Blocking T-cell egress with FTY720 extends DNA vaccine expression but reduces immunogenicity
Author(s)
Type
Journal Article
Abstract
Optimal immunogenicity from nucleic acid vaccines requires a balance of antigen expression that effectively engages the host immune system without generating a cellular response that rapidly destroys cells producing the antigen and thereby limiting vaccine antigen expression. We investigated the role of the cellular response on the expression and antigenicity of DNA vaccines using a plasmid DNA construct expressing luciferase. Repeated intramuscular administration led to diminished luciferase expression, suggesting a role for immune-mediated clearance of expression. To investigate the role of cell trafficking, we used the sphingosine 1-phosphate receptor (S1PR) modulator, FTY720 (Fingolimod), which traps lymphocytes within the lymphoid tissues. When lymphocyte trafficking was blocked with FTY720, DNA transgene expression was maintained at a constant level for a significantly extended time period. Both continuous and staggered administration of FTY720 prolonged transgene expression. However, blocking lymphocyte egress during primary transgene administration did not result in an increase of transgene expression during secondary administration. Interestingly, there was a disconnect between transgene expression and immunogenicity, as increasing expression by this approach did not enhance the overall immune response. Furthermore, when FTY720 was administered alongside a DNA vaccine expressing the HIV gp140 envelope antigen, there was a significant reduction in both antigen-specific antibody and T-cell responses. This indicates that the developing antigen-specific cellular response clears DNA vaccine expression but requires access to the site of expression in order to develop an effective immune response.
Date Issued
2022-03
Date Acceptance
2021-09-24
ISSN
0019-2805
Publisher
Wiley
Start Page
301
End Page
311
Journal / Book Title
Immunology
Volume
165
Issue
3
Copyright Statement
© 2021 The Authors. Immunology published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Identifier
https://onlinelibrary.wiley.com/doi/10.1111/imm.13429
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000729281200001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
immunity
immunotherapy
infection
vaccine
virus
IMMUNE-RESPONSES
ANTIGEN-EXPRESSION
LYMPHOCYTES
PROTECTION
CHALLENGE
INFLUENZA
INFECTION
CHEMOKINE
EFFICACY
CD4(+)
immunity
immunotherapy
infection
vaccine
virus
Science & Technology
Life Sciences & Biomedicine
Immunology
immunity
immunotherapy
infection
vaccine
virus
IMMUNE-RESPONSES
ANTIGEN-EXPRESSION
LYMPHOCYTES
PROTECTION
CHALLENGE
INFLUENZA
INFECTION
CHEMOKINE
EFFICACY
CD4(+)
Immunology
1107 Immunology
1114 Paediatrics and Reproductive Medicine
Publication Status
Published
OA Location
https://onlinelibrary.wiley.com/doi/10.1111/imm.13429
Date Publish Online
2021-11-14