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Title: Vaccination and leukocyte homing in gastrointestinal nematode infection models
Author: Dixon, Helen
ISNI:       0000 0004 2682 8762
Awarding Body: The University of Manchester
Current Institution: University of Manchester
Date of Award: 2007
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Trichuriasis, caused by the whipworm T. trichiura, is endemic in tropical and subtropical areas, affecting approximately one fifth of the world's population. Child anthelminthic treatment programmes are being implemented in countries with endemic disease but repeated treatments are costly, may prevent the development of acquired immunity and can lead to the development of drug resistant parasites. Thus, the development of a vaccine which would lead to the acquisition of immunity at an earlier age and reduce community faecal egg output would be beneficial. Development of subunit vaccines requires the identification of protective antigens and their formulation in a suitable adjuvant. T. muris is an antigenically similar laboratory model for T. trichiura. Subcutaneous (s.c.) vaccination with adult excretory-secretory (ES) proteins protects susceptible mouse strains from T. muris. Larval stages may contain novel antigens which when incorporated in a vaccine induce worm expulsion earlier in infection. This study finds no difference in the cellular and humoral immune response to T. muris adult and L3 ES but identifies high molecular weight proteins in both adult and L3 ES as potential vaccine candidates. Recombinant IL-13 failed to restore protection to a nonprotective vaccine dose of ES, but further work is required prior to ruling out IL-13 as a potential Th2 polarising adjuvant. This is the first study to describe the cellular and humoral components of the protective immune response following s.c. vaccination against T. muris. Protection of susceptible mice involved the development of a Th2 response and down-regulation of IL-12 while IFN-γ levels remained high. Goblet cell hyperplasia and macrophage influx were induced by vaccination. Epithelial turnover did not appear to be increased by vaccination, suggesting that there are differences in the mechanisms of expulsion between 'natural resistance' and 'vaccinated resistance'. Genes involved in serum IgG1 production were highly expressed in the peripheral lymph node cells (PLNC) following s.c. vaccination with ES/FIA. This, combined with the high levels of serum IgGl and mucosal IgGl and IgA in the colon of mice protected by the ES/FIA vaccine suggests that antibody is involved in vaccination-induced worm expulsion. This is further supported by the fact that anti-CCR10 treatment of PLNC prior to adoptive transfer to SCID mice reduces lymphocyte recruitment to the colonic mucosa and delays worm expulsion. This is the first study on the role of CCL11 in eosinophil recruitment to the small and large intestine during gastrointestinal helminth infection. A peripheral eosinophilia was seen in wild type BALB/c mice and CCL11 deficient mice infected with T spiralis but not with T muris. Gastrointestinal eosinophilia was markedly reduced but not ablated in CCL11 deficient mice - and negligible in CCL11 IL-5 deficient mice - infected with either nematode. The residual eosinophilia and up-regulation of CCL24 mRNA in the gastrointestinal tract of CCL11 deficient mice infected with either nematode, together with the presence of an eosinophilactive factor in T. spiralis and T. muris products, suggest that CCL11 is the salient but not the sole eosinophil chemoattractant of biological significance during gastrointestinal helminth infection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available