One form of vitamin D significantly reduced a dangerous inflammatory response associated with leukemia in laboratory tests, according to research by scientists at the University of Debrecen. The findings could eventually contribute to the development of new supportive treatments, but vitamin D cannot currently replace the life-saving steroid therapy used to treat the condition. The researchers reported their findings in a prestigious international biomedical journal, and their study was recognized with the Publication Award of the University of Debrecen and the Gróf Tisza István Foundation for the University of Debrecen.
The research focused on acute promyelocytic leukemia (APL), a rare type of blood cancer. In APL, the development of certain white blood cells becomes arrested at an immature stage, preventing them from properly performing their defensive functions.
One of the highly effective treatments for the disease is all-trans retinoic acid (ATRA), a derivative of vitamin A that stimulates these cells to mature. However, the treatment can also trigger a serious inflammatory complication known as differentiation syndrome. This can cause fever, edema, breathing difficulties, a drop in blood pressure, and impaired function of several organs.
“We investigated whether 25-hydroxyvitamin D₃, the circulating form of vitamin D₃ in the blood, also known as calcidiol and the form measured when determining vitamin D levels, could reduce this excessive inflammatory response,” explained Károly Jambrovics, assistant professor at the Institute of Biochemistry and Molecular Biology of the Faculty of General Medicine at the University of Debrecen.
Jambrovics Károly added that their previous research had shown that ATRA treatment causes large amounts of a protein called transglutaminase 2 (TG2) to appear in leukemia cells. TG2 amplifies a cellular system known as NF-κB, which can be thought of as a major “master switch” for inflammation. Once activated, the cells can produce large quantities of inflammatory signaling molecules. While these normally help the body defend itself, excessive production can lead to a “cytokine storm” that damages the body’s own tissues.
When differentiation syndrome is suspected, patients receive high-dose anti-inflammatory steroid treatment. This is currently an essential and potentially life-saving therapy. At the same time, vitamin D’s role in regulating the immune system has received considerably less attention in this area, despite the fact that, according to Hungarian professional consensus, vitamin D deficiency is extremely common in Hungary, particularly toward the end of winter. The researchers therefore wanted to determine whether calcidiol could suppress the inflammation amplified by TG2.
“ATRA strongly activated the NF-κB inflammatory master switch, while calcidiol significantly reduced its activity depending on the amount used. Under laboratory conditions, the highest concentration tested resulted in an approximately 90 percent reduction. Calcidiol also reduced the amount of the inflammation-promoting TG2 protein and decreased the production of several inflammatory substances. In addition, it strengthened the cells’ own anti-inflammatory defense system. We observed the same inflammation-reducing effect when examining white blood cells obtained from healthy blood donors,” the University of Debrecen researcher said.
The researchers studied human APL-derived cells that could be maintained in laboratory conditions. They also used cell variants in which TG2 production had been reduced or completely eliminated. This allowed them to directly compare what happens in the presence and absence of TG2. The specific research project lasted approximately five years, while the researchers have been investigating the role of TG2 in APL since 2006.
The findings could have practical applications in medicine in the longer term, but vitamin D cannot currently replace the life-saving steroid treatment used for differentiation syndrome. The research group’s findings were presented in an article published in a prestigious scientific journal, which received the Publication Award of the University of Debrecen and the Gróf Tisza István Foundation for the University of Debrecen.
“Our findings suggest a possible complementary approach: it would be worth investigating whether patients’ vitamin D levels at the time of diagnosis are associated with the development or severity of the complication, and whether correcting a deficiency could reduce the inflammatory response. In addition to successful experiments, the research involved many dead ends, redesigns and checks. The publication is the result of many years of collaborative work. It means a great deal that the University of Debrecen and the Gróf Tisza István Foundation for the University of Debrecen have recognized this achievement. It is confirmation that basic research has value: any future targeted treatment can only be built on a precise understanding of how the disease works at the cellular level,” the University of Debrecen researcher said.
Researchers from several institutes of the University of Debrecen participated in the study. As first author, Károly Jambrovics was involved in conducting the experiments, analyzing the data and writing the manuscript. The research program was designed and led 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 participated in work involving clinical samples.
Károly Jambrovics is currently preparing an independent line of research. He is investigating whether transglutaminase also amplifies inflammation in lung epithelial cells — the cells lining the airways and among the first to encounter pathogens — for example during viral infections. The researchers plan to use human lung cell models to examine how the inflammatory response changes in the presence of transglutaminase. In the longer term, they aim to determine whether this enzyme could represent a common link between infections, excessive immune responses and certain inflammatory lung diseases.
(unideb.hu)
