Combined structural and functional approach for identifying new human MHC class I-restricted viral CTL epitopes in vivo
By: by Eve Sik-Yu Cheuk.
Published: 2006
Language: eng
Number of pages: 219
ISBN-13: 9780494158296
Description: Contemporary influenza vaccines primarily elicit humoral immunity. Our laboratory believes that harnessing CD8+ T cell responses together with neutralizing antibody responses would enhance the protective efficacy of these vaccines. However, priming CD8+ T cell responses using CTL vaccines in the general human population is challenging. In addition to the fact that not all CTL epitopes for influenza A are known for all HLA class I molecules, in cases where HLA class I-restricted epitopes are known, they often represent focused CTL responses which can be evaded by the virus. Therefore, the goal here is: first, to identify additional CTL epitopes for specific HLA class I alleles which can be used in CTL vaccines capable of inducing broader CD8+ T cell responses, and second, to devise a new strategy whereby a CTL vaccine can be used with the traditional antibody vaccine in a prime-boost regimen.Lastly, an influenza prime-boost vaccine strategy was assessed. Tg HLA-B27/DKO mice were primed with a peptide vaccine then boosted with a heat-killed virus vaccine. Preliminary results showed that the dead virus booster augments the peptide-specific CD8+ T cell response induced by the priming peptide vaccine. Although further investigation is warranted, this novel vaccine regimen may improve current vaccination strategies for influenza A and other pathogens.To facilitate such studies in the context of human MHC class I molecules, our laboratory generated a panel of HLA class I-transgenic (Tg) mice deficient in expression of H2-K/H2-D class I molecules (i.e. double-knockout; DKO). Initial characterization of these HLA class I Tg mice showed that individual HLA-A2, -B7, and -B27 transgenes select a normal range of CD8+ T cells in the absence of endogenous MHC class I molecules comparable to mice having only a single H2-K or -D gene. These CD8+ T cells exhibit usage of TCR Vbeta chains similar to H2b wildtype mice, and can respond to the same influenza A epitopes as CTLs from HLA-matched humans.Subsequently, the use of Tg HLA-B27/DKO mice led to identification of three new influenza A CTL epitopes out of seven peptides tested. These new epitopes can potentially be used in CTL vaccines, as specific CD8+  T cells were reactivated and proliferated extensively following secondary viral challenge.
Notes: Source: Dissertation Abstracts International, Volume: 67-06, Section: B, page: 3043.

Thesis (Ph.D.)--University of Toronto, 2006.

Includes bibliographic references.

Electronic version licensed for access by U. of T. users.