Potent induction of trained immunity by Saccharomyces cerevisiae ß-glucans.

Candida albicans cell wall component ß-glucan has been extensively studied for its ability to induce epigenetic and functional reprogramming of innate immune cells, a process termed trained immunity. We show that a high-complexity blend of two individual ß-glucans from Saccharomyces cerevisiae possesses strong bioactivity, resulting in an enhanced trained innate immune response by human primary monocytes. The training required the Dectin-1/CR3, TLR4, and MMR receptors, as well as the Raf-1, Syk, and PI3K downstream signaling molecules. By activating multiple receptors and downstream signaling pathways, the components of this ß-glucan preparation are able to act synergistically, causing a robust secondary response upon an unrelated challenge. In in-vivo murine models of melanoma and bladder cell carcinoma, pre-treatment of mice with the ß-glucan preparation led to a significant reduction in tumor growth. These insights may aid in the development of future therapies based on ß-glucan structures that induce an effective trained immunity response.

MMR vaccination induces trained immunity via functional and metabolic reprogramming of γδ T cells.

The measles, mumps, and rubella (MMR) vaccine protects against all-cause mortality in children, but the immunological mechanisms mediating these effects are poorly known. We systematically investigated whether MMR can induce long-term functional changes in innate immune cells, a process termed trained immunity, that could at least partially mediate this heterologous protection. In a randomized, placebo-controlled trial, 39 healthy adults received either the MMR vaccine or a placebo. Using single-cell RNA-Seq, we found that MMR caused transcriptomic changes in CD14+ monocytes and NK cells, but most profoundly in γδ T cells. Monocyte function was not altered by MMR vaccination. In contrast, the function of γδ T cells was markedly enhanced by MMR vaccination, with higher production of TNF and IFN-γ, as well as upregulation of cellular metabolic pathways. In conclusion, we describe a trained immunity program characterized by modulation of γδ T cell function induced by MMR vaccination.

Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.

Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 µg/mL, while C5-eculizumab levels were 22 and 26 µg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 µg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 µg/g, and of C5 20 ± 3 and 30 ± 2 µg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.