REVIEW ARTICLE Plasma-mediated immune suppression: a neonatal perspective Mirjam E. Belderbos 1,2 , Ofer Levy 3 , Linde Meyaard 2 & Louis Bont 2 1 University Medical Center Groningen, Groningen, The Netherlands; 2 University Medical Center, Utrecht, The Netherlands; 3 Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA To cite this article: Belderbos ME, Levy O, Meyaard L, Bont L. Plasma-mediated immune suppression: a neonatal perspective. Pediatr Allergy Immunol 2012: 00. Keywords plasma; immune suppression; neonate; immune regulation; soluble; serum Correspondence Mirjam E. Belderbos, University Medical Center Groningen, Groningen, The Netherlands. Tel.: +31 50 361 6161 Fax: +31 50 361 1704 E-mail: m.belderbos@umcutrecht.nl Accepted for publication 4 October 2012 DOI:10.1111/pai.12023 Abstract Plasma is a rich mixture of immune regulatory factors that shape immune cell function. This immunomodulatory role of plasma is especially important in neonates. To maintain in utero feto-maternal tolerance and to allow for microbial colonization after birth, the neonatal immune system is biased against pro-inflammatory responses while favoring immune suppression. Therefore, the neonatal period provides a unique opportunity to study the physiologic mechanisms regulating the immune system. Several recent studies in neonates have identified plasma factors that play a key role in immune regulation. Insight into immune regulation by neonatal and adult plasma may have clinical implications, because plasma is easily accessible, affordable, and widely available. Herein, we review plasma-mediated immune regulation, with specific focus on neonatal plasma. We discuss how immune suppression is a key function of plasma and provide a systematic overview of the published literature regarding plasma- derived immune suppressive proteins, lipids, purines, and sugars. Finally, we outline how immune regulation by these factors, which are particularly abundant in neonatal plasma, may eventually be used to treat immune-mediated diseases, such as autoimmune, allergic, and inflammatory diseases. Immune regulation by human plasma Human plasma is a rich mixture of soluble factors with immune regulatory potential. Immune regulation is a key property of plasma that may be understood in relation to its biologic function. Plasma is an essential transport medium, supplying oxygen and nutrients to all cells of the body and allowing for communication between distant cells or organ systems. During infection, plasma serves to transmit signals from the affected organ throughout the body, alerting it to danger and initiating its defense mechanisms. Communication through plasma has multiple advantages over cell–cell contact. First, production of soluble factors allows for one cell to rapidly reach multiple target cells localized throughout the body. Second, whereas cell–cell contact is hampered by biologic barriers, certain soluble factors, especially small lipophilic molecules, readily cross these barriers (1), thus providing a mechanism for immune signaling to shielded organs. Third, while cell–cell contact only transmits signals from a single cell to another, the presence in plasma of many factors produced by multiple organ systems provides a cell with a more integrated picture of the host condition, allowing it to tailor its immune response in more detail. Overall, plasma has the important task of rapidly distrib- uting the signals that initiate host defense mechanisms during infection. However, the ubiquitous presence of plasma and the highly toxic nature of many of these signals (2) render this a potentially dangerous task, which, if left unchecked, might result in lethal inflammation (2). Therefore, suppression of pro- inflammatory immune responses might be a key function of plasma, allowing for the transport of danger signals through- out the body, without causing systemic inflammation to the host. However, the immune regulatory factors in plasma and the mechanisms by which they regulate immune cell function are incompletely characterized. Herein, we provide a system- atic overview of immune suppressive factors in cord blood and adult blood plasma and describe potential therapeutic implications. The neonatal immune system is highly regulated The neonatal period provides a unique opportunity to study the mechanisms regulating the human immune system. Neo- natal immune responses are generally biased against generation of pro-inflammatory or Th1-type immune responses, while favoring regulatory and Th2-type responses (3, 4). This bias is ª 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd 1 Pediatric Allergy and Immunology