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Blocking T-cell egress with FTY720 extends DNA vaccine expression but reduces immunogenicity. | LitMetric

AI Article Synopsis

  • Nucleic acid vaccines need a careful balance in antigen expression to engage the immune system without triggering a response that destroys the cells producing the antigen.
  • Researchers studied how the immune response affects DNA vaccine expression by using a luciferase-expressing plasmid, finding that repeated doses led to reduced antigen expression due to immune clearance.
  • Blocking lymphocyte movement with a drug (FTY720) maintained DNA transgene expression longer but did not boost the immune response, showing that for effective immunity, the immune response needs access to the expression site despite the potential negative effects on antigen production.

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9426614PMC
http://dx.doi.org/10.1111/imm.13429DOI Listing

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