Regulation and Effector Function of TH1 and TH2 Cells in Immunity to Bordetella Pertussis

The evaluation of vaccines for human use requires reliable models of infection, that are predictive of protective efficacy. Traditionally whole cell pertussis vaccines (Pw) have been controlled using the Kendrick test, which measures protection following intracerebral challenge with Bordetella pertussis. However, this test is unsuitable for assessing the potency o f the new acellular pertussis vaccines (Pa). In this study, it was demonstrated that protection in a murine respiratory challenge model correlates with the protective efficacy of Pa and Pw in children, but vaccine potency could not be predicted on the basis of antibody responses against individual antigens. Furthermore, the murine model was shown to be a reliable method for the determination of consistency between different batches o f Pa and Pw. This study highlights the possible applications of the murine model in the regulatory control and future development of pertussis vaccines. The murine model of infection has been used in the elucidation of the protective mechanisms induced following immunization with Pw or Pa, revealing roles for both antibody and T-cells in protection against B. p ertu ssis. It has been demonstrated that children still appear to be protected against infection, despite a rapid decline in antibody levels after vaccination. In the murine model, antibody levels quickly decline after immunization, but significant levels of protection were observed following aerosol challenge. Recall T-cell responses detectable for prolonged periods after immunization, together with an anamnestic antibody response post-challenge suggest that immunological memory is more significant in protection, than the induction of immediate antibody responses in vaccine-induced protection against B. pertussis. It has been demonstrated that Thl responses and particularly the cytokine IFN-y, play a critical role in immunity to B. pertussis. In the present study, the role of IL-12 and IL-18 in the induction of a protective Thl response to B. p ertu ssis was examined. Lack of IL-12 during primary and secondary infection effected protection only at the early stages of infection, suggesting that IL-12 plays an important role at the induction stage of the immune response to B. pertussis, but also suggests that other cytokines may be involved. IL-18 is rapidly produced in the lungs of B. p ertu ssis infected IL-1 2~'~ and wild-type mice, which may compensate for the lack of IL-12 at the later stages of infection. The importance of Thl responses and IFN-y were fiirther highlighted in this study, through the investigation of the effect of helminth infection on the outcome o f B. p ertu ssis infection, or immunization with Pw. Infection with the parasite Fasciolahepatica , was shown to suppress B. pertussis-specific Thl responses, and delay bacterial clearance from the lungs, and was also shown to inhibit this Thl response after it had become established. Furthermore, it was demonstrated that infection with F. hepatic a was capable of downregulating the Thl response induced by systemic immunization with Pw, and reducing its protective efficacy. In addition, a role for IL-4 was demonstrated in the parasite-induced immunoregulation.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

National University of Ireland Maynooth

Year dc:date.issued

2001

Author dc:creator

• Brady, Miriam T.

Language dc:language

en