Abstract:
Successful vaccination requires the delivery of exogenous antigen to antigen presenting cells (APC) for presentation at the cell surface resulting in activation of effector T cells and B cells. Active targeting of antigen into APC by receptor mediated endocytosis could improve vaccine efficacy compared to antigens taken up via passive routes of internalization e.g. phagocytosis or pinocytosis. This thesis investigated the potential of the non-toxic superantigen variant, SMEZ-2M1 to target antigen to APCs through its high affinity binding to MffC II. Proteins or peptides chemically coupled to SMEZ-2M1 are targeted to APCs leading to more efficient stimulation of T cells. PBMC exposed to a TΠ epitope from tetanus toxoid coupled to SMEZ-2M1 resulted in increased T-cell proliferation and IFNγ-secretion by up to 100-fold compared to the molar equivalent of peptide, hi addition, SMEZ-2M1 was able to deliver a CTL epitope from CMV into the MHC I pathway resulting in presentation at the dendritic cell (DC) surface and activation of specific CTL. Presentation of the CTL epitope was shown to occur via a pathway reliant on the synthesis of new MHC I molecules. Finally the ability of SMEZ-2M1 to deliver HBcAg particles and activate HBcAg-specific T cells was investigated. DC pulsed with the SMEZ-2Ml-HBcAg conjugate Upregulated a number of co-stimulatory molecules associated with a mature DC phenotype. Crosspresentation of an epitope from HBcAg was observed but presentation of this epitope was only moderately enhanced by conjugation to SMEZ-2M1. Finally, in one group of patients, the chimeric HBcAg induced a statistically significant increase in IFNγ-secretion by TΠ cells compared to HBcAg alone.
