August 2007(I): 347–360 Lead Article Nutritional Support for the Infant’s Immune System Laetitia Niers, MD, Marianne Stasse-Wolthuis, PhD, Frans M. Rombouts, PhD, and Ger T. Rijkers, PhD Newborn babies possess a functional but immature immune system as a defense against a world teeming with microorganisms. Breast milk contains a number of biological, active compounds that support the in- fant’s immune system. These include secretory immu- noglobulin A (IgA), which confers specific protection against enteric pathogens, as well as numerous other immunological, active ingredients. A number of these ingredients can be used as supplements for infant formulas based on cow’s milk. Here, the strength of evidence regarding the immune-stimulating effects of selected minerals, vitamins, fatty acids, pre- and pro- biotics, and nucleotides is reviewed. An assessment of how these ingredients are used in infant-formula products currently available on the market is also presented. Key words: breast milk, infant formula, infant immu- nity, immune stimulation, probiotics, nucleotides © 2007 International Life Sciences Institute doi: 10.1301/nr.2007.aug.347–360 INTRODUCTION Newborn babies and infants are exposed to a vast array of potentially infectious microorganisms. The immune sys- tem, which has the foremost function of protecting against infections, is developed at birth, but it is still immature and, therefore, not fully functional. The ability of the newborn to resist infections is consequently impaired, but this can be, and is, supported by passive immunity. Transferred from mother to child, passive immunity is provided by maternal IgG antibodies, which are transported transplacentally dur- ing the last trimester of pregnancy, and by IgA antibodies in breast milk. In addition to possessing IgA, breast milk contains a range of other nutritional components that can improve the infant’s immune system. The IgA antibodies in breast milk can not be repro- duced in infant formula, but other nutritional components can. In this review, the development of the immune system in babies and infants is described, with an emphasis on the function of the immune system for protecting against infec- tions. The nutritional components in breast milk and the evidence for an immunomodulatory role are also reviewed, based on a PubMed search for human trials performed during the last 10 years and other relevant literature. The data collected was examined and the evidence was graded. Finally, the results of a market survey are presented. This survey was conducted to determine how the existing knowledge on immunomodulation by nutrition ingredients has been translated to incorporate these in- gredients into the currently available infant formulas. THE INFANT IMMUNE SYSTEM Development of the Immune System The immune system starts to develop during embry- ogenesis, when the first hematopoietic cells develop outside the embryo, in the yolk sac. In week 6 of gestation, committed hematopoietic stem cells develop in the mesoderm of the fetus, the so-called aorta-gonad- mesonephros. 1 Hematopoietic stem cells then migrate to the fetal liver where they initiate erythropoiesis. 2 During week 7 of gestation, cells seed the developing thymus. Seeding into the bone marrow occurs much later (by week 20). 3,4 In the thymus, T lymphocytes develop in a process that involves rearrangement of the T-cell recep- tors followed by selection for functionality and negative selection against self-antigens. Development of natural killer (NK) cells as well as various dendritic cell (DC) Dr. Niers is with the Department of Pediatrics, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, The Netherlands; Dr. Stasse-Wolthuis is with Stasse Consultancy, Udenhout, The Nether- lands; Dr. Rombouts is with the Laboratory of Food Microbiology, Wageningen University, Wageningen, The Netherlands; Dr. Rijkers is with the Department of Pediatrics, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, The Netherlands and the Laboratory of Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein, The Netherlands. Please address all correspondence to: Professor Ger T. Rijkers, Department of Pediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, KC03.068.0, Lundlaan 6, 3584 EA Utrecht, The Neth- erlands; Phone: +31-30-2504353, Fax: +31-30- 2505311, E-mail: grijkers@umcutrecht.nl 347 Nutrition Reviews, Vol. 65, No. 8