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J. Arab Neonatal Forum 2005; 2: 5-11

5

Development of the Immune System in Neonates

Gaetano Chirico Division of Neonatology and Neonatal Intensive Care, Spedali Civili, Brescia, Italy

Introduction

Neonatal age is characterized by a delicate process ofadaptation from intra- to extra-uterine life. Theimmune system is particularly subject to problems ofadaptation; indeed, a mature immune competencecould cause unfavorable effects due to maternal-fetalantigenic incompatibility, and is unnecessary to thefetus, which develops in a highly protective germ-freeenvironment. The newborn infant, on the other hand,must be capable of defending himself against hostilemicro-organisms in the surroundings. As a result ofthese contradictory requirements the immune system isincompletely developed at birth. The antigenicinexperience and the prevalence of suppression factorsduring fetal life are responsible for the physiologicalimmaturity of the immune function in newborn infants.The high incidence of infectious disease (e.g. 1% ofsepticemia) in the perinatal period is a directconsequence of the precarious host-parasite balance. In

preterm neonates the immunodeficiency is more severe

and prolonged, and is associated with a higher

incidence of infection and sepsis1, 2

, and increased riskof morbidity, mortality and neurological sequelae 3. Inaddition, due to immaturity of hematological system,anemia, thrombocytopenia or neutropenia arefrequently observed during sepsis, particularly in verylow birth weight infants.

Detrimental consequences of immunodeficiency aremostly mitigated by some naturally occurringcompensatory mechanisms. The transplacental passageof high avidity IgG antibodies 4 (particularly of theIgG1 subclass 5) from mother to fetus duringintrauterine life is probably the most important one.After birth human milk maintains the mother-newbornimmunological link by providing a host of protectivecomponents. Indeed, most of the cells and solublefactors that are deficient in the neonate are present inhuman milk (Table 1) 6, 7 .

Host defense mechanisms against pathogens areusually classified into two main components,the innate (natural, non specific) and the adaptive

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Correspondence to: Gaetano Chirico, Divisione di Neonatologiae Terapia Intensiva Neonatale, Spedali Civili, 25123 Brescia,Italy, Tel. No. +39 030 3995219; Fax No. +39 030 3700817 E-mail: [email protected]

(acquired, specific) immune systems. Skin andmucosal barriers, neutrophils, monocytes,macrophages, dendritic cells, antigen presentingcells derived cytokines, mast cells, T and B-1

lymphocytes, type I interferon, natural killer cells,complement, fibronectin, defensins, lysozyme,myeloperoxidase, natural antibodies and othernatural antimicrobial agents provides protection

Table 1. Immunological and Antiinfective Components in Human Milk _____________________________________________________________________________________________Soluble Specific immunity factors: Immunoglobulins sIgA (11S), 7S IgA, IgG, IgM, IgE, IgD, Secretory component, Anti-

idiotypes, Histocompatibility antigens Cytokines, Chemokines and receptors : IL-1 IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-16, IL-18, IFN- ,

TNF- , G-CSF, M-CSF, GM-CSF, GRO- MCP-1, RANTES, TGF- 1 e 2, sCD14, Toll Like receptor, sFas,sFasL.

Innate immunity factors : Complement, Chemotactic factors, Lactoferrin, Lysozyme, Properdin factors, Mannan binding lectin, Interferon, Alphafetoprotein, Antiadherence substances (oligosaccharides, mucins, lactadherin,glycans, k-casein), Antiviral factors, MiIk fat globule, Migration inhibition factor, sCD14, -defensin-1, Fattyacids, monoglycerids, pre- and postdigestion antimicrobial peptides

Prebiotics, Bifidogenic factors, Oligosaccharides Hormones and growth factors : prolactin, cortisol, insulin, thyroxine, prostaglandins, erythropoietin, EGF, VEGF,

NGF,TGF) Others : Carrier proteins, Enzymes, Nucleotides, LCPUFA, HAMLET (human -lactalbumin made lethal to tumor

cells)

Breast Milk Cells Total counts: Colostrum: 1-3 x 10 6/ml; mature milk: ~ 1 x 10 5/ml Cell types :

o Macrophages: ~ 60% (Lisozime, Lactoferrine, IgA, Complement, Cytokines, Factor B, Phagocytosis,Bactericidal activity, APC)

o Neutrophils: ~ 25% (Phagocytosis, Bactericidal activity)o Lymphocytes: ~ 10% (80% Activated T lymphocytes, Cytokines, IgA)

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without the need for prior sensitization to theforeign antigen and represents a rapid first line

barrier against pathogens. Most cells of the innateimmunity contribute to the antigen processing and

presentation 8. T and B lymphocytes, antibodies,natural killer cells, colony stimulating factors, T

cell derived effector and immunoregulatorycytokines, and Interferon- , are the maincomponents of the adaptive immunity. A previousexposure and sensitization is necessary for theacquired specific response against antigens. Thetwo components are strictly interconnected; severalfactors of both innate and adaptive immune systemare usually involved and may simultaneously

participate in the response against infection.

Hematopoietic progenitor cellsThe ontogeny of immune system starts early in theembryo, continues during fetal life and iscompleted only several years after birth.Hematopoietic cells appear in the embryo at the3rd-4th week of gestation, migrate from the yolksac to the liver and spleen during the 5th-12thweek and ultimately reach the bone marrowthrough the fetal circulation at the 2nd-3rdtrimester of gestation. T lymphocyte differentiationinitiates in the thymus after the 7th week ofgestation, but T-cells only colonize the fetal liver,spleen and bone marrow after the 13th week.Helper and suppressor activities of fetalthymocytes and splenocytes are acquired between

the 12th and the 16th week. HLA antigens are firstdetected in the lymphocytes at the beginning of thesecond trimester 9.

Hematopoietic progenitor cells usually express theCD34 surface antigen and the so-called stem cellsmay be identified by the absence of CD38, HLA-

DR and lineage committed antigens on CD34 + cells 10. Human umbilical cord blood is considered arich source of early hematopoietic progenitor cells.The percentage and the absolute number of CD34 + cells are significantly higher in very pretermfoetuses less than 25 weeks of gestation compared

to more mature preterm and term newborns, with asignificant inverse correlation between number ofCD34 + cells and advancing gestational age. Thehighest proliferative activity is observed at thelowest gestational ages, especially for the mostundifferentiated hematopoietic stem cells, and

progressively decreases with advancing gestationalage. The extremely preterm foetus has asignificantly more immature pool of circulatingcord blood hematopoietic progenitor cells ascompared to term infants, furthermore the processof development in foetal blood appear to be veryactive during the last two trimesters of pregnancy 11 .

Lymphocytes and cytokines Neonatal T lymphocytes immunoproliferation toConcanavalin A, in both preterm and term infants,is significantly lower as compared to children andadults 12. Most studies have reported significant

phenotypic differences between neonatal and adultT cells, suggesting a reduction of cell mediatedimmune response, although more recent reportshave documented that neonatal T cell, thoughnave, can raise competent immune responsesunder appropriate stimuli 13. The percentage of

CD4+

T lymphocytes is higher in newborns, particularly in preterm infants, than in children andadults. On the contrary, CD8 + cells are higher atolder ages, with a resulting gradual decline withage of the CD4 +/CD8 + ratio, suggesting a gradualcytotoxic response maturation with advancing age(Figure 1).

Figure 1. Percentage of CD4 + and CD8 + T lymphocytes and CD4 +/CD8 + ratio in very preterm newborns of 20-29 weeksgestational age, preterm newborns of 30-37 weeks gestational age, term newborns, children and adults 10.


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Percentages of CD4 +/CD45RA + are significantlyhigher and of CD4 +/CD45RO + T cells lower innewborns than in children and adult. The fetal-neonatal

predominant nave phenotype is likely to be related tothe absence of antigenic stimulation in the germ freeintrauterine environment. 12 Under standard activation

conditions, naive neonatal T cells are functionally(although not intrinsically) deficient, both in vitro andin vivo 14. Th1 derived IFN - and TNF - are lower inthe neonate 15. A reduction of CD40-ligand expression

by neonatal T cells may contribute to the delayeddifferentiation of nave T cell into Th1 effector cells 16.

The percentage of IL-2 producing cells is higher, bothfor CD4 + and CD8 + T cells, in newborns, while the

percentage of IL-4 producing cells is higher for CD8 + and lower for CD4 + T cells in cord blood than at olderages. On the other hand, IFN- synthesis issignificantly impaired in both CD4 + (about ten folds)and CD8 + cells (about five folds). 12 The decreased

percentage production of IL-4 and IFN- in cord bloodas compared to that in children and adults may be

justified by a switch from CD45RA + to CD45RO + phenotype, since in adults both IL-4 and IFN- aremostly produced by CD45RO + cells 17,18 . A reduced

production of IL-12 by mononuclear and dendriticcells may contribute to the neonatal IFN- deficiency. 19, 20, 21 The percentage of IL-10 secretingcells is reduced in the CD4 + population and increasedin CD8 + population during fetal life. 12 This finding may

partly explain the apparent discrepancy in studies

reporting low or high IL-10 production in neonates.22,

23 The high IL-10 levels produced by neonatal T cellsmay play an important role in the reduced incidence ofGVHD that is associated with cord bloodtransplantation 24.On the whole, cord blood T lymphocytes are less ableto perform Th1 and Th2-like responses 25. Due to themore important IFN- deficiency, it is suggested thatthe Th1-like response is more compromised inneonates 26, 27 and that a progressive maturation towardsthe Th1-like response occurs with age 28. It should benoted, however, that neonatal T cells are capable ofraising type 1 and 2 immune responses uponappropriate stimulus. 29, 30

Several differences of B cell surface phenotype, asincreased CD10 and CD38 and reduced CD21, CD32,adhesion molecules and class II MHC expression have

been observed in neonates. 1

The immaturity of T and B lymphocytes and of antigen presenting cells (in particular reduced level ofexpression of HLA-DR, CD1a, CD40, CD80, ICAM-1and IL-12) are responsible for the marked deficiencyof antibody production in the neonate 31. Indeed, theswitch from IgM to other immunoglobulin isotypes isdelayed, only low levels of IgM are produced duringthe first month of life in response to antigenicchallenge, and no response to lipopolysaccharide

antigen may be observed. In addition, levels of IgG arelow in preterm infants because transplacental passagefrom the mother mostly occurs during the last trimesterof gestation. Therefore, preterm neonates may lack the

protection ensured by maternal derived pathogen-specific IgG 32.

Neonatal immunization does not generally lead to rapidantibody responses; however, it may result in efficientimmunologic priming which can act as a basis forfuture responses. It is therefore possible to induce early

protection, for instance against hepatitis B infection 33 or pertussis disease 34, by immunization at birth, even in

preterm infants 35.

Monocytes, macrophages and dendritic cells.Main activities of these components of immune systemare phagocytosis and subsequent antigen processingand presentation to lymphocytes, or pathogen killing.

This last activity depends on the secretions ofcytokines, mainly IFN- , IL-12 and IL-18. The reducedsynthesis of these cytokines in newborn infants mayresults in increased susceptibility to infection byintracellular bacteria. 8

Polymorphonuclear GranulocytesSince neonates have an already compromisedneutrophil storage pool, during neonatal sepsis themarrow stores of neutrophils are rapidly exhausted. In

peripheral blood high neutrophil counts can be foundinitially during infection but later neutropenia developsfrequently. A severe leucopenia may often be observedduring early sepsis, particularly by Group BStreptococcus. Together with the reduced leukocytenumbers during severe infections or stress, variousabnormalities have been demonstrated in the functionof neonatal polymorphonuclear granulocytes, likedecreased deformability, adhesion, chemotaxis,

phagocytosis, receptor expression, depressed oxidativemetabolism and bacterial killing. 1, 36 The quantitative(compromised neutrophil storage pool and rapidexhaustion of the marrow stores of neutrophils duringsepsis) and qualitative deficiency of the phagocytesystem is considered one of the most importantcontributory cause of the neonatal increasedsusceptibility to infection. The combined neonataldeficiency of immunoglobulin, complement andneutrophil activity results in increased susceptibility tosystemic infections from encapsulated pathogens, suchas Group B Streptococcus, Staphylococci andKlebsiella sp, which require opsonization for efficient

phagocytosis and killing 37.

Hematopoietic growth factorsGranulocyte Colony Stimulating Factor (G-CSF) andGranulocyte-Macrophage Colony Stimulating Factor(GM-CSF) are important cytokines for proliferation,

differentiation, survival and functional activation of phagocytes. G-CSF and GM-CSF have been shown tostimulate myeloid progenitor proliferation, to increase

bone marrow neutrophil storage pool, to induce


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neutrophilia in the peripheral blood, to prime maturecell function including chemotaxis, oxidativemetabolism, phagocytosis and antibody dependentcellular cytotoxicity, to modulate C3bi, FcRIII andCR3 receptor expression and to enhance the

bactericidal activity of polymorphonuclearneutrophils. 38, 39, 40 A reduced GM-CSF and G-CSF

gene expression, due to mRNA post-transcriptionalinstability, and protein production from mononuclearcells 41 and GM-CSF production by T cells 42 wasobserved in neonates. We found a significant reductionof G-CSF serum concentration in preterm infants, thelower the gestational age or birth weight, the greaterthe deficiency, and a reduced response to infection 43.The neutropenia observed during sepsis may be partlydue to inability of infants to produce G-CSF. 44, 45

The use of G-CSF and GM-CSF is considered a firstline treatment for the severe congenital neutropenia(Kostmanns syndrome) 46. Other possible indicationsfor the use of G-CSF in newborns are neutropenia ininfants of mothers with preeclampsia 47, 48 and neonatalisoimmune (alloimmune) neutropenia 49. The deficiencyof G-CSF and GM-CSF production, particularly in

preterm infants, and a resistance, or delayed response,of myeloid precursors to the higher concentration ofendogenous G-CSF in infected term newborn infantshave justified therapeutic trials with pharmacologicaldoses of G-CSF and GM-CSF. These cytokines have

been evaluated in neutropenic infected term infants, toaccelerate the onset of neutrophilia, or in preterminfected infants, even in the absence of severeneutropenia, to improve neutrophil function, or inneutropenic term and preterm infants for prophylaxisof infection 50. Preliminary clinical trials on the use ofG-CSF and GM-CSF for prevention or treatment ofsepsis have given promising results, suggesting that 5-10 g/kg/day of G-CSF or GM-CSF for 3-10 days mayimprove neutrophil counts or prevent infection inneutropenic infants. Hematopoietic growth factors were well tolerated, and no significant short or longterm side effects were observed 51.

These reports were evaluated in two meta-analysis 52, 53 ,the most recent including seven studies with 257

infected neonates, and three infection prophylaxis trialsinvolving 359 high risk newborns. The conclusionsdrawn from these meta-analyses were that nosignificant effect was observed of CSFs treatment ofsepsis in non neutropenic infants, while a significantimprovement of mortality at 14 days was found whenthe infants were neutropenic, as compared to untreated

controls [RR 0.34 (95% CI 0.12, 0.92); RD -0.18 (95%CI -0.33, -0.03); NNT 6 (95% CI 3-33)], and that GM-CSF use did not appear significantly effective ininfection prophylaxis [RR 0.59 (95% CI 0.24,1.44);RD -0.03 (95% CI -0.08,0.02)].

Although further studies on larger population of infantsare necessary to confirm the efficacy and to rule outthe possibility of significant side effects, such as non-lymphoblastic leukemia observed in infants withKostmann syndrome treated for long periods, G-CSFand GM-CSF may represent a valuable therapeutic toolfor treating neonatal neutropenia and improve thedepressed neutrophil function of the neonate.

Evaluation of association of several cytokines orcombination with other factors, as intravenousimmunoglobulin, may be the next step in neonatalresearch.Hematopoietic growth factors (in particular G-CSF anderythropoietin solutions for enteral administration) arecurrently being evaluated to improve intestinalmaturation during total parenteral nutrition or afterintestinal surgery for necrotizing enterocolitis ormalformation 54.

ComplementSynthesis of classic and alternative complement

pathway factors is reduced in neonates, the lower thegestational age, the greater the deficiency. In addition,kinetics of both classical and alternative pathwayactivity of complement are delayed, particularly in

preterm newborns. C3b and C5a complement factorsdeficiency is responsible for the severe impairment ofneonatal serum opsonic and chemotactic activities 55.

Figure 2 . Natural Killer (NK) cell activity with effector:target ratios of 100:1, 30:1 and 10:1 in very pretermnewborns of 20-29 weeks gestational age, preterm newborns of 30-37 weeks gestational age, term newborns,children and adults. 12

0

10

20

30

40

50

60

NK 100:1 NK 30:1 NK 10:1

Very preterm

Preterm

Term

Children

Adults

%

Figure 2 . Natural Killer (NK) cell activity with effector: target ratios of 100:1, 30:1 and 10:1 in very preterm newborns of20-29 weeks gestational age, preterm newborns of 30-37 weeks gestational age, term newborns, children and adults 10


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Natural killer cell Natural killer (NK) cell activity, that is implicated inGVHD pathogenesis and represents an importantinnate immune defense mechanism against tumors andviral infections, is significantly reduced in preterm andterm infants 56 as compared to children and adults,although in adults a tendency to a reduction may be

observed (figure 2). In addition, NK activity issignificantly correlated with gestational age. 12 Areduced CD56 high and increased CD56 low expression ischaracteristic of neonatal immature NK cells. 16 Thereduction of NK activity could be related to the IL-12and IL-15 deficiency 57. The NK insufficiency cancontribute to increased incidence, severity andtendency to chronicity of perinatal viral infections.

In conclusion, the reduced cytotoxic response duringfetal life, the poor T lymphocytes response tomitogens, the immaturity of T and B lymphocytes, theinadequate cytokine synthesis, the marked deficiencyof antibody production and the reduced neutrophil,complement and natural killer cell activity areimportant contributory factors to the complexdeficiency of immunological function in the neonateand may represent the biological basis for the increasedsusceptibility to various infections and the reducedclearance of intracellular pathogens. At the same time,these characteristics of the neonatal immunity maycontribute to the reduced incidence and severity ofGVHD in patients transplanted with umbilical cord

blood (CB) compared to bone marrow 58, 59 .

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si nos neonatos

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