Retinoic acid elicits a coordinated expression of gut homing markers on T lymphocytes of Zambian men receiving oral Vivotif, but not Rotarix, Dukoral or OPVERO vaccines.

All-trans retinoic acid (ATRA) up-regulates, in laboratory animals, the expression of the gut homing markers α4ß7 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 α4ß7 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/ß 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.

Potential for use of retinoic acid as an oral vaccine adjuvant.

Despite the heavy burden of diarrhoeal disease across much of the tropical world, only two diarrhoea-causing pathogens, cholera and rotavirus, are the target of commercially available vaccines. Oral vaccines are generally less immunogenic than the best parenteral vaccines, but the reasons for this are still debated. Over the past decade, several lines of evidence from work in experimental animals have suggested that all-trans retinoic acid (ATRA), a form of vitamin A which is highly transcriptionally active, can alter the homing receptor expression of T lymphocytes. Increased expression of α4ß7 integrin and the chemokine receptor CCR9 following exposure to ATRA can be used to redirect T cells to the gut. Early work in human volunteers suggests that oral ATRA administration 1 h prior to dosing with oral typhoid vaccine can augment secretion of specific IgA against vaccine-derived lipopolysaccharide into gut secretions. In this review, we set out the rationale for using ATRA in this way and assess its likely applicability to vaccination programmes for protection of children in low-income countries from the considerable mortality caused by diarrhoeal disease. Comparison of recent work in experimental animals, non-human primates and men suggests that a more detailed understanding of ATRA dosage and kinetics will be important to taking forward translational work into human vaccinology.

Gastric cancer in Zambian adults: a prospective case-control study that assessed dietary intake and antioxidant status by using urinary isoprostane excretion.

BACKGROUND: Gastric cancer is increasingly recognized in Zambia. Although nutritional factors contribute to gastric cancer risk, their effect in Zambia is unknown. OBJECTIVE: The objective was to investigate the association between intake of dietary antioxidants, urinary 8-iso prostaglandin F2α (8-iso PGF2α) as a marker of oxidative stress, and gastric cancer. DESIGN: This was a case-control study at the University Teaching Hospital in Zambia. Gastric cancer cases were compared with age- and sex-matched controls. Urine 8-iso PGF2α was measured primarily by ELISA, and by gas chromatography-mass spectrometry in a subset, expressed as a ratio to creatinine. Blood was collected for Helicobacter pylori, HIV serology, gastrin-17, and pepsinogen 1 and 2 concentrations. Clinical and dietary data were collected by using questionnaires. Food items were broadly classified into 7 major categories (fruit, vegetables, fish, meat, insects, cereals, and starches). RESULTS: Fifty cases with gastric cancer (mean age: 61 y; n = 31 males) and 90 controls (mean age: 54 y; n = 41 males) were enrolled. Median urinary 8-iso PGF2α excretion was higher in cases (0.014; IQR: 0.008-0.021) than in controls (0.011; IQR: 0.006-0.018; P = 0.039). On univariate analysis, habitual fruit intake was lower in cases than in controls during the dry season (P = 0.02). On multivariate analysis, smoking (OR: 7.22; IQR: 1.38-37.9) and gastric atrophy (OR: 2.43; IQR: 1.12-5.13) were independently associated with cancer, and higher fruit intake was protective (OR: 0.44; IQR: 0.20-0.95). Isoprostane excretion was inversely correlated with total fruit intake (ρ = -0.23; n = 140; P = 0.006). CONCLUSION: Urinary 8-iso PGF2α excretion was associated with the risk of gastric cancer, as were smoking and gastric atrophy, but increased fruit intake conferred protection. This trial was registered at www.pactr.org as ISRCTN52971746.