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The research focused on a rare hematologic cancer, acute promyelocytic leukemia (APL). In APL, the development of certain white blood cells stalls at an immature stage, preventing them from properly performing their defensive functions.
- One of the most effective treatments for this disease is all-trans retinoic acid (ATRA), derived from vitamin A, which induces the maturation of these cells. However, the treatment can also trigger a severe inflammatory complication known as differentiation syndrome. This can be accompanied by fever, edema, difficulty breathing, a drop in blood pressure, and dysfunction of multiple organs. We investigated whether the circulating form of vitamin D₃ in the blood, 25-hydroxy-D₃ —also known as calcidiol, which is measured when determining vitamin D levels—is capable of moderating this excessive inflammatory response- explained Károly Jambrovics, assistant professor at the Institute of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen.
Károly Jambrovics added that their previous research had shown that, as a result of ATRA treatment, large amounts of a protein called transglutaminase 2 (TG2) appear in leukemic cells. TG2 activates the intracellular NF-κB pathway, which can be thought of as one of the main switches for inflammation. Once activated, the cells produce large amounts of inflammatory mediators. While these normally aid the body’s defenses, their excessive production can lead to a “cytokine storm” that damages the body’s own tissues. When differentiation syndrome is suspected, patients are given high doses of steroid anti-inflammatory drugs. This is currently an indispensable and even life-saving treatment. At the same time, the immune-regulating effect of vitamin D is much less prominent in this area, even though, according to the Hungarian professional consensus, vitamin D deficiency is extremely common in Hungary, especially at the end of winter. Therefore, the researchers wanted to know whether calcidiol could curb the inflammation amplified by TG2.
- ATRA strongly activated the NF-κB inflammatory master switch, whereas calcidiol significantly reduced its activity, depending on the dose used. The highest concentration tested resulted in a reduction of approximately 90 percent under laboratory conditions. Calcidiol reduced the levels of the pro-inflammatory TG2 protein and moderated the production of several pro-inflammatory substances. In addition, it strengthened the cells’ own anti-inflammatory defense system. “We observed the same anti-inflammatory effect when examining white blood cells from healthy blood donors- said the researcher from the University of Debrecen.
The results may have practical applications in medical treatment in the long term, but vitamin D cannot currently replace the life-saving steroid treatment for differentiation syndrome. The research team presented its findings in an article published in a prestigious scientific journal, which won the Publication Award from the University of Debrecen and the Count István Tisza Foundation for the University of Debrecen.
- Our findings suggest a possible complementary approach: it would be worthwhile to investigate whether baseline vitamin D levels in patients with APL are associated with the development or severity of complications, and whether correcting the deficiency could mitigate the inflammatory response. In addition to successful experiments, the research involved many dead ends, redesigns, and verifications; the paper is the result of many years of collaborative work. It is significant that the University of Debrecen and the Count István Tisza Foundation for the University of Debrecen have recognized this achievement. This confirms that basic research is valuable: any future targeted treatment can only be based on a precise understanding of the disease’s cellular mechanisms- stated the researcher from the University of Debrecen.
Staff members from several institutes at the University of Debrecen participated in the study. As the first author, Károly Jambrovics worked on conducting the experiments, analyzing the data, and writing the manuscript. The research program was designed and directed by Zoltán Balajthy; Wedean Al-Hadban, Anett Mázló-Türk, István Szatmári, and Gábor Koncz contributed to the laboratory work, while Boglárka Dobó, Gyula Reményi, and Ádám Jóna contributed to the clinical samples.
Károly Jambrovics is currently working on preparing an independent line of research. He is investigating whether transglutaminase also amplifies inflammation in the epithelial cells of the lungs—that is, the cells that line the airways from the inside and are the first to encounter pathogens—for example, during viral infections. They plan to use human lung cell models to investigate how the inflammatory response changes in the presence of transglutaminase. In the longer term, they are investigating whether this enzyme could be the common link between infections, excessive immune responses, and certain inflammatory lung diseases.
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