously been shown to modulate the responses of several immune cell types to promote an anti-inflammatory immune response in vitro and in vivo. Thus, it was hypothesised that ES-62 may exhibit anti-inflammatory potential in models of inflammatory disease prevalent in the Western world. Indeed, in a collagen-induced model of rheumatoid arthritis (CIA) ES-62 treatment induced amelioration of inflammation. Furthermore, this effect was mediated when ES-62 was administered before or after the onset of clinically detectable inflammation. In Chapter 3 of this thesis, progress towards dissection of the mechanisms of action of ES-62 in the CIA model was made, by analysing the role of phosphorylcholine (PC), a component of ES-62 and several other immunomodulatory pathogen-derived products. Utilising a TH2 mediated ovalbumin (OVA)-induced model of allergic airway inflammation (such as that exhibited in asthma), it was determined that treatment with ES-62 during or after the onset of disease reduced peri-bronchial inflammation and airway eosinophilia (Chapter 4). In Chapter 5, prophylactic ES-62 treatment of MRL/lpr mice was demonstrated to inhibit development of nephritis and articular inflammation, two pathologies commonly associated with SLE in humans. It was demonstrated in Chapter 6 that A. suum-derived GSL inhibited the response of DC to LPS, evidenced by a reduction in LPS- induced cytokine production and upregulation of cell surface co-stimulatory molecules. In Chapter 7, it was demonstrated that 2S seed albumins, SFA 8 and Ber e 1, which exhibited distinct allergenic properties also mediated distinct effects on DC functions in vitro. It was concluded that allergenic proteins can also mediate their effects via modulation of DC in susceptible individuals. In summary, the novel findings presented in this thesis support the theory that parasite infection may be protective against development of autoimmune and allergic inflammatory diseases prevalent in developed society. Furthermore, this protective effect may be facilitated by the immunomodulatory actions of parasite-derived, PC-containing ES products. Thus, via modulation of the function of innate antigen-presenting cells, such as dendritic cells, immunomodulatory molecules are capable of manipulating the action of immune system as a whole. This discovery draws attention to a highly evolved anti-inflammatory mechanism employed by parasites, which could potentially be exploited to design therapy for human inflammatory diseases of today. (Abstract shortened by ProQuest.).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Immunology, parasitology.
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Harnett, Prof. Maggie
Date of Award: 2006
Depositing User: Enlighten Team
Unique ID: glathesis:2006-71021
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 09 May 2019 14:28
Last Modified: 20 May 2021 09:34
URI: https://theses.gla.ac.uk/id/eprint/71021
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