The Journal of Nutrition

Influence of Diet on Infection and Allergy in Infants

Breast-Feeding and Its Role in Early

Development of the Immune System in Infants:
Consequences for Health Later in Life1,2
Laura M’Rabet,3 Arjen Paul Vos,4 Günther Boehm,5 and Johan Garssen3,4*
3
Utrecht Institute of Pharmaceutical Sciences, Faculty of Beta Sciences, Utrecht University, 3508 TC Utrecht, The Netherlands;
4
Department of Biomedical Research, Numico Research, 6704 PH Wageningen, The Netherlands; and 5Infant Nutrition Department,
Numico Research, 61381 Friedrichsdorf, Germany

Introduction
abortion,’’ the immune system of the fetus is actively down-
Respiratory tract infections and gastrointestinal tract infections regulated during pregnancy. This is reflected by the presence of
of both bacterial and viral origin cause the highest mortality and high amounts of active inhibitory T cells, also called regulatory
morbidity in neonates and infants. This is true not only for T (Treg)6 cells, by downregulation of antigen-specific T-cell
developing countries but also for industrialized countries (1). proliferation (6–9), by the production of suppressive metabolites
Increased susceptibility to infections and decreased immune via indoleamine 2,3-dioxygenase (10), and by deletion of
responsiveness to these infectious agents continue to be present activated T cells via FasL-induced apoptosis (11). A conse-
significantly in y 2 of life. However, it should be realized that the quence of the immunological status during pregnancy is a not yet
induction of an immune response against nonharmful common fully active and developed immune system postpartum.
environmental antigens, such as food antigens and particular The immune system consists essentially of the innate immune
commensals (bacteria), has to be inhibited lest it give rise to system and the adaptive immune system. The innate immune
undesirable, excessive, and destructive inflammatory and aller- system is the sum of physical barriers, chemical barriers, and the
gic reactions (2,3). It appears that the development of the reactivity of local nonspecific cells and cells recruited to the site
immune system in neonates and young infants is reflected in the of inflammation. The innate nonspecific immune system is not
enhancement of ‘‘specific’’ immune responses to danger signals fully developed or active in y 1 of life.
and in the induction of tolerance toward common nonharmful The skin and the respiratory and intestinal tracts all play
environmental antigens such as food components as well as the pivotal roles in the innate immune response. In the latter 2 organs,
microbiota of the infant gut. It should be realized that the human the mucosal tissues form the physical and chemical barrier. In
immune system can be modulated easily during the first months infants, the integrity of the epithelial layer is not complete, as
of life (4), when it can be affected not only positively but, characterized by the existence of a higher permeability of the
unfortunately, also negatively. This dichotomy is illustrated by, epithelial layer in both the respiratory and gastrointestinal tracts.
e.g., survival advantage after surgery early in life and survival In adults, the creation of a low-pH environment in the stomach
postsurgery health consequences later on (5). and the secretion of proteases and antipathogenic peptides are
This article provides a brief overview of the current knowl- important features of the chemical barrier, inhibiting and killing
edge of the development of the infant immune system and invading pathogens. In infants, the secretion of these compounds
possibilities for intervention and immunomodulation. is not fully developed (12,13). Another example of the physical
barrier in the gastrointestinal and respiratory tracts is the group of
Immune maturation in early life: late-stage pregnancy glycoproteins, such as mucins, covering the entire epithelial layer
and y 1 of infancy as mucus. The composition and glycosylation of the mucus layer
To prevent excessive, destructive, and adverse immunological differ significantly between neonates and adults. As a conse-
reactions between mother and fetus that might lead to ‘‘immune quence, this may lead to differences in the composition of the gut
microbiota between neonates and adults, which in turn might
play a role in different susceptibilities to pathogens (14,15).
1
Published as a supplement to The Journal of Nutrition. Presented at the Granulocytes comprise a subset of immune cells that play a
symposium ‘‘Infant Nutrition’’ held in Rotterdam, The Netherlands, September crucial role in innate immune responses. It is known that neonatal
8, 2006. The symposium was organized by the Sophia Children’s Hospital, neutrophils are reduced in number. In addition to a reduced
Erasmus University, Rotterdam, The Netherlands, and was cosponsored by
number of neutrophils, functional impairment of innate immune
Danone Research, Wageningen, The Netherlands. Supplement coordinators: G.
Boehm and J. B. van Goudoever, Erasmus University, The Netherlands. responses is reflected by a reduced expression of complement
Supplement coordinator disclosures: G. Boehm is an employee of Danone receptor CR3, diminished expression of L-selectin, impaired
Research, the sponsor of the supplement; J. B. van Goudoever, no relationships
to disclose.
2 6
Author disclosures: L. M’Rabet, A. P. Vos, and J. Garssen, no conflicts of Abbreviations used: APC, antigen-presenting cell; BCG, bacillus Calmette-Guérin;
interest; G. Boehm is an employee of Danone Research. DC, dendritic cell; ID, idiotypic antibody network; MHC, major histocompatibility
* To whom correspondence should be addressed. E-mail: johan.garssen@ complex; Th1, T helper 1; Th2, T helper 2; TLR, Toll-like receptor; Treg, regulatory
numico-research.nl. T cell.

1782S 0022-3166/08 $8.00 ª 2008 American Society for Nutrition. J. Nutr. 138: 1782S–1790S, 2008.
chemotaxis, rolling adhesion, transmigration, and lamellipodia innate immune response. Although the acute-phase response is
formation. Neonatal neutrophils have a reduced capacity to caused by stress and hypoxia during labor and uterine contrac-
upregulate CD14 as well. tions, the response might play a role in the clearance of any
Antigen-presenting cells (APC) play an important role in the microbial product that the neonate encounters during its ac-
innate immune system as well. These cells trigger and initiate the quaintance with the extrauterine environment. The acute-phase
specific adaptive immune response by taking up antigens and response is mostly IL-6 driven together with a preserved IL-23,
subsequently presenting them to lymphocytes, such as T cells. IL-17 axis (13). This is in accordance with the notion that TNFa
Overall, APC activity in neonates is less than that in adults. and IL-1b signaling, 2 other cytokines involved in the activation
Several mechanisms play a crucial role in the reduction of of the acute-phase response, are downregulated during preg-
neonatal APC activity. First, the neonatal APC activity is nancy to avoid miscarriages (32). Perhaps downregulation of
intrinsically lower because of alteration in signaling cascades TNFa and IL-1b signaling might avoid excessive and destructive
compared with adult cells. Second, there is a defective interac- inflammation during the first days of life as well.
tion between APC and T cells, and third, the function of APC is The interplay between DC and T cells determines the fate of
downregulated by Treg cells very efficiently (16). T-cell responses and the general T-cell repertoire. As nicely reviewed
Lower IL-12p70 production and IL-12p35 mRNA produc- by Marchant and Goldman (33), neonatal T cells contain high
tion was found in cord blood dendritic cells (DC) compared with concentrations of T-cell receptor excision circles, which are
adult blood DC after a variety of stimuli (17–21). Moreover, the episomal DNA by-products produced after T-cell receptor re-
absolute number of DC is not affected by age, although the arrangements. They have a high cell turnover with long telomeric
expression of major histocompatibility complex (MHC) class II sequences, because of high telomerase activity. Neonatal T cells
and costimulatory molecules is lower on cord blood DC (19– have an increased susceptibility to apoptosis that can be prevented
22). The reduced production of IL-12 by cord blood DC might by IL-2; they proliferate after IL-7 and IL-15 stimulation (33–35).
be compensated by a higher production of IL-23, another Th1- Neonatal T cells are effective in producing IL-2 and TGFb, but they
type cytokine (22). produce only 50% of TNFa and only 10% of IFNg and IL-4
Reduced expression of MHC class II and costimulatory compared with T cells from adults. Still, T cells of the neonate are
molecules might result in less activation of DC and subsequently able to respond to environmental antigens (36).
hampered signaling toward T cells. Whole-blood stimulation Recently it has been reported that DC-T cell interactions in
leads to lower IL-12p70 and IFNa production and to higher Hassal bodies (in the thymus) are important for the generation
IL-10 production compared with adult whole-blood stimulation of Treg cells (37). Because infants have a larger thymus and a
(23). Similar effects were found for monocyte-derived DC high thymic output (T-cell receptor excision circles), this might
(18,24). play a crucial role in the induction of ‘‘immune’’ tolerance.
However, neonatal DC can be activated and skewed toward Indeed CD251 Treg cells are present at high numbers during
a Th1-type immune response very efficiently. For instance, ex- fetal life (6,8,38,39).
pression of CD80 and CD86 and production of IL-12 could be In addition to the overall impaired neonatal T-cell functions,
elevated by costimulation with bacterial CpG DNA or IFNg cytotoxic T-cell functions are limited as well, resulting in less
(25–28). Highly purified CD141 DC show similar IL-12 proliferation and ‘‘immature’’ cytokine profiles. Because of de-
production and IFNg production as adult DC (29,30), indicat- fects in IFNg production, natural killer cell activity is impaired as
ing that the impaired IL-12 production and APC function are not well (40).
merely intrinsic properties of neonatal APC but that the Humoral immune responses are also different between adults
interplay between DC and T cells is altered as well. and young infants. Although the number of B cells in the neonate
The impaired activity of cord blood DC is reflected in a is very high, the maturation of plasma B cells is not yet
reduced capacity in phagocytosis and endocytosis (18,24). The completed at birth, leading to a defective antibody isotype
latter report is highly interesting because the phagocytosis was switching. As a consequence of the relative T-cell and B-cell
directed against debris from dying cells, both apoptotic and immaturity, neonates are capable of only rapid IgM and anti-
necrotic cells. Apoptosis plays an important role in the morpho- IgM responses. Neonatal B cells are efficient in their capacity to
genesis of the fetus. Perhaps the diminished DC activity is not produce IgE if they are stimulated by exogenous IL-4. However,
important only for the induction of tolerance against maternal because of the minimal level of IL-4 produced by neonatal
proteins but also to avoid destructive inflammation during the T cells, the level of IgE production by neonatal B cells is very low
development of the fetus as well. In accordance with this (41). During the first 2 y of life the switch to IgG1 and IgG3 is
hypothesis, DC remain immature during development because functional in the neonate, whereas the switch to IgG2 and IgG4
of tolerance-inducing exosomes that contain morphogens (31). is inadequate in this period. Serum sIgA levels can reach adult
Follow-up research is essential to prove this hypothesis. levels within a few weeks under heavy microbial exposure (42).
Because of the recent hygiene hypothesis, attention has been Many bacteria are targeted by sIgA in human milk, including E.
paid to the role of Toll-like receptors (TLR) in the immune coli, Shigella, Salmonella, Campylobacter, Vibrio cholerae, H.
response and immune development. TLR play an important role influenzae, S. pneumoniae, Clostridium difficile and C. botuli-
in sensing bacterial products and in activating and skewing the num, Klebsiella pneumoniae, as well as the parasite Giardia and
immune system. Although the expression of TLR on neonatal the fungus Candida albicans (43).
macrophages and monocytes is similar to that in adults, TLR As recommended by the WHO International Life Science
signaling itself is different in infants because TLR stimulations in Institute (44), the immune response after vaccination can be used
response to TLR1–7 agonist are different. The production of as a model or measure for controlled exposure to antigens. This
Th1 cytokines TNFa, IFN, IL-12, and IL-1b are downregulated, model is used in young infants to compare the in vivo immune
whereas IL-6, IL-8, IL-10, and IL-23 are unregulated compared response between infants and adults. In most cases, the response
with adult production (13). is studied by vaccine-specific ex vivo cell proliferation and
After birth, a rapid activation of the acute-phase response is cytokine production and by levels of neutralizing antibodies.
induced. The acute-phase response plays an essential role in the The data are nicely reviewed by Marchant and Goldman (33). In
The role of breastfeeding on immune maturation 1783S
general, in infants an antigen-specific immune response can be compared with healthy nonatopic children (57), whereas the
generated. The reaction is mostly characterized by a Th2-type amount of mature plasmoid DC (CD11c-CD123high1) was
response as reflected by high production of Th2-type cytokines decreased significantly.
and high levels of antigen-specific type 2 immunoglobulins. This Maternal atopy is found to be associated with high CD41IL-
1
is the case for vaccines such as hepatitis B (45), polio (46), and 13 cord blood cells and stronger Th2 IL-13 responses to the
measles (47). Some vaccines, for instance antituberculosis milk allergen b-lactoglobulin (55,58). Atopic diseases at 1 y of
bacillus Calmette-Guérin (BCG) vaccine (48) or whole-cell age have been associated with high IL-13 production and
pertussis vaccine (49), do induce a Th1 response in infants, CD41IL-131 cells in cord blood as well (59).
indicating that a Th1 response can be generated in infants, It is of great interest to note that the development of atopy in
although less efficiently. Some studies in which BCG is used as an childhood is associated with a reduced capacity to develop
adjuvant for unrelated vaccine antigens show that BCG merely immunological memory against BCG immunization during
induces both Th1 and Th2 responses in infants (50), again infancy (60) and slower development of responses to diphthe-
indicating that a Th1 response can be induced in infants when ria/pertussis/tetanus vaccination (61).
triggered with a strong immune inducer. Consequences of an impaired immune maturation for the
onset of autoimmunity are not yet known. Some studies suggest
Consequences of impaired immune maturation that breast-feeding may protect against type 1 diabetes, and
Data support the hypothesis that delayed or impaired maturation others suggest a protective effect against multiple sclerosis and
of the immune system early in life can result in immune dys- rheumatoid arthritis as well. However, the results are still
function later in life, leading to, e.g., allergy or atopy (51). The controversial, and further research is needed (62). An interesting
production of IL-10, a cytokine released by Treg cells, is lower in research hypothesis is to test the role of IL-6 and TGFb in the
cord blood DC of neonates of atopic mothers compared with onset of autoimmune diseases in infants (63,64). Because IL-6
nonatopic mothers after TLR-2 stimulation with peptidoglycan. and IL-23 are present in the serum of infants, and breast milk
(52). A lower number of IL-12-producing cells was found in both contains both IL-6 and TGFb, there might be improper Th17 cell
unstimulated (53,54) and LPS-stimulated immune cells (55) in activity in infants who develop autoimmunity later in life. Th17
children from allergic mothers. The expression of HLA Class II on cells have been shown to be involved in autoimmune disorders
monocytes is lower in children in whom allergy emerged within and are a newly identified subset of T cells (Fig. 1).
the first 2 y of life (56). Although the DC distribution did not
differ in cord blood of healthy neonates compared with cord The interplay among genes, nutrition,
blood DC in neonates that acquired atopy at a later age, the and environment
number of immature plasmoid DC (CD11c-CD123low1, DC) The interplay between mother and child during pregnancy and
was increased in children who acquired atopic dermatitis after birth and the introduction of nutrition (breast-feeding and

FIGURE 1 Relative activity of different T-helper

subsets in infants compared with adults and the
possible consequence for acquiring immune disor-
ders. The development and differentiation process
of T-helper subsets are shown as illustrated
by Reiner (89). As described in the text, during
pregnancy, Th1 and Th2 activity in infants is down-
regulated via increased production of IL-10 and
TGFb and activity of Treg cells compared with
adults. Also, stress responses are altered as char-
acterized by an increase in IL-6, IL-23, and IL-17
production, whereas TNFa and IL-1b production are
tempered. Because Th17 cells have been only
recently discovered, no knowledge is available on
the activity of this subset in infants. However,
based on levels of IL-6, IL-7, and IL-23 found in
serum in infants, it is postulated that the activity of
Th17 is increased in infants. Investigations are
needed to prove this. The differential development
process of each T-helper subset does not exclude
the interaction between T-cell subsets. For in-
stance, Th1 cells are known to produce IL-23 and
thereby to activate the formation of Th17 cells (90).
Maturation of the immune response in infants is
characterized by a higher induction of an antigen-
specific Th1 response compared with an antigen-
specific Th2 response and downregulation of a Treg
cell response. Improper orchestration of the devel-
opment of the different subsets of T cells might
lead to immune-related disorders. For example,
delayed induction of Th1 responses and subsequent
relatively higher Th2 and Th17 activity with simul-
taneous loss of Treg cells during maturation might lead to uncontrolled immune responses. Data suggesting the onset of allergy via this
mechanism are also described. There are no data to support the hypothesis for autoimmunity.

1784S Supplement
the introduction of solid foods) influence the development of the offspring, to prove that the ID network does play a role in the
immune system of the child. Breast milk can be a source of immune response of offspring (68). A systematic review of all
antigens to which the immune system becomes tolerant easily. these data concluded that maternal ID and anti-ID interactions
Breast milk provides factors that modulate immune maturation during the first 3 wk of life in mice induce immune imprinting
and subsequently the immune response. Breast milk provides (programming) and are decisive for the repertoire of T cells and
factors that influence the microbiota and in turn affect antigen B cells. The effects of maternal antibodies on the immune
exposure and immune maturation (3). response later in life in the offspring are shown repeatedly, as
The content of breast milk has evolved over millions of years reviewed by Lemke et al. (68) (Table 1).
not only to provide nutrition but also to protect the offspring There are serious indications that breast-feeding modulates
from infections and to induce immunological tolerance against vaccination responses in infants positively as compared with
common nondangerous compounds. It is generally thought that formula-feeding in children. Measles, mumps, and rubella
each individual mother provides for the specific developmental vaccination resulted in significant changes in CD81 T cells,
needs of her individual child, which are rapidly evolving during natural killer cells, and mitogen-induced IFNg production
the first months of life (65). However, what is the immunological compared with baseline in 1-y-old breast-fed children but not
consequence if the mother is genetically or environmentally in formula-fed children. No differences were observed in
disposed to cause improper immune maturation in her offspring mitogen-induced IL-4 or IL-10 production, suggesting enhanced
and subsequently transfers, indirectly or directly, immunological development of Th1 responses in breast-fed children (69).
disorders? Another study demonstrated that breast-feeding induced higher
serum antibody responses to oral polio vaccination but not to
Breast milk and its immune-modulating compounds other systemic vaccines (70). In addition, multiple reports in
The concept that breast-feeding can modulate the immune system literature show that breast-feeding lowers the incidence of
despite a genetic predisposition has been supported by funda- infections (71–73) and atopy-related disorders (74–78).
mental experiments using specific strains of mice. If rag21/– In contrast, there are some studies showing a higher risk of
mouse pups, mice that do not contain T cells, are breast-fed after developing allergic diseases and sensitization if duration of
birth by rag22/2 mice, the immune response as measured by breast-feeding is relatively long in asthmatic mothers. The most
antigen-specific immunoglobulins is impaired, whereas rag21/– recent of these (79) reported that New Zealand children were
pups breast-fed on rag21/1 mice showed specific immune re- more likely to develop allergic diseases and sensitization at 13 y
sponses (66). of age if they had been breast-fed (n ¼ 504) compared with
Antibodies in milk were detected in 1903 by Schlossman and formula-fed infants (n ¼ 533). The duration of breast-feeding
Moro. Maternal antibodies do have immune-modulating effects was also positively associated with the onset of allergic diseases
in the offspring. Availability of maternal antibodies during in these children. Other studies, including a German investiga-
pregnancy is guaranteed by transport across the placenta by tion (80,81) and a report from North America (82), documented
neonatal Fc-receptors. After birth, immunoglobulins are found an increased risk of asthma in breast-fed children whose mothers
in colostrum and mature breast milk. were asthmatic, compared with those without maternal asthma.
IgG and IgM are transferred from mother to her infant via These data suggest that the genetic predisposition of the mother
breast milk. As for IgA, it is known that these antibodies protect is reflected in the composition of breast milk and subsequently
the infant against infections passively. They also influence the leads to alteration of the immune response in the children.
immune repertoire of the offspring. The repertoire of idiotypic The studies cited above are highly controversial because
(ID) antibodies, T-cell clones, and B-cell clones is determined by systematic reviews still show a protective effect of breast-feeding
antiidiotypic interactions of the autologous host, in this case the against allergic diseases (76–78). However, it should be noted
receiving infant. This idiotypic network has been postulated by that most studies only compare infants with paternal and
Jerne (67) in the early 1970s. Subsequently, in the late 1970s and maternal heredity for atopic disease and do not correct for other
early 1980s, many experiments were performed to establish the factors in the analysis. In addition, confounding factors for the
effect of maternal antibodies on the immune response in onset of asthma are respiratory infections, and, as discussed

TABLE 1 Known effects of maternal antibodies on the immune response in the offspring in mice1

Short description of effect Summary of studies

Improvement of immune function Quantitative improvement of immune responses were found as measured by the enhancement of antigen-specific immune
responses, conversion of a primary into a secondary humoral response. Induction of antigen-reactive IgM antibodies
in nonimmunized F1 animals by maternal immunization with antigen or antiidiotype antibodies.
Improvement of immune function Maternal immunization(s) or transfer of quaternary monoclonal antihapten (2-phenyl-oxazolone) antibodies induce IgM antibody
in F2 progeny formation in nonimmunized F1 mice and production of secondary antibody titers after primary immunization of F2 progeny.
Moreover a diversification of the primary antibody repertoire was found together with a selection of primary antibodies with strongly
enhanced affinities.
Increase of resistance against Maternally derived antiidiotype antibodies can protect adult mice against microbial infection or tumor cell growth.
infections and tumors
Inhibition of allergic responses Allergen- and isotype-specific suppression of IgEresponsiveness. Maternally derived immune or exogenous monoclonal IgG
antibodies inhibit systemic and airway IgE responses. The effects are only found until age 4 mo; IgE suppression is then
prolonged until age . 1 y. Maternal IgG thus reverses a seemingly genetically based IgE high-responder state into non- or
low responsiveness
Transfer of autoimmunity Abrogation of autoantibody transfer from mother to child prevents the incidence of diabetes in NOD mice later in life.
1
The data presented in this table are taken from Lemke et al. (68) and references therein and from Greeley et al. (83).

The role of breastfeeding on immune maturation 1785S

above, breast-feeding does protect against respiratory infections. noic acid, docosahexaenoic acid), monoglycerides, leuric acid,
Most studies do not correct for this phenomenon. linoleic acid, cytokines (IL-8, IL-7, TNFa, adiponectin, leptin),
The evidence in regard to autoimmune diseases is very poor. isoforms of immunoglobulins (sIgA), soluble receptors (CD14,
Sjögren’s syndrome, a syndrome caused by autoantibodies sTLR2), cytokines and chemokines, antibacterial proteins/peptides
against Ro/Sjögren’s syndrome A antigen and lupus/Sjögren’s (lactoferrin, lysozyme, b-lactoglobulin, casein), and intact im-
syndrome B antigen and systemic lupus erythematosus and mune cells. Table 2 includes a list of compounds that can be
autoimmune ovarian diseases are examples in which maternal found in breast milk with experimental proof for immune
transfer of autoimmunoglobulins might play a role in the onset of modulation in mice and/or humans.
the disease in the infant (68,83). Similarly as in allergic disorders, Recently much attention has been paid to the effects of
infections play an important role in the onset of autoimmunity probiotics, prebiotics, or oligosaccharides and polyunsaturated
(84). It is very difficult, therefore, to prove the concept in fatty acids. Several reviews have appeared in this area recently
epidemiological studies.Although there are indeed indications (3,85).
that breast-feeding influences the development of the immune To indicate current knowledge of immune-modulatory com-
system in infants, unfortunately, not all compounds in breast milk pounds from breast milk, a brief summary is given on the known
responsible for immune modulation have been discovered as yet, effects of the gut microbiota. It is known that the maturation of
and this area needs more research attention. the gastrointestinal tract is influenced by the microbiota. This
In addition to IgGs and IgMs, breast milk contains other was already shown in 1905. The microbiota of breast-fed infants
immune-modulatory compounds as well, including nucleotides, contains more bifidobacteria than that of adults or formula-fed
specific amino acids (taurine, polyamines), PUFA (eicosapentae- infants. This has been described repeatedly. The microbiota

TABLE 2 Compounds in breast milk with immune-modulating capacities1

Components Activity References

Proteins
Cytokines/chemokines Immune modulation
TGFb, IL-10, etc. Antiinflammatory effects (28,91–96)
TNFa, IL-1b, IL-6, etc. Proinflammatory effects
IL-4, IL-5, IL-13 Stimulation of Th2 immunity
IFNg, IL-2, IL-12 Stimulation of Th1 immunity
IL-8, eotaxin, RANTES, etc. Chemoattractant function
Soluble receptors/antagonists Antiinflammatory effects (97,98)
sCD14, TNFR I and II, IL-1RA, etc.
Defensins Antimicrobial activity (99)
sIgA, IgM, IgG antibodies Antiadhesive, antiinfective effects (100,101)
Hormones/growth factors Stimulate barrier function, gut development, immune modulation (102–106)
Prolactin, leptin, IGF-1, etc.
Enzymes/abundant proteins Antimicrobial activity, immune modulation
Lysozyme Microbicidal effects, immune modulation (107,108)
Lactoferrin Microbicidal effects, iron-binding capacity, immune modulation (109,110)
a-Lactalbumin Antimicrobial peptides on digestion (111)
k-Casein Contains an antiadhesive carbohydrate component (112)
Haptocorrin Antimicrobial activity by vitamin B-12 binding (113)
Lactoperoxidase Antimicrobial activity (114)
Carbohydrates
Oligosaccharides, glycoconjugates Antiadhesive function, modulation of microbiota and immune function (85,115,116)
Antioxidants Radical scavenging, antiinflammatory activity (117)
Vitamins A, C, E, catalase, glutathion peroxidase, etc.
Lipids
Free fatty acids, monoglycerides Detergent-like antimicrobial and antiviral effects (118)
PUFA Immune modulation, modulation of prostaglandin production (38,119)
Arachidonic acid, docosahexaenoic acid, etc.
Nucleic acids
Nucleotides, nucleosides, oligonucleotides Enhancement of antibody production, metabolic effects (70,120,121)
Subcellular components
Gangliosides Modulation of microbiota and immune function (122,123)
Exosomes Immune modulation, induction of Treg cells (124)
Cells (125,126)
Neutrophils, macrophages Antimicrobial activity
T and B lymphocytes Possible impact on immune maturation
Bacteria Modulation of microbiota and immune function (127,128)
Bifidobacteria
1
The list as shown depicts only compounds that can influence the immune system in the offspring in well-nourished circumstances. For instance, zinc is not depicted in the list,
although zinc deprivation/malnourishment does lead to immune deficiency in the offspring.

1786S Supplement
species are thought to acidify the content of the gastrointestinal 3. Calder PC, Krauss-Etschmann S, de Jong EC, Dupont C, Frick JS,
tract and therefore inhibit its colonization by pathogenic (pH- Frokiaer H, Heinrich J, Garn H, Koletzko S, et al. Early nutrition and
immunity—progress and perspectives. Br J Nutr. 2006;96:774–90.
sensitive) bacteria (reviewed by Vos et al. (85)). Recent work
4. West LJ. Defining critical windows in the development of the human
suggests that viable bacteria are present in breast milk. Bacterial immune system. Hum Exp Toxicol. 2002;21:499–505.
DNA is transported from the mother’s intestine to the mammary 5. Morrow WR, Chinnock RE. Survival after heart transplantation. In:
gland via an endogenous cellular route (86). Tejani AH, Fine RM, Harmon WE, editors. Pediatric solid organ
Data from domestic and experimental animals and epidemi- transplantation. London: Blackwell; 2000. p. 417–426.
ological studies suggest that the microbiological environment of 6. Godfrey WR, Spoden DJ, Ge YG, Baker SR, Liu B, Levine BL, June
the infant plays a crucial role in the maturation of the immune CH, Blazar BR, Porter SB. Cord blood CD4(1)CD25(1)-derived
T regulatory cell lines express FoxP3 protein and manifest potent
system. In particular, research has been performed on the role of
suppressor function. Blood. 2005;105:750–8.
the commensal microbiota of the gastrointestinal tract. Infections,
7. Wing K, Larsson P, Sandstrom K, Lundin SB, Suri-Payer E, Rudin A.
in particular in the gastrointestinal tract and the respiratory tract, CD41 CD251 FOXP31 regulatory T cells from human thymus and
may also contribute to the maturation of the immune system. cord blood suppress antigen-specific T cell responses. Immunology.
Most articles are focused on the upregulation of the Th1 response 2005;115:516–25.
(51). Although the targets of the microbial agents are not as yet 8. Thornton CA, Upham JW, Wikstrom ME, Holt BJ, White GP, Sharp
fully known, it is thought that APC play a pivotal role (87). MJ, Sly PD, Holt PG. Functional maturation of CD41CD251
CTLA41CD45RA1 T regulatory cells in human neonatal T cell
Most studies have dealt with the effects of specific probiotic
responses to environmental antigens/allergens. J Immunol. 2004;173:
strains or prebiotics in infants on allergic symptoms and the 3084–92.
incidence and severity of infections. Long-term effects of changing 9. Michaelsson J, Mold JE, McCune JM, Nixon DF. Regulation of
the microbiota on the immune system of the offspring have not T cell responses in the developing human fetus. J Immunol. 2006;
yet been studied (85). Therefore, the question remains whether 176:5741–8.
other immune-modulating compounds from human breast milk 10. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall
can have the similar long-term effects as described in mice. B, Brown C, Mellor AL. Prevention of allogeneic fetal rejection by
tryptophan catabolism. Science. 1998;281:1191–3.
11. Guller S, LaChapelle L. The role of placental Fas ligand in
maintaining immune privilege at maternal-fetal interfaces. Semin
Summary Reprod Endocrinol. 1999;17:39–44.
Because of the interaction between mother and child during 12. Henning S. (1987) Functional development of the gastrointestinal
tract, 2nd ed. New York: Raven Press; 1987.
pregnancy, excessive and destructive inflammatory responses
13. Levy O. Innate immunity of the newborn: basic mechanisms and
must be avoided during the development of the fetus. Active clinical correlates. Nat Rev Immunol. 2007;7:379–90.
inhibition of the immune system of the fetus to inhibit ‘‘immune 14. Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA. Inflam-
abortions’’ results in an immature immune system at birth and mation in the developing human intestine: A possible pathophysio-
during the first years of life, making the child susceptible to logic contribution to necrotizing enterocolitis. Proc Natl Acad Sci
infections and immune disorders. USA. 2000;97:6043–8.
The development of the immune system in infants is 15. Robbe C, Capon C, Coddeville B, Michalski JC. Structural diversity
characterized by the induction of an antigen-specific immune and specific distribution of O-glycans in normal human mucins along
the intestinal tract. Biochem J. 2004;384:307–16.
response and maintenance of immunological tolerance against
16. Velilla PA, Rugeles MT, Chougnet CA. Defective antigen-presenting
commonly found compounds in the environment of the infant. cell function in human neonates. Clin Immunol. 2006;121:251–9.
Improper immune maturation may lead to lifetime immunolog- 17. Joyner JL, Augustine NH, Taylor KA, La Pine TR, Hill HR. Effects of
ical disorders such as allergic disorders and autoimmunity. group B streptococci on cord and adult mononuclear cell interleukin-
The interaction between mother and child postpartum plays 12 and interferon-gamma mRNA accumulation and protein secre-
an important role in the development of the infant’s immune tion. J Infect Dis. 2000;182:974–7.
system. The immunological memory of the mother is passed to 18. Goriely S, Vincart B, Stordeur P, Vekemans J, Willems F, Goldman M,
De Wit D. Deficient IL-12(p35) gene expression by dendritic cells
her infant via breast milk, and breast milk contains a variety of
derived from neonatal monocytes. J Immunol. 2001;166:2141–6.
immune-modulating compounds causing immunological im-
19. Upham JW, Lee PT, Holt BJ, Heaton T, Prescott SL, Sharp MJ, Sly
printing and programming (88). PD, Holt PG. Development of interleukin-12-producing capacity
This review clearly illustrates that knowledge of the devel- throughout childhood. Infect Immun. 2002;70:6583–8.
opment of the immune system in infants has numerous black 20. Stefanovic V, Golubovic E, Vlahovic P, Mitic-Zlatkovic M. Age-
holes. Investigations on the interplay between mother and child related changes in IL-12 production by peripheral blood mononu-
after birth, including studies of the content of breast milk, are clear cells (PBMC). J Intern Med. 1998;243:83–4.
needed to support the described concepts. Because the active 21. Langrish CL, Buddle JC, Thrasher AJ, Goldblatt D. Neonatal
dendritic cells are intrinsically biased against Th-1 immune responses.
downregulation of the immune system during pregnancy and Clin Exp Immunol. 2002;128:118–23.
infancy shows similarities with immunological tolerance in later 22. Vanden Eijnden S, Goriely S, De Wit D, Goldman M, Willems F.
life (2), the investigations will not only fulfill our academic Preferential production of the IL-12(p40)/IL-23(p19) heterodimer by
curiosity but will also lead to new targets and therapeutics to dendritic cells from human newborns. Eur J Immunol. 2006;36:21–6.
prevent and/or inhibit allergies and autoimmune diseases. 23. De Wit D, Tonon S, Olislagers V, Goriely S, Boutriaux M, Goldman
M, Willems F. Impaired responses to toll-like receptor 4 and toll-like
Other articles in this supplement include references (129–138). receptor 3 ligands in human cord blood. J Autoimmun. 2003;21:
277–81.
24. Wong OH, Huang FP, Chiang AK. Differential responses of cord and
Literature Cited adult blood-derived dendritic cells to dying cells. Immunology. 2005;
116:13–20.
1. Wright PF, Wright PF. Infectious diseases in early life in industrialized 25. Marodi L, Goda K, Palicz A, Szabo G. Cytokine receptor signalling
countries. Vaccine. 1998;16:1355–9. in neonatal macrophages: defective STAT-1 phosphorylation in
2. Niederkorn JY. See no evil, hear no evil, do no evil: the lessons of response to stimulation with IFN-gamma. Clin Exp Immunol. 2001;
immune privilege. Nat Immunol. 2006;7:354–9. 126:456–60.

The role of breastfeeding on immune maturation 1787S

26. De Wit D, Olislagers V, Goriely S, Vermeulen F, Wagner H, Goldman 48. Marchant A, Goetghebuer T, Ota MO, Wolfe I, Ceesay SJ, De Groote
M, Willems F. Blood plasmacytoid dendritic cell responses to CpG D, Corrah T, Bennett S, Wheeler J, et al. Newborns develop a Th1-
oligodeoxynucleotides are impaired in human newborns. Blood. type immune response to Mycobacterium bovis bacillus Calmette-
2004;103:1030–2. Guerin vaccination. J Immunol. 1999;163:2249–55.
27. Hunt DW, Huppertz HI, Jiang HJ, Petty RE. Studies of human cord 49. Mascart F, Verscheure V, Malfroot A, Hainaut M, Pierard D,
blood dendritic cells: evidence for functional immaturity. Blood. Temerman S, Peltier A, Debrie AS, Levy J, et al. Bordetella pertussis
1994;84:4333–43. infection in 2-month-old infants promotes type 1 T cell responses.
28. Garofalo R, Chheda S, Mei F, Palkowetz KH, Rudloff HE, J Immunol. 2003;170:1504–9.
Schmalstieg FC, Rassin DK, Goldman AS. Interleukin-10 in human 50. Ota MO, Vekemans J, Schlegel-Haueter SE, Fielding K, Sanneh M,
milk. Pediatr Res. 1995;37:444–9. Kidd M, Newport MJ, Aaby P, Whittle H, et al. Influence of
29. Karlsson H, Hessle C, Rudin A. Innate immune responses of human Mycobacterium bovis bacillus Calmette-Guerin on antibody and
neonatal cells to bacteria from the normal gastrointestinal flora. cytokine responses to human neonatal vaccination. J Immunol.
Infect Immun. 2002;70:6688–96. 2002;168:919–25.
30. Salio M, Dulphy N, Renneson J, Herbert M, McMichael A, 51. Holt PG, Jones CA. The development of the immune system during
Marchant A, Cerundolo V. Efficient priming of antigen-specific cyto- pregnancy and early life. Allergy. 2000;55:688–97.
toxic T lymphocytes by human cord blood dendritic cells. Int Immunol. 52. Schaub B, Campo M, He H, Perkins D, Gillman MW, Gold DR,
2003;15:1265–73. Weiss S, Lieberman E, Finn PW. Neonatal immune responses to
31. Stoorvogel W, Kleijmeer MJ, Geuze HJ, Raposo G. The biogenesis TLR2 stimulation: influence of maternal atopy on Foxp3 and IL-10
and functions of exosomes. Traffic. 2002;3:321–30. expression. Respir Res. 2006;7:40.
32. Vitoratos N, Papadias C, Economou E, Makrakis E, Panoulis C, 53. Gabrielsson S, Soderlund A, Nilsson C, Lilja G, Nordlund M, Troye-
Creatsas G. Elevated circulating IL-1beta and TNF-alpha, and Blomberg M. Influence of atopic heredity on IL-4-, IL-12- and IFN-
unaltered IL-6 in first-trimester pregnancies complicated by threat- gamma-producing cells in in vitro activated cord blood mononuclear
ened abortion with an adverse outcome. Mediators Inflamm. 2006; cells. Clin Exp Immunol. 2001;126:390–6.
2006:30485. 54. Nilsson C, Larsson AK, Hoglind A, Gabrielsson S, Troye Blomberg
33. Marchant A, Goldman M. T cell-mediated immune responses in M, Lilja G. Low numbers of interleukin-12-producing cord blood
human newborns: ready to learn? Clin Exp Immunol. 2005;141: mononuclear cells and immunoglobulin E sensitization in early
10–8. childhood. Clin Exp Allergy. 2004;34:373–80.
34. Hassan J, Reen DJ. Human recent thymic emigrants–identification, 55. Prescott SL. Early origins of allergic disease: a review of processes
expansion, and survival characteristics. J Immunol. 2001;167:1970–6. and influences during early immune development. Curr Opin Allergy
35. Schonland SO, Zimmer JK, Lopez-Benitez CM, Widmann T, Ramin Clin Immunol. 2003;3:125–32.
KD, Goronzy JJ, Weyand CM. Homeostatic control of T-cell 56. Upham JW, Holt PG, Taylor A, Thornton CA, Prescott SL. HLA-DR
generation in neonates. Blood. 2003;102:1428–34. expression on neonatal monocytes is associated with allergen-specific
36. Hanson LA, Dahlman-Hoglund A, Lundin S, Karlsson M, Dahlgren immune responses. J Allergy Clin Immunol. 2004;114:1202–8.
U, Ahlstedt S, Telemo E. The maturation of the immune system. 57. Hagendorens MM, Ebo DG, Schuerwegh AJ, Huybrechs A, Van
Monogr Allergy. 1996;32:10–5. Bever HP, Bridts CH, De Clerck LS, Stevens WJ. Differences in
37. Watanabe N, Wang YH, Lee HK, Ito T, Wang YH, Cao W, Liu YJ. circulating dendritic cell subtypes in cord blood and peripheral blood
Hassall’s corpuscles instruct dendritic cells to induce CD41CD251 of healthy and allergic children. Clin Exp Allergy. 2003;33:633–9.
regulatory T cells in human thymus. Nature. 2005;436:1181–5. 58. Kopp MV, Zehle C, Pichler J, Szepfalusi Z, Moseler M, Deichmann
38. Duchen K, Bjorksten B. Polyunsaturated n-3 fatty acids and the K, Forster J, Kuehr J. Allergen-specific T cell reactivity in cord blood:
development of atopic disease. Lipids. 2001;36:1033–42. the influence of maternal cytokine production. Clin Exp Allergy.
2001;31:1536–43.
39. Takahata Y, Nomura A, Takada H, Ohga S, Furuno K, Hikino S,
Nakayama H, Sakaguchi S, Hara T. CD251CD41 T cells in human 59. Ohshima Y, Yasutomi M, Omata N, Yamada A, Fujisawa K, Kasuga
cord blood: an immunoregulatory subset with naive phenotype and K, Hiraoka M, Mayumi M. Dysregulation of IL-13 production by
specific expression of forkhead box p3 (Foxp3) gene. Exp Hematol. cord blood CD41 T cells is associated with the subsequent develop-
2004;32:622–9. ment of atopic disease in infants. Pediatr Res. 2002;51:195–200.
40. Nesin M, Cunningham-Rundles S. Cytokines and neonates. Am J 60. Shirakawa T, Enomoto T, Shimazu S, Hopkin JM. The inverse
Perinatol. 2000;17:393–404. association between tuberculin responses and atopic disorder. Science.
1997;275:77–9.
41. Pastorelli G, Rousset F, Pene J, Peronne C, Roncarolo MG, Tovo PA,
de Vries JE. Cord blood B cells are mature in their capacity to switch 61. Prescott SL, Sly PD, Holt PG. Raised serum IgE associated with
to IgE-producing cells in response to interleukin-4 in vitro. Clin Exp reduced responsiveness to DPT vaccination during infancy. Lancet.
Immunol. 1990;82:114–9. 1998;351:1489.
42. Mellander L, Carlsson B, Jalil F, Soderstrom T, Hanson LA. Secretory 62. Dahlgren UI, Hanson LA, Telemo E. Maturation of immunocompe-
IgA antibody response against Escherichia coli antigens in infants in tence in breast-fed vs. formula-fed infants. Adv Nutr Res. 2001;
relation to exposure. J Pediatr. 1985;107:430–3. 10:311–25.
43. Goldman AS. The immune system of human milk: antimicrobial, 63. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy
antiinflammatory and immunomodulating properties. Pediatr Infect DE, Leonard WJ, Littman DR. IL-6 programs T(H)-17 cell differ-
Dis J. 1993;12:664–71. entiation by promoting sequential engagement of the IL-21 and IL-23
pathways. Nat Immunol. 2007;8:967–74.
44. Albers R, Antoine JM, Bourdet-Sicard R, Calder PC, Gleeson M,
Lesourd B, Samartin S, Sanderson IR, Van Loo J, et al. Markers to 64. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille
measure immunomodulation in human nutrition intervention studies. JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat
Br J Nutr. 2005;94:452–81. directs the differentiation program of proinflammatory IL-171 T
helper cells. Cell. 2006;126:1121–33.
45. Ota MO, Vekemans J, Schlegel-Haueter SE, Fielding K, Whittle H,
Lambert PH, McAdam KP, Siegrist CA, Marchant A. Hepatitis B 65. Lawrence RM, Pane CA. Human breast milk: current concepts of
immunisation induces higher antibody and memory Th2 responses in immunology and infectious diseases. Curr Probl Pediatr Adolesc
new-borns than in adults. Vaccine. 2004;22:511–9. Health Care. 2007;37:7–36.
46. Vekemans J, Ota MO, Wang EC, Kidd M, Borysiewicz LK, Whittle 66. Shimamura M, Huang YY, Goji H. Antibody production in early life
H, McAdam KP, Morgan G, Marchant A. T cell responses to supported by maternal lymphocyte factors. Biochim Biophys Acta.
vaccines in infants: defective IFNgamma production after oral polio 2003;1637:55–8.
vaccination. Clin Exp Immunol. 2002;127:495–8. 67. Jerne NK. Towards a network theory of the immune system. Ann
47. Gans H, Yasukawa L, Rinki M, DeHovitz R, Forghani B, Beeler J, Immunol (Paris). 1974;125C:373–89.
Audet S, Maldonado Y, Arvin AM. Immune responses to measles and 68. Lemke H, Coutinho A, Lange H. Lamarckian inheritance by
mumps vaccination of infants at 6, 9, and 12 months. J Infect Dis. somatically acquired maternal IgG phenotypes. Trends Immunol.
2001;184:817–26. 2004;25:180–6.

1788S Supplement
69. Pabst HF, Spady DW, Pilarski LM, Carson MM, Beeler JA, Krezolek 92. Bottcher MF, Jenmalm MC, Garofalo RP, Bjorksten B. Cytokines in
MP. Differential modulation of the immune response by breast- or breast milk from allergic and nonallergic mothers. Pediatr Res.
formula-feeding of infants. Acta Paediatr. 1997;86:1291–7. 2000;47:157–62.
70. Pickering LK, Granoff DM, Erickson JR, Masor ML, Cordle CT, 93. Bryan DL, Hawkes JS, Gibson RA. Interleukin-12 in human milk.
Schaller JP, Winship TR, Paule CL, Hilty MD. Modulation of the Pediatr Res. 1999;45:858–9.
immune system by human milk and infant formula containing 94. Hawkes J, Bryan DL, Gibson R. Cells from mature human milk are
nucleotides. Pediatrics. 1998;101:242–9. capable of cytokine production following in vitro stimulation. Adv
71. Blaymore Bier JA, Oliver T, Ferguson A, Vohr BR. Human milk Exp Med Biol. 2004;554:467–70.
reduces outpatient upper respiratory symptoms in premature infants 95. Hawkes JS, Bryan DL, James MJ, Gibson RA. Cytokines (IL-1beta,
during their first year of life. J Perinatol. 2002;22:354–9. IL-6, TNF-alpha, TGF-beta1, and TGF-beta2) and prostaglandin E2
72. Cushing AH, Samet JM, Lambert WE, Skipper BJ, Hunt WC, Young in human milk during the first three months postpartum. Pediatr Res.
SA, McLaren LC. Breastfeeding reduces risk of respiratory illness in 1999;46:194–9.
infants. Am J Epidemiol. 1998;147:863–70. 96. Oddy WH, Halonen M, Martinez FD, Lohman IC, Stern DA, Kurzius-
73. Pabst HF, Godel J, Grace M, Cho H, Spady DW. Effect of breast- Spencer M, Guerra S, Wright AL. TGF-beta in human milk is associated
feeding on immune response to BCG vaccination. Lancet. 1989; with wheeze in infancy. J Allergy Clin Immunol. 2003;112:723–8.
1:295–7. 97. Buescher ES, Malinowska I. Soluble receptors and cytokine antag-
74. Hahn-Zoric M, Fulconis F, Minoli I, Moro G, Carlsson B, Bottiger onists in human milk. Pediatr Res. 1996;40:839–44.
M, Raiha N, Hanson LA. Antibody responses to parenteral and oral 98. Buescher ES, McWilliams-Koeppen P. Soluble tumor necrosis factor-
vaccines are impaired by conventional and low protein formulas as alpha (TNF-alpha) receptors in human colostrum and milk bind to
compared to breast-feeding. Acta Paediatr Scand. 1990;79:1137–42. TNF-alpha and neutralize TNF-alpha bioactivity. Pediatr Res.
75. Mimouni Bloch A, Mimouni D, Mimouni M, Gdalevich M. Does 1998;44:37–42.
breastfeeding protect against allergic rhinitis during childhood? A 99. Armogida SA, Yannaras NM, Melton AL, Srivastava MD. Identifi-
meta-analysis of prospective studies. Acta Paediatr. 2002;91:275–9. cation and quantification of innate immune system mediators in
76. Gdalevich M, Mimouni D, Mimouni M. Breast-feeding and the risk human breast milk. Allergy Asthma Proc. 2004;25:297–304.
of bronchial asthma in childhood: a systematic review with meta- 100. Hanson LA. Comparative immunological studies of the immune
analysis of prospective studies. J Pediatr. 2001;139:261–6.
globulins of human milk and of blood serum. Int Arch Allergy Appl
77. Gdalevich M, Mimouni D, David M, Mimouni M. Breast-feeding Immunol. 1961;18:241–67.
and the onset of atopic dermatitis in childhood: a systematic review
101. Slade HB, Schwartz SA. Antigen-driven immunoglobulin production
and meta-analysis of prospective studies. J Am Acad Dermatol.
by human colostral lymphocytes. Pediatr Res. 1989;25:295–9.
2001;45:520–7.
102. Lam QL, Lu L. Role of leptin in immunity. Cell Mol Immunol.
78. van Odijk J, Kull I, Borres MP, Brandtzaeg P, Edberg U, Hanson LA,
2007;4:1–13.
Host A, Kuitunen M, Olsen SF, et al. Breastfeeding and allergic
disease: a multidisciplinary review of the literature (1966–2001) on 103. Casabiell X, Pineiro V, Tome MA, Peino R, Dieguez C, Casanueva
the mode of early feeding in infancy and its impact on later atopic FF. Presence of leptin in colostrum and/or breast milk from lactating
manifestations. Allergy. 2003;58:833–43. mothers: a potential role in the regulation of neonatal food intake.
J Clin Endocrinol Metab. 1997;82:4270–3.
79. Sears MR, Greene JM, Willan AR, Taylor DR, Flannery EM, Cowan
JO, Herbison GP, Poulton R. Long-term relation between breastfeed- 104. Bos JL, Franke B, M’Rabet L, Reedquist K, Zwartkruis F. In search of
ing and development of atopy and asthma in children and young a function for the Ras-like GTPase Rap1. FEBS Lett. 1997;410:59–62.
adults: a longitudinal study. Lancet. 2002;360:901–7. 105. Read LC, Upton FM, Francis GL, Wallace JC, Dahlenberg GW,
80. Bergmann RL, Diepgen TL, Kuss O, Bergmann KE, Kujat J, Ballard FJ. Changes in the growth-promoting activity of human milk
Dudenhausen JW, Wahn U. Breastfeeding duration is a risk factor during lactation. Pediatr Res. 1984;18:133–9.
for atopic eczema. Clin Exp Allergy. 2002;32:205–9. 106. Reber PM. Prolactin and immunomodulation. Am J Med. 1993;
81. Oberle D, Von Kries R, Von Mutius E. Asthma and breast feeding. 95:637–44.
Thorax. 2001;56:896. 107. Chipman DM, Sharon N. Mechanism of lysozyme action. Science.
82. Wright AL, Holberg CJ, Taussig LM, Martinez FD. Factors 1969;165:454–65.
influencing the relation of infant feeding to asthma and recurrent 108. Ellison, 3rd RT, Giehl TJ. Killing of gram-negative bacteria by
wheeze in childhood. Thorax. 2001;56:192–7. lactoferrin and lysozyme. J Clin Invest. 1991;88:1080–91.
83. Greeley SA, Katsumata M, Yu L, Eisenbarth GS, Moore DJ, 109. Sanchez L, Calvo M, Brock JH. Biological role of lactoferrin. Arch
Goodarzi H, Barker CF, Naji A, Noorchashm H. Elimination of Dis Child. 1992;67:657–61.
maternally transmitted autoantibodies prevents diabetes in nonobese 110. Tomita M, Takase M, Wakabayashi H, Bellamy W. Antimicrobial
diabetic mice. Nat Med. 2002;8:399–402. peptides of lactoferrin. Adv Exp Med Biol. 1994;357:209–18.
84. Zinkernagel RM. Maternal antibodies, childhood infections, and 111. Pellegrini A, Thomas U, Bramaz N, Hunziker P, von Fellenberg R.
autoimmune diseases. N Engl J Med. 2001;345:1331–5. Isolation and identification of three bactericidal domains in the
85. Vos A, M’Rabet L, Stahl B, Boehm G, Garssen J. Immune-modulatory bovine alpha-lactalbumin molecule. Biochim Biophys Acta. 1999;
effects and potential working mechanisms of orally applied non- 1426:439–48.
digestible carbohydrates. Crit Rev Immunol. 2007;27:97–140. 112. Stromqvist M, Falk P, Bergstrom S, Hansson L, Lonnerdal B,
86. Perez PF, Dore J, Leclerc M, Levenez F, Benyacoub J, Serrant P, Normark S, Hernell O. Human milk kappa-casein and inhibition of
Segura-Roggero I, Schiffrin EJ, Donnet-Hughes A. Bacterial imprint- Helicobacter pylori adhesion to human gastric mucosa. J Pediatr
ing of the neonatal immune system: lessons from maternal cells? Gastroenterol Nutr. 1995;21:288–96.
Pediatrics. 2007;119:e724–32. 113. Adkins Y, Lonnerdal B. Potential host-defense role of a human milk
87. Ridge JP, Fuchs EJ, Matzinger P. Neonatal tolerance revisited: turning vitamin B-12-binding protein, haptocorrin, in the gastrointestinal
on newborn T cells with dendritic cells. Science. 1996;271:1723–6. tract of breastfed infants, as assessed with porcine haptocorrin in
88. Lemke H, Lange H. Is there a maternally induced immunological vitro. Am J Clin Nutr. 2003;77:1234–40.
imprinting phase a la Konrad Lorenz? Scand J Immunol. 1999;50: 114. Cawston T, Carrere S, Catterall J, Duggleby R, Elliott S, Shingleton
348–54. B, Rowan A. Matrix metalloproteinases and TIMPs: properties and
89. Reiner SL. Development in motion: helper T cells at work. Cell. implications for the treatment of chronic obstructive pulmonary
2007;129:33–6. disease. Novartis Found Symp. 2001;234:205–18.
90. Gocke AR, Cravens PD, Ben LH, Hussain RZ, Northrop SC, Racke 115. Peterson JA, Patton S, Hamosh M. Glycoproteins of the human milk
MK, Lovett-Racke AE. T-bet regulates the fate of Th1 and Th17 fat globule in the protection of the breast-fed infant against
lymphocytes in autoimmunity. J Immunol. 2007;178:1341–8. infections. Biol Neonate. 1998;74:143–62.
91. Bottcher MF, Jenmalm MC, Bjorksten B, Garofalo RP. Chemo- 116. Newburg DS, Ruiz-Palacios GM, Morrow AL. Human milk glycans
attractant factors in breast milk from allergic and nonallergic protect infants against enteric pathogens. Annu Rev Nutr. 2005;25:
mothers. Pediatr Res. 2000;47:592–7. 37–58.

The role of breastfeeding on immune maturation 1789S

117. Garofalo RP, Goldman AS. Expression of functional immunomod- 127. Lara-Villoslada F, Olivares M, Sierra S, Rodriguez JM, Boza J, Xaus
ulatory and anti-inflammatory factors in human milk. Clin Perinatol. J. Beneficial effects of probiotic bacteria isolated from breast milk.
1999;26:361–77. Br J Nutr. 2007;98: Suppl 1:S96–100.
118. Hamosh M, Peterson JA, Henderson TR, Scallan CD, Kiwan R, 128. Martin R, Heilig GH, Zoetendal EG, Smidt H, Rodriguez JM.
Ceriani RL, Armand M, Mehta NR, Hamosh P. Protective function Diversity of the Lactobacillus group in breast milk and vagina of
of human milk: the milk fat globule. Semin Perinatol. 1999;23: healthy women and potential role in the colonization of the infant
242–9. gut. J Appl Microbiol. 2007;103:2638–44.
119. Duchen K, Yu G, Bjorksten B. Atopic sensitization during the first 129. Visser HKA. Dietary influences on infection and allergy in infants:
year of life in relation to long chain polyunsaturated fatty acid levels Introduction. J Nutr. 2008;138:1768S–9S.
in human milk. Pediatr Res. 1998;44:478–84. 130. Wahn HU. Strategies for atopy prevention. J Nutr. 2008;138:1770S–2S.
120. Jyonouchi H, Zhang-Shanbhag L, Georgieff M, Tomita Y. Immuno- 131. Szépfalusi Z. The maturation of the fetal and neonatal immune
modulating actions of nucleotides: enhancement of immunoglobulin system and allergy. J Nutr. 2008;138:1773S–81S.
production by human cord blood lymphocytes. Pediatr Res. 1993;
132. Morelli L. Postnatal development of interstinal microflora as
34:565–71.
influenced by infant nutrition. J Nutr. 2008;138:1791S–5S.
121. Schlimme E, Martin D, Meisel H. Nucleosides and nucleotides:
133. Biasucci G, Benenati B, Morelli L, Bessi E, Boehm G. Cesarean
natural bioactive substances in milk and colostrum. Br J Nutr. 2000;
delivery may affect the early biodiversity of intestinal bacteria.
84: Suppl 1:S59–68.
J Nutr. 2008;138:1796S–800S.
122. Rueda R. The role of dietary gangliosides on immunity and the
134. Chirico G, Marzollo R, Cortinovis S, Fonte C, Gasparoni A.
prevention of infection. Br J Nutr. 2007;98: Suppl 1:S68–73.
Antiinfective properties of human milk. J Nutr. 2008;138:1801S–6S.
123. Pan XL, Izumi T. Chronological changes in the ganglioside compo-
135. Gottrand F. Long-chain polyunsaturated fatty acids influence the
sition of human milk during lactation. Early Hum Dev. 1999;55:1–8.
immune system of infants. J Nutr. 2008;138:1807S–12S.
124. Admyre C, Johansson SM, Qazi KR, Filen JJ, Lahesmaa R, Norman
136. Lafeber HN, Westerbeek EAM, van den Berg A, Fetter WPF, van
M, Neve EP, Scheynius A, Gabrielsson S. Exosomes with immune
Elburg RM. Nutritional factors influencing infections in preterm
modulatory features are present in human breast milk. J Immunol.
infants. J Nutr. 2008;138:1813S–7S.
2007;179:1969–78.
137. Boehm G, Moro, G. Structural and functional aspects of prebiotics
125. Jarvinen KM, Suomalainen H. Leucocytes in human milk and
used in infant nutrition. J Nutr. 2008;138:1818S–28S.
lymphocyte subsets in cow’s milk-allergic infants. Pediatr Allergy
Immunol. 2002;13:243–54. 138. van Goudoever J, Corpeleijn W, Riedijk M, Schaart M, Renes I, van
der Schoor S. The impact of enteral IGF-1 and nutrition on gut
126. Xanthou M. Human milk cells. Acta Paediatr. 1997;86:1288–90.
permeability and amino acid utilization. J Nutr. 2008;138:1829S–33S.

1790S Supplement