Stürner, K.H.K.H.StürnerStellmann, J.-P.J.-P.StellmannDörr, J.-M.J.-M.DörrPaul, F.F.PaulKeminer, O.O.KeminerVaas, L.L.VaasPless, O.O.PlessMartin, R.R.MartinHeesen, C.C.Heesen2022-03-052022-03-052016https://publica.fraunhofer.de/handle/publica/250175Background: Boswellic Acids (BAs), the main biologically active compound of frankincense (Boswellia ssp.), are orally available and have exhibited a safe and favourable side effect profile for the treatment of relapsing-remitting Multiple Sclerosis (RR-MS) in an open-label, two-center, baseline-to-treatment phase IIa trial. Effects on the primary MRI outcome and secondary clinical outcome parameters strongly suggest a positive influence on disease activity in RR-MS patients. BAs are known to exhibit anti-inflammatory activities, however, their immunological effect/s in RR-MS patients are not fully understood. Methods: In parallel to the phase IIa study with a standardized frankincense extract (produced by Alpinia Laudanum, Switzerland, and containing BAs as active ingredient) we performed an immunological substudy in n = 28 BA-treated RR-MS patients, who completed the study. Multicolour flow cytometric analysis was performed longitudinally ex vivo in n = 26 patients at three time points before, during early and during late treatment, respectively. Cytokine levels for interleukin(IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, tumor necrosis factor-alpha, interferon-gamma and transforming growth factor-beta in serum were measured at the same time points in n = 28 patients by highly sensitive single or multiplex analysis (MesoScale; Singulex) after all patients had completed the study. Results: We observed distinct alterations in CD3+ T cell subpopulations in our BA-treated patient cohort: While in the CD4+ T cell subset CTLA-4 expression and the percentage of CD4+CD25high Foxp3+ T cells increased significantly during treatment (p < 0.01), we found a significant decrease in the percentage of IL17-producing CD8+T cells coinciding with an increase in IL10-producing CD8+ T cells (p < 0.01). The analysis of other leucocyte and lymphocyte subpopulations, i.e. monocytes, B cells, natural killer cells and dendritic cells showed no alterations before and after BA-treatment. White blood cell counts and lymphocyte counts in general remained unaltered throughout the whole study. In regard to cytokine levels in serum, we observed significant decreases in IL-17A, GM-CSF and IL-2 during BA-treatment (p < 0.05). Conclusions: Treatment with boswellic acids in a phase IIa clinical trial leads to immunomodulatory effects on T cell subsets consistent with the inhibition of inflammatory disease activity as shown by MRI and clinical outcomes.en616journal article