The outbreaks of human influenza caused by highly pathogenic avian influenza
H5N1 virus have attracted a lot of attention and public concern. Effective and
universal vaccines may be the best means for prevention and control of the influenza.
Taking into account that viral clearance and recovery from influenza A virus infection
have been demonstrated to be correlated to specific cytoxic T lymphocyte (CTL)
instead of neutralizing antibodies, it is important to develop effective vaccines which
are capable of inducing not only neutralizing antibody but also CTL responses.
Furthermore, T cell epitopes are usually more conserved than neutralizing epitopes.
However, rare information concerning human T cell epitopes specific to H5N1 virus
has been reported so far.
This study was designed to test our hypothesis that novel and potent human CTL and
Th epitopes specific to NP protein of H5N1 virus may be identified in vaccinated
and/or infected HLA-A2/DR1 transgenic mice (SURE/L1), while protective epitopes
may be further defined from the identified T cell epitopes in the mice challenged with
lethal dose of the virus. We used SURE/L1 mouse model because it contains HLA-A2
(*0201) and -DR1 (*0701), both are the second highest frequency of HLA class I and
II in Chinese. Since the NP gene is relatively conserved among different clades or
strains of H5N1 virus, we selected viral protein NP as the target. Furthermore, we
screened the T cell epitopes in splenocytes not only from vaccinated mice but also
from survived mice infected with gradually increased dose of H5N1 virus, because
the T cell epitopes identified in both vaccinated and infected mice or in infected mice
alone might have higher potential to be protective epitopes.
In this study, a novel HLA-DR1 (class II) restricted T cell epitope NP368-382, NPII-7,
was identified in both vaccinated and infected mice. Two doses of NPII-7 peptide
boosting in the mice induced very strong Th1 and CTL responses but no NP specific
antibody responses. The vaccination of additional 2 doses of NPII-7 also provided
partial protection against lethal challenge of H5N1 virus in the mice, whereas NP
DNA vaccination alone did not show any protective effect. The protective effect may
be attributed to the strong Th1 and CTL responses induced by the NPII-7 vaccination,
because both NP DNA and NPII-7 vaccinations could not induce neutralizing
antibody response.
Notably, a HLA class II restricted peptide, NPII-7, may induce not only Th1
responses but also more strong HLA class I restricted T cell (CTL) responses. It may
probably due to that the HLA-DR1 restricted T cell epitope
(NENMEAMDSNTLELR) contained the full sequence of a reported HLA-A2
restricted CTL epitope (AMDSNTLEL), named NP-17 in this study. Although it
needs to be further defined whether this novel epitope is really a HLA-DR1 restricted
T cell epitope, or it shares the activity of HLA-A2 restricted T cell epitope, or it is
just an alternate HLA-A2 restricted T cell epitope, this study has identified a novel T
cell epitope and proved that it is a protective T cell epitope. / published_or_final_version / Microbiology / Master / Master of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/174380 |
| Date | January 2012 |
| Creators | Cao, Tingting., 曹婷婷. |
| Contributors | Zheng, B |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47323218 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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