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The Effects of Caffeine and Phosphodiesterase Inhibitors on the Activation of Neonatal T Lymphocytes

Presented at the Neonatal Society 2017 Summer Meeting.

Orbán C, Vásárhelyi Z, Bajnok A, Toldi G

Neonatal Unit, Birmingham Women’s Hospital, Birmingham, UK
First Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary

Background: Caffeine and selective PDE inhibitors are widely used in the clinical management of preterm and term neonates. However, little is known about how these compounds interact with the neonatal adaptive immune system. We aimed to describe the effects of caffeine, milrinone and sildenafil on the activation and cytokine production of T cells from umbilical cord blood (UCB) compared to adult peripheral blood (APB). We hypothesized that these compounds do not have immunosuppressive effects on neonatal T cells.

Methods: We isolated mononuclear cells from 10 APB and 6 UCB samples. We assessed intracellular cytokine production (IFN-g, IL-2, IL-4, IL-6, IL-17) of stimulated CD4 cells and parameters of calcium influx (AUC and maximal cytoplasmic calcium level) in lymphocytes upon phytohemagglutinin (PHA) activation following treatment with caffeine (50 μM), milrinone (30 μM), sildenafil (30 μM), dbcAMP (100 μM) or a specific A2A receptor antagonist, ZM241385 (10 μM) using flow cytometry.

Results: ZM241385, but none of the other compounds increased parameters of calcium influx in APB samples. On the contrary, all compounds increased calcium influx in UCB. This effect was more pronounced in the case of caffeine and dbcAMP compared to milrinone, sildenafil or ZM241385. In line with data from the literature, intracellular levels of IFN-g in CD4 cells was lower in UCB compared to APB. The frequency of CD4+ IFN-g+ cells did not differ between the two groups. The frequency of CD4+ IL-2+ cells increased following treatment with sildenafil in UCB but not in APB. Intracellular levels of the studied cytokines were unaffected by the applied compounds in both APB and UCB samples.

Conclusion: Our results demonstrate that neonatal T cells show sensitivity to caffeine and selective PDE inhibitors in contrast with adult T cells. Caffeine increases short-term activation in neonatal lymphocytes to a larger extent than milrinone or sildenafil. This effect appears to be mediated primarily via increased cAMP levels rather than A2A receptor inhibition. However, cytokine production of neonatal CD4 cells remains relatively unaffected. Sildenafil may contribute to an increase in the number of IL-2-producing neonatal CD4 cells. Overall, the application of caffeine, sildenafil or milrinone does not appear to have immunosuppressive effects on neonatal T cells based on our findings.

Corresponding author: toldigergely@yahoo.com

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