Immunosuppressive Cells in Newborns Play Important Role in Controlling Inflammation in Early Life

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PHILADELPHIA — (Jan. 15, 2018) — New research led by The Wistar Institute, in collaboration with Sun Yat-sen University in China, has characterized the transitory presence of myeloid-derived suppressor cells (MDSCs) in mouse and human newborns, revealing a critical role of these cells in regulation of inflammation in the early stages of life. This study was published online in Nature Medicine.

MDSCs are immature myeloid cells with the ability to suppress immune responses. In healthy adults, these cells are rarely detected but accumulate during certain pathological conditions, altering the immune response to cancer and chronic infection and promoting tumor progression.  

Our research sheds light on the function of MDSCs in newborns, suggesting that they are critical for the regulation of inflammation during the first weeks of life,” said Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and program leader of the Immunology, Microenvironment and Metastasis Program at Wistar. “We also revealed a physiological role of MDSCs expansion, which was widely considered to be driven by pathological conditions or pregnancy, broadening the importance of MDSCs in the immune system.”

Gabrilovich and colleagues compared the proportion of MDSCs in newborn, adult and postpartum mice. Those that were three to 10 days old had substantially higher numbers of these cells with a potent immunosuppressive ability and the proportion gradually decreased to levels comparable to those in adult mice by the end of the second week of life.

Analyzing the transcription profile of MDSCs from newborn mice, the team observed increased expression of genes that are critical for the immunosuppressive functions of these cells. Mechanistically, they demonstrated that the accumulation of MDSCs is linked with milk feeding, as it depends on lactoferrin, a milk component with potent immunoregulatory activity, which can induce upregulation of these genes.

The researchers also found that MDSCs are important for the control of inflammation in newborns. In fact, human newborns with normal birth weight had significantly higher proportion of MDSCs and higher immunosuppressive activity compared with adults as well as infants with low birth weight. These infants are at a higher risk for development of pathological inflammatory conditions, such as necrotizing enterocolitis, a condition that causes inflammation of the intestine and may put the infant at risk for developing potentially life-threatening infections.

 

“Our findings demonstrate that MDSCs reduce inflammation and increase survival in a model of necrotizing enterocolitis, thus suggesting that MDSCs not only can be present in healthy individuals but also could be an important protection mechanism evolved in response to the microbial colonization of the gut that takes place during the first days of life,” said Gabrilovich.

“Based on our data, MDSCs may be used as a potential therapeutic target for treating necrotizing enterocolitis and other inflammatory conditions in infants,” said Michela Perego, Ph.D., an associate staff scientist in the Gabrilovich Lab and co-first author of the study. “Our finding that accumulation of MDSCs depends on lactoferrin may also provide a rationale as to why feeding infants human milk versus formula has been shown to reduce the risk of necrotizing enterocolitis.”

This work was supported by National Institutes of Health grant R01 CA165065. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30 CA010815. The work was also supported by the Recruitment Program for Foreign Experts (Thousand Talents Plan), the Start-up Fund for High-level Talents of Sun Yat-sen University, and the Leading Talents of Guangdong Province Program. Other funding included the Introduction of Innovative R&D Team Program of Guangdong Province, the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme, the National Natural Science Foundation of China, and the Provincial Talents Cultivated by the ‘Thousand- Hundred-Ten’ Program of Guangdong Province.

Jie Zhou from Sun Yat-sen University, China, is co-lead author of this study. Yu-Mei He and Xing Li from Sun Yat-sen University and Michela Perego from The Wistar Institute contributed equally to this work as co-first authors. Other co-authors from Wistar include Yulia Nefedova and Andrew V Kossenkov. Other co-authors include Erik A. Jensen from Children’s Hospital of Philadelphia, Valerian Kagan from University of Pittsburgh, Yu-Feng Liu, Shu-Yu Fu, Qing-Jian Ye, and Lai Wei from Sun Yat-sen University, and Yan-Hong Zhou from Guangzhou Women and Children’s Medical Center, China. 

 

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

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