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Researchers have discovered an endogenous molecule that in animal studies makes the immune system in the intestine and the intestinal flora more balanced and reduces severe side effects of stem cell transplants / confirmation in human samples

Stem cell transplants are an increasingly common treatment option for blood cancer. However, around 20 percent of those affected experience severe side effects. In acute graft-versus-host disease (aGVHD), the donor's immune system attacks the recipient's cells, which can lead to inflammation and damage in organs such as the skin, liver and intestines. The body's own molecule Lipocalin-2, LCN2 for short, significantly reduces these side effects, also by altering the immune system in the intestine and the intestinal flora. This has now been shown by researchers from the Faculty of Medicine - University of Freiburg, the Max Planck Institute of Immunobiology and Epigenetics Freiburg and the Technical University of Munich based on animal studies and the analysis of patient samples. The study was published on February 21, 2024 in the journal Science Translational Medicine.

"We were able to slow down the excessive immune response in the intestine and promote protective intestinal flora. A corresponding therapy could make stem cell transplants significantly safer," says study leader Prof. Dr. Robert Zeiser, Head of the Department of Tumor Immunology and Immune Regulation at the Department of Medicine I at the Medical Center - University of Freiburg. Zeiser is the spokesperson for the Collaborative Research Center 1479 OncoEscape and conducts research at the Cluster of Excellence Centre for Integrative Biological Signalling Studies (CIBSS) at the University of Freiburg. His research has been funded by an ERC Advanced Grant since 2023. "We were able to decipher the mechanism in the animal model and then confirm it in patient samples. This is an important step towards further clinical studies," says Zeiser.

Patient samples provide important clinical confirmation

In the mouse model, the researchers found that certain immune-regulating cells release LCN2 and thereby dampen the activity of macrophages and other immune cells in the intestine. The team of Prof. Dr. Dominic Grün, also a participating scientist and at the time of the research project working group leader at the Max Planck Institute of Immunobiology and Epigenetics, had analyzed various immune cells in the intestine using single-cell RNA sequencing and thus helped to identify LCN2. The scientists also observed that LCN2 changes the intestinal flora from more harmful bacterial strains to more beneficial bacterial strains. This also resulted in fewer side effects in the animals.

In evaluations of more than 100 patient samples, the researchers were able to confirm that high LCN2 concentrations in the blood are associated with a more severe course of GVHD. A lot of LCN2 was also produced in the intestines of GvHD patients. "We understand this as a modulating reaction of the body to the immune response," says the third study leader Prof. Dr. Romana Gerner from the Technical University of Munich. "The results are very promising. Now we want to investigate the mechanisms and effectiveness of LCN2 in more detail in further clinical studies," adds Zeiser.

Original title of the publication: Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease

DOI: 10.1126/scitranslmed.adi1501

Link to the study: https: //pubmed.ncbi.nlm.nih.gov/38381845/