Understanding the link between interleukin 17 and vaccine-induced protection in tuberculosis
<p>Tuberculosis (TB), caused by infection with <em>Mycobacterium tuberculosis (M.tb)</em>, remains a global health problem and although BCG offers some protection against childhood disseminated disease and other mycobacterial infections, its efficacy against pulmonary TB varies bet...
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| Format: | Thesis |
| Language: | English |
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2012
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| _version_ | 1826316395037589504 |
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| author | Griffiths, K |
| author2 | McShane, H |
| author_facet | McShane, H Griffiths, K |
| author_sort | Griffiths, K |
| collection | OXFORD |
| description | <p>Tuberculosis (TB), caused by infection with <em>Mycobacterium tuberculosis (M.tb)</em>, remains a global health problem and although BCG offers some protection against childhood disseminated disease and other mycobacterial infections, its efficacy against pulmonary TB varies between 0 and 80%. Modified Vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel TB vaccine designed to boost mycobacterium-specific CD4+ T cell response primed by BCG. MVA85A induces strong interferon (IFN)-γ responses, a cytokine known to be essential for protection following <em>M.tb</em> infection. A strong IFN-γ response is not a correlate of protection and in terms of the adaptive response, interleukin (IL)-17 is emerging as an important cytokine following vaccination as it is thought to help boost IFN-γ production by CD4+ T cells. This thesis shows that MVA85A induces IL-17 in PBMC and whole blood of human BCG – MVA85A vaccinees. This is replicated in mice receiving BCG – MVA85A intranasally. The administration of cholera toxin (CT) with BCG enhances IL-17 and confers improved protection following <em>M.tb</em> challenge, which is partially dependent on IL-17 and on the mucosal route of administration. Since CT is not a suitable adjuvant in humans, an alternative IL-17-inducing pathway was investigated. In human BCG – MVA85A-vaccinated volunteers, blocking the hydrolysing ability of the CD39, an apyrase responsible for hydrolysing pro-inflammatory ATP, enhances IL-17 production. Challenge of BCG – MVA85A-vaccinated CD39-/- mice with <em>M.tb</em> slightly improved the protective capacity of the vaccine, suggesting that a pathway dependent on ATP-driven inflammation may be a target for improving the immunogenicity of a vaccine against <em>M.tb</em> disease. Overall, this thesis has confirmed the important role of IL-17 in vaccine-induced protection against TB disease and identifies a possible target pathway for improvement of a novel vaccine.</p> |
| first_indexed | 2024-03-06T21:09:00Z |
| format | Thesis |
| id | oxford-uuid:3d7f5e42-59b8-4fda-a1a8-6a764ea219df |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:44:23Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:3d7f5e42-59b8-4fda-a1a8-6a764ea219df2024-12-07T15:49:17ZUnderstanding the link between interleukin 17 and vaccine-induced protection in tuberculosisThesishttp://purl.org/coar/resource_type/c_db06uuid:3d7f5e42-59b8-4fda-a1a8-6a764ea219dfImmunologyMedical SciencesVaccinologyInfectious diseasesBiologyEnglishOxford University Research Archive - Valet2012Griffiths, KMcShane, HFletcher, H<p>Tuberculosis (TB), caused by infection with <em>Mycobacterium tuberculosis (M.tb)</em>, remains a global health problem and although BCG offers some protection against childhood disseminated disease and other mycobacterial infections, its efficacy against pulmonary TB varies between 0 and 80%. Modified Vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel TB vaccine designed to boost mycobacterium-specific CD4+ T cell response primed by BCG. MVA85A induces strong interferon (IFN)-γ responses, a cytokine known to be essential for protection following <em>M.tb</em> infection. A strong IFN-γ response is not a correlate of protection and in terms of the adaptive response, interleukin (IL)-17 is emerging as an important cytokine following vaccination as it is thought to help boost IFN-γ production by CD4+ T cells. This thesis shows that MVA85A induces IL-17 in PBMC and whole blood of human BCG – MVA85A vaccinees. This is replicated in mice receiving BCG – MVA85A intranasally. The administration of cholera toxin (CT) with BCG enhances IL-17 and confers improved protection following <em>M.tb</em> challenge, which is partially dependent on IL-17 and on the mucosal route of administration. Since CT is not a suitable adjuvant in humans, an alternative IL-17-inducing pathway was investigated. In human BCG – MVA85A-vaccinated volunteers, blocking the hydrolysing ability of the CD39, an apyrase responsible for hydrolysing pro-inflammatory ATP, enhances IL-17 production. Challenge of BCG – MVA85A-vaccinated CD39-/- mice with <em>M.tb</em> slightly improved the protective capacity of the vaccine, suggesting that a pathway dependent on ATP-driven inflammation may be a target for improving the immunogenicity of a vaccine against <em>M.tb</em> disease. Overall, this thesis has confirmed the important role of IL-17 in vaccine-induced protection against TB disease and identifies a possible target pathway for improvement of a novel vaccine.</p> |
| spellingShingle | Immunology Medical Sciences Vaccinology Infectious diseases Biology Griffiths, K Understanding the link between interleukin 17 and vaccine-induced protection in tuberculosis |
| title | Understanding the link between interleukin 17 and vaccine-induced protection in tuberculosis |
| title_full | Understanding the link between interleukin 17 and vaccine-induced protection in tuberculosis |
| title_fullStr | Understanding the link between interleukin 17 and vaccine-induced protection in tuberculosis |
| title_full_unstemmed | Understanding the link between interleukin 17 and vaccine-induced protection in tuberculosis |
| title_short | Understanding the link between interleukin 17 and vaccine-induced protection in tuberculosis |
| title_sort | understanding the link between interleukin 17 and vaccine induced protection in tuberculosis |
| topic | Immunology Medical Sciences Vaccinology Infectious diseases Biology |
| work_keys_str_mv | AT griffithsk understandingthelinkbetweeninterleukin17andvaccineinducedprotectionintuberculosis |