Stem cell transplants are a steadily growing therapy option for the treatment of blood cancer. Severe side effects appear in around 20 percent of treated patients, though. During the acute graft-versus-host disease (aGVHD), the immune system of the donator attacks the cells of the recipient, which can lead to inflammation und damage to skin, liver, or intestinal tissue. The endogenous molecule Lipocalin-2, in short LCN2, reduces these side effects significantly, also by changing the intestinal immune system and flora. This is now shown by researchers of the Medical Center of the University of Freiburg, the Max Planck Institute of Immunobiology and Epigenetics Freiburg and the Technical University of Munich with animal studies and reviewing patient samples. The study appeared on February 21, 2024, in the journal ScienceTranslational Medicine.
A molecule produced naturally in the body could make leukemia therapy safer
In animal studies it reduces severe side effects of stem cell transplants / confirmed in human samples
“We could slow down the overshooting immune reaction in the intestine and promote a protective intestinal flora. An according therapy could make stem cell transplants far safer,” says lead investigator Prof. Dr. Robert Zeiser, head of the Department of Tumor Immunology and Immunoregulation of the Clinic for Internal Medicine I at the Medical Center of the University of Freiburg. Zeiser is speaker of the special research area 1479 OncoEscape and works at the Excellence Cluster Centre for Integrative Biological Signalling Studies (CIBSS) of the University of Freiburg. Since 2023, his research is funded by the ERC Advanced Grant. “We could decode the mechanism in animal models and subsequently confirm it in patient samples. It is a crucial step in the direction of further clinical studies,” according to Zeiser.
Patient samples provide important clinical confirmation
The researchers determined in the mouse model that certain immunoregulatory cells release LCN2, leading to suppressed activity in phagocytes, so-called macrophages, and other gut immune cells. The team of Prof. Dr. Dominic Grün, another researcher involved in the project, and, at the time, group leader at the Max Planck Institute for Immunobiology and Epigenetics, contributed to the identification of LCN2 through the analysis of various intestinal immune cells with single cell RNA sequencing. The researchers also observed that LCN2 changes the intestinal flora from harmful bacterial strains to those with more positive effects. This also led to less side effects in animals.
With the evaluation of more than a hundred patient samples, researchers could confirm that high blood concentrations of LCN2 accompanied severe GVHD courses. The intestines of patients with GVHD also produced high levels of LCN2. “We understand this as a modulatory reaction of the body to the immune system activity,” says the third study leader Prof. Dr. Romana Gerner of the Technical University of Munich. “The results are promising. We now want to investigate the mechanisms and effectiveness of LCN2 in further studies in more depth,” adds Zeiser.
Original publication
Marie Czech et al. (2024) Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease.In: Sci. Transl. Med. DOI: 10.1126/scitranslmed.adi1501
CIBSS profile of Prof. Dr. Robert Zeiser
CIBSS profile of Dr. Dominic Grün