Wang, Chun-Chi; (1997) Therapeutic vaccines based on Mycobacterium vaccae for treatment of an established IgE response to ovalbumin in BALB/c mice. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Allergic disorders affect at least 20% of the population of developed countries. They include hay fever, asthma, atopic dermatitis and food allergies. These symptoms are associated with high serum levels of allergen-specific IgE and eosinophilia, and are dependent upon IL-4 and IL-5 released from allergen-specific CD4 T cells expressing the Th2 cytokine profile. Recent strategies aim to switch allergen specific Th2 responses to Th1, with predominant production of IFN-ỿ and IL-2. The basis of this strategy is the supposed mutual opposition between Th1 and Th2, where Th1 cytokines downregulate Th2 function, and so would be expected to reduce IgE. The purpose of this study was the development of a therapeutic vaccine for treatment of allergy based on Mycobacterium vaccae, since the mycobacteria have been highlighted as suitable carriers possessing appropriate Th1 adjuvanticity and this organism is used as a killed preparation, and has undergone extensive toxicological studies and safety assessment in man. A specific murine model of ovalbumin (OVA)-induced Th2 type immune response was developed for this study. BALB/c mice that receive two doses of OVA develop high levels of IgE and IL-5 which are crucial factors for allergic responses. The therapeutic vaccines compared in this murine model included unmodified M. vaccae, M. vaccae conjugated to OVA and recombinant M.vaccae expressing the major epitope recognised by murine T cells (OVA323-339). The efficacy of the vaccine is judged by inhibition of the IgE response and switching the specific cytokine pattern from Th2 to Th1. Interestingly, treatment with unmodified M.vaccae was most effective at reducing IgE and IL-5 release, whereas M.vaccae conjugated to OVA or expressing OVA323- 339 had enhanced capacity to evoke a allergen specific IL-2 response but a diminished capacity for downregulation of IL-5. Meanwhile, the procedure of conjugation between OVA and mycobacteria appeared to damage the ability of M.vaccae to suppress the serum IgE response. The data suggest dissociation between the ability of M.vaccae to downregulate IgE, and its ability to downregulate the potential for IL-5 secretion. Results of this study will be very important in development of immunotherapy and of an effective vaccine for allergy, and will add to our understanding of immunoregulation by pathogenic mycobacteria.

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