BIOL 520 Advanced Immunology W2009 Lecture 1 Overview Immunology Lecture 1 Overview Immunology.
Charani Ranasinghe Molecular Mucosal Vaccine Immunology Group, Dept Immunology
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Transcript of Charani Ranasinghe Molecular Mucosal Vaccine Immunology Group, Dept Immunology
Charani RanasingheMolecular Mucosal Vaccine Immunology Group, Dept Immunology
The John Curtin School of Medical ResearchThe Australian National University
Novel HIV IL-4R antagonist vaccine strategy can induce both high avidity CD8 and excellent B cell immunity
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Mucosal vaccination induces high quality/avidity HIV-specific CD8 T cells
Induction of high quality/avidity HIV-specific CD8 T cells following mucosal vaccination is associated with lower expression of IL-4/IL-13 by CD8 T cells
Ranasinghe et al. J. Immunol 2007
Ranasinghe et al. Euro J Immunol 2009
Ranasinghe et al. Mucosal Immunology 2013
Absence of IL-4/IL-13 induces high avidity HIV-specific CD8 T cells
Construction of poxviral vector-based vaccines that co-express IL-4R antagonist using homologous recombination
IL-4R antagonist HIV gag/pol/env
Recombinant vaccinia virus (rVV) or Modified Vaccinia Ankara (rMVA) - booster vaccine
Recombinant fowlpox virus (rFPV) - priming vaccine
HIV gag/polIL-4R antagonist
Jackson Boyle Ranasinghe Methods in Molecular Biology (2014)
intranasal/ intramuscular (i.n./i.m.) combined mucosal/systemic strategy
IL-4
Rα
γc IL-4
Rα
IL-1
3Rα
1
IL-13Rα2m
STAT6
IL-4 IL-13
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Novel IL-4R antagonist adjuvanted vaccine will bind to IL-4R and transiently block IL-4/IL-13 signaling via the STAT6 pathway
Ranasinghe et al Cytokine and Growth Factor Reviews (In press)
96 hrs
12 hrs
Jackson Worley Trivedi Ranasinghe (submitted)
5Jackson Worley Trivedi Ranasinghe (submitted)
i.n./i.m. IL-4R antagonist adjuvanted vaccine strategy can induce HIV-specific CD8 T cells of high avidity
Inclusion of the inhibitor in the priming vaccination is crucial to induce the high avidity T cell repertoire
6.9% 9.8% 21.8% 19.6%
0.38% 1.16% 0.76% 0.98%
FPV HIVIL-4C118/VVHIVIL-4C118
Spleen
Genito-rectal nodes
FPV HIV/VV HIV FPV HIVIL-4C118/VV HIV
CD8
Kd
-Gag
Inclusion of the inhibitor in the i.n. rFPV priming vaccination is crucial to induce high avidity CD8 T cell repertoire
FPV HIV/VV HIVIL-4C118
Jackson Worley Trivedi Ranasinghe (submitted)
( i)
FP
V H
IV∆
10/ V
V H
IV∆
10(i
i) F
PV
HIV
VV
HIV
Spleen Iliac nodes Lung Lung nodes
Ranasinghe Mucosal Immunology 2013
Novel vaccines can enhance both systemic & mucosal HIV-specific poly-functional HIV-specific CD8 T cell immunity
8Jackson Worley Trivedi Ranasinghe (submitted)Ranasinghe et al Mucosal Immunology 2013;
i.n./i.m. IL-4R antagonist adjuvanted HIV vaccine strategy induces excellent CD8 T cell mediated protective immunity
* * *
P < 0.05 compared to control vaccination
* 0.0567
i.n./i.m. IL-4R antagonist adjuvanted vaccine strategy can induce Gag-specific antibody class switching
Statistics were calculated using Mann – Whitney U test
* 0.0256*** 0.0006* 0.0566
* 0.0256
6 weeks 12 weeks
IgG1
IgG2a
9Jackson Worley Trivedi Ranasinghe (submitted)
10Ranasinghe et al Mucosal Immunology 2013 ; Trivedi Jackson Ranasinghe (Submitted)
100 101 102 103 104
cd103 FITC-A
DC_1 fpv balbc.fcs
100 101 102 103 104
cd103 FITC-A
DC_1 fpv balbc.fcs
100 101 102 103 104
cd103 FITC-A
DC_3 fpv c118.fcs
100 101 102 103 104
cd103 FITC-A
DC_3 fpv c118.fcs
CD
11b
CD103
FPV-HIV - unadjuvanted FPV-HIV IL-4RC118 (IL-4R antagonist)
73.5%
1.03%
45.1%
1.92%
i.n. delivery of FPV-HIV IL-4R antagonist adjuvanted vaccine recruits unique antigen presenting cells to the lung mucosae responsible for
the induction of high avidity CD8 T and excellent B cell immunity
CD11C+ CD11b+ CD103-
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Unique features of the novel i.n./i.m. HIV IL-4R antagonist adjuvanted vaccine strategy.
Help recruit unique antigen presenting cell subsets to the lung mucosae
Induce enhanced high quality/avidity mucosal & systemic HIV Gag-specific CD8 T cell immunity*
HIV Gag-specific antibody class switching (IgG1 and IgG2a)* Env-specific IgG1 following a second i.m. Env protein booster**
Induce triple action immunity
The immune responses induced are consistent with • HIV controllers* and • Features of partial protective efficacy in the RV144 trial**
=> Platform technology against other chronic pathogens
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Acknowledgements
Molecular Mucosal Vaccine Immunology Group:Ronald JacksonAnnette BuchananLisa Pavlinovic, Megan Glidden, Sherry Tu
Students: Danushka Wijsundara, Shubhanshi
Trivedi, Matthew Worley
ANU/BRF - Kerong Zhang
JCSMR/MCRF - Harpreet Vohra, Mick Devoy
ANU/Animal services staffCollaborators:
David Boyle - CSIRO AAHL
John Stambas - Deakin Uni/ CSIRO AAHL
Robert Center - Burnet Institute/ Uni of Melbourne