A study coordinated by the Tettamanti Foundation, in collaboration with Sapienza University of Rome and other Italian research centres, discovered that the interaction between two proteins might be crucial in counteracting one of the most frequent complications caused by the transplantation of haematopoietic stem cells (those capable of generating all other blood cells) from a donor. An invaluable tool for fighting blood cancers, the transplant causes GvHD, Graft-versus-Host Disease, which induces inflammation and damage in the tissues of the intestine in around 60% of patients.

At the centre of the study are chemerin and its receptor, another protein referred to as CMKLR1, present on the surface of certain leucocytes, including macrophages, which are frontline cells in the defence against pathogens and are essential for eliminating 'waste' present in damaged tissues. It was observed that CMKLR1 interacting with chemerin promotes the protective action of macrophages in the inflamed and damaged intestines due to GvHD.

The study, conducted in animal models and observing the plasma of 71 stem cell transplant patients, has been published in the international scientific journal JCI -The Journal of Clinical Investigation - Insight. If demonstrated in a larger group of patients, the observed results may confirm the role of the chemerin/CMKLR1 system in controlling intestinal inflammation.

"Our study shows, for the first time, an important involvement of the chemerin/ CMKLR1 axis in the modulation of inflammation accompanying intestinal GvHD and the important protective role played by macrophages through the expression of the CMKLR1 receptor", says Giovanna D'Amico, a researcher at the Tettamanti Foundation and the study's last author. "Our finding highlights the importance of the chemerin/CMKLR1 system as a possible mechanism to be exploited therapeutically to increase the presence of macrophages, with protective action, in the intestines, in order to reduce intestinal damage and protect patients from GvHD. Furthermore, we showed how increased blood concentrations of chemerin in transplanted patients precede the onset of GVHD. Chemerin could thus act as an early predictive biomarker of the onset of this complication, allowing for the timely initiation of a tailored therapy".

Giovanna D'amico and Erica Dander, researchers at the Tettamanti Foundation, coordinated the research in collaboration with the Paediatrics Department of the IRCCS San Gerardo dei Tintori Foundation in Monza, the team of Professor Silvano Sozzani of Sapienza University of Rome, Humanitas Clinical and Research Centre, Humanitas University, Unimi Foundation, the University of Milan, University of Milan Bicocca, University of Brescia, the Haematology Division and the Bone Marrow Unit of San Gerardo dei Tintori in Monza.

As a first step, the team studied the outcomes of allogeneic transplantation in experimental mouse models. This revealed a marked increase in chemerin concentration in the plasma and tissue of animals that developed acute GvHD.

Secondly, the authors used genetically modified mice lacking the CMKLR1 receptor (knock-out mice for the CMKLR1 gene) as cell donors for allogeneic transplantation. These experiments showed that mice transplanted with cells lacking this receptor developed more severe GvHD and had a reduced survival compared to those transplanted with normal cells. The GvHD that developed in mice lacking CMKLR1 mainly affected the intestine and was characterised by severe inflammation, destruction of the intestinal barrier and consequent penetration of intestinal flora bacteria into the tissues.

In terms of worsening the intestinal inflammation picture, a similar result was obtained in another experimental model, i.e. mice that did not express the chemerin receptor in which the researchers induced the development of colitis.

The administration of macrophage precursors capable of expressing CMKLR1 caused a reduction in the severity of GvHD and associated intestinal inflammation. Confirmation of the important protective action of macrophages came from the lack of improvement observed following the transfer of other immune cells that share the ability to express the receptor with macrophages.

Finally, the authors analysed the plasma of 71 patients undergoing allogeneic stem cell transplantation and found that only subjects who had developed GvHD showed an increase in circulating levels of chemerin. This result thus highlighted the predictive role of chemerin levels for the development of GvHD. In other words, finding increased chemerin values in a patient could be a telltale sign for the physician of the possibility of GvHD occurring in the patient, thus enabling early diagnosis and timely personalised treatment.

GvHD, Graft-versus-Host Disease, is a disease in which the transplant donor's cells recognise the recipient's cells as foreign and start attacking them, destroying tissues and organs, to the point of causing the death of the patient in the most severe cases. In particular, intestinal GvHD is one of the most frequent complications (it affects up to 60% of patients) of allogeneic transplantation and is one of the main causes of mortality related to this procedure.

Early diagnosis of GvHD is also tricky since many of its manifestations are indistinguishable from those common to other gastrointestinal disorders. The disease is commonly treated in the first instance with steroids, which in addition to not always being effective, have significant side effects, such as increased risk of infection and relapse of the cancerous disease. There are currently no well-studied second-line therapies in case steroids are ineffective.

For these reasons, it is important both to identify biomarkers that can set off alarm bells that warn of the risk of developing GvHD at an early stage and to direct therapy towards new therapeutic targets. 

References: 

The chemerin/CMKLR1 axis regulates intestinal graft-versus-host disease - Erica Dander, Paola Vinci, Stefania Vetrano, Camilla Recordati, Rocco Piazza,Grazia Fazio,Donatella Bardelli, Mattia Bugatti, Francesca Sozio, Andrea Piontini, Sonia Bonanomi, Luca Bertola, Elena Tassistro, Maria Grazia Valsecchi, Stefano Calza, William Vermi, Andrea Biondi, Annalisa Del Prete, Silvano Sozzani,and Giovanna D’Amico - JCI Insight. 2023 Mar 8;8(5):e154440. doi: 10.1172/jci.insight.154440.

Further Information 

Silvano Sozzani
Department of Molecular Medicine
silvano.sozzani@uniroma1.it