Abstract
All-trans retinoic acid (ATRA) up-regulates, in laboratory animals, the expression of the gut homing markers α4β7 integrin and CCR9 on lymphocytes, increasing their gut tropism. Here, we show that, in healthy adult volunteers, ATRA induced an increase of these gut homing markers on T cells in vivo in a time dependent manner. The coordinated increase of α4β7 and CCR9 by ATRA was seen in 57% (12/21) of volunteers and only when given together with an oral Vivotif vaccine. When this coordinated response to ATRA and Vivotif vaccine was present, it was strongly correlated with the gut immunoglobulin A (IgA) specific response to vaccine LPS (ρ = 0.82; P = 0.02). Using RNA-Seq analysis of whole blood transcription, patients receiving ATRA and Vivotif in conjunction showed transcriptomic changes in immune-related pathways, particularly including interferon α/β signaling pathway, membrane-ECM interactions and immune hubs. These results suggest that exogenous ATRA can be used to manipulate responses to a subclass of oral vaccines, so far limited to a live attenuated Vivotif vaccine.
Highlights
There is strong evidence of diminished immunogenicity and efficacy of oral vaccines in developing country populations [1]
The present study investigated whether the all-trans retinoic acid (RA) (ATRA) adjuvanticity seen with Vivotif vaccine in African men could be generalized to other oral vaccines
The global burden of diarrheal disease and the reduced efficacy of oral vaccines in populations from developing nations have highlighted the need for new strategies for vaccination against
Summary
There is strong evidence of diminished immunogenicity and efficacy of oral vaccines in developing country populations [1]. In recent preliminary work [14], we found that ATRA could enhance gut IgA responses to Vivotif typhoid vaccine in intestinal washes These observations suggest that RA-assisted immunization generates intestinal immunity and confers the benefits of mucosal protection. Retinoic acid has been known to affect expression of the polymeric immunoglobulin receptor (pIgR) [15] which transports polymeric immunoglobulin A (pIgA) into external secretions as secretory IgA (S-IgA) This suggests that vitamin A might be required for the proper regulation of IgA transport in response to mucosal infection, which would be a desirable characteristic of an orally-active adjuvant [16,17]. We asked if ATRA given alongside oral vaccines could improve the immune response by enhancing expression of a4b7-integrin and CCR9 gut homing molecules, and if so, under what circumstances
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