6inmunidadenneonatosperez-mena

8/6/2019 6inmunidadenneonatosperez-mena

1/7

Veterinary Immunology and Immunopathology 87 (2002) 207213

Immunity in neonates

Bror Moreina, Izzeldin Abusugraa, Gunilla Blomqvistb,*

Section of Virology, Department of Veterinary Microbiology, Faculty of Veterinary Medicine,Swedish University of Agricultural Sciences, Biomedical Centre, Box 585, S-751 23 Uppsala, Sweden

bVirology Department, National Veterinary Institute, Biomedical Centre, Box 585, S-751 23 Uppsala, Sweden

a

Abstract

Passively derived maternal immunity hampers active immunization of newborns. Further, an immature immune systemcontributes to a weak and Th2 polarized immunity. This state of immunity in early life sustains endemic infections in manandcontinuous reinfections in animal herds. The endemic infections of the young occur preferentially when the immune systemisstill functionally immature and when the low levels of maternal antibodies are no longer protective but yet blocks protectiveimmune responses. Vaccines overcoming these problems would have strong positive effects on the herd health and environ-mental benets. The Th2 bias of the newborn is mediated by high levels of progesterone and Th2 cytokines produced in thematernalfetal interface. The activity of the innate system is enhanced in the mother during the prepartus period, certainlyhaving effects on the offspring. Newborn, 2-days-old, mice can be primed with Sendai virus envelope proteins as modelantigensto induce Th1 or Th2 responses, dependent on the supplementation of the virus antigen formulation with Th1 or Th2

adjuvants.This priming has a strong life-long effect when complemented with subsequent boosts. However and importantly this primingeffect can be modulated by adjuvants focusing for Th1 and Th2 when applied to the mice at 6 weeks of age, i.e. when theyareimmunologically adult. It has been shown in various species, besides mice, i.e. dog, sheep, horse and seal, that a strong Th1driving adjuvant can induce immune response and protection in newborns when conventional vaccines fail. In conclusion, the

Th2 bias prevailing around partus can be overcome by appropriate immunological treatments, permitting effectivevaccinationand protective immunity in the newborn. # 2002 Elsevier Science B.V. All rights reserved.Keywords: Veterinary immunology; Neonate; Maternal immunity; Vaccine; Adjuvants; T helper cells; Th1/Th2

1. Introduction

Active immunization of newborns by natural infec-tion or vaccination is hampered by an immatureimmune system and by passively derived maternalimmunity. This early life situation prevails in most ifnot all mammalian species and contributes to endemicinfections of human and animal populations, sustain-ing a continuous prevalence of viral infections in

Corresponding author. Tel.: 46-18-674335;fax: 46-18-4714517.E-mail address: [email protected] (G. Blomqvist).

*

animal herds. Infections of the young occur preferen-tially when the immune system is still functionallyimmature and when the maternal antibodies have

vanished to non-protective levels, but still block pro-tective immune responses. Vaccines overcoming theproblem with the immature immune status and block-ing effects of passively transferred antibodies wouldhave strong positive effects on the herd health, dimin-ish the use of antibiotics and result in economical andenvironmental benets.

It is becoming more and more evident that new-borns are immune competent although with a biased

Th2 prole. In early days it was conceived that

0165-2427/02/$ see front matter # 2002 Elsevier Science B.V. All rights reserved.PII: S 0 1 6 5 - 2 4 2 7 ( 0 2 ) 0 0 0 7 8 - 8


2/7


3/7

B. Morein et al. / Veterinary Immunology and Immunopathology 87 (2002) 207213 209

Fig. 1. The window of susceptibility to infectious disease circulating in the herd. During the time period, marked by the arrows, neither thelevels of maternal antibodies nor the endogenous produced antibodies are high enough to prevent infection.

competence of newborns to respond to active immu-nization has gradually changed to realize that thecompetence might be low, but it is there, and canbe used if the conditions of the newborn is taken intoconsideration.

4.1. Defects of the neonate innate immune system

The initiation of the adapted immune response

occurs in the innate system. There are a number ofprerequisites required from this system for inductionof a specic immune response, which are not fullledby the newborn. The antigen presenting cells (APCs)most importantly the dendritic cells (DCs) of thenewborn have reduced capacity to express CD86and CD40 (Marshall-Clarke et al., 2000) and thecorresponding ligands on the lymphocytes arereduced. These surface molecules are required onthe APCs to give signal to the T cells via correspond-ing ligands (costimulation) to expand antigen specicclones. The upregulation of the MHC class II antigenson the surface of the APCs is also reduced. The MHCclass II antigens are required to present the vaccineantigens, after that the vaccine antigens have beenezymatically processed in the APC, to the T lympho-cytes to obtain the specic T cell response. Theneonate spleen is not developed. It lacks a structure(architecture) of the adult spleen. To achieve themature structure the proinammatory cytokines lym-photoxin (LT) and tumor necrosis factor (TNF) arerequired. Structures missing in the neonate spleen are

perarteriolar lymphoid sheath (PALS), germinal cen-ters (GC) and B cell follicles develop late. FurtherMHC class II DCs and macrophages are sparse orundetectable and the antigen processing and present-ing capacities are acquired late in ontogeny. Interest-ingly, in vitro, the antigen presenting capacity, byadding adult APCs (DC), having appropriate expres-sion of CD40, can tip the immune response to adultlevels. Simultaneous there is an upregulation of thecorresponding ligand (CD40L) on the T cells.

The neonatal B cells have also a number of defec-tives hampering their immunological capacity. B cellsare also APCs. The B cell ligation is defective result-ing in incomplete signaling to acquire immune spe-cic immune response. Incomplete signaling is alsodue to low expression of MHC class II, lack of CD86and its ligand on T cells lead to lack of costimulationand hampers BT cell cross talk. It should be born inmind that a B and T cell interaction is, in most cases,required for specic B cell (antibody) response. Thelack of upregulation of CD40 and CD40L hampers theB cell response and the B cell switch to different B cellclasses and subclasses. These defects are likely tocause anergy and possibly Th2 bias (Marshall-Clarke

et al., 2000).

5. The Th2 bias of the immature immune system

There is conicting information about the Th2bias and the tolerance of the immune system of the


4/7

210 B. Morein et al. / Veterinary Immunology and Immunopathology 87 (2002) 207213

Fig. 2. The placenta of the maternalfetal interface is a strongproducer of Th2 cytokines including IL-4, IL-10 and TGF-b drivenby progesterone and prostaglandin E2. The Th2 inuence isconceived to prevent immunological driven abortion.

newborns. There are certainly differences betweenspecies and most information is derived from workin mice and in man. From above it can be concludedthat a partially defective innate system may contributeto a Th2 bias. Besides, the placenta during the preg-nancy period is likely to have a strong effect both onthe mother as well as on the offspring (Fig. 2).Th1responses are suppressed by placental products such asprogesterone, prostaglandin E2 and cytokines such asIL-4 and IL-10. (Wegmann et al., 1993; Sacks et al.,1999; Rukavina and Podack, 2000). It is likely that the

Th2 inclination exerted by the placenta on the motherand probably also on the fetus has evolved to evadeimmunological rejection of the fetus.

5.1. Potent adjuvants can overcome the Th2 bias

Experiments were carried out in Uppsala to explorethe rigidity of the dogma that the newborn has a strongtendency to adopt a Th2 prole, and that an early lifeimmunization conserves this polarization. Th1 and

Th2 responses were induced to Sendai virus (SV) inneonate, i.e. 2-days-old mice, by aid of adjuvants. Theaim was to investigate the nature of the primaryneonate immunity and the inuence of the primaryresponse on a subsequent adult secondary immuniza-tion. Further, the immune ontogeny was analyzed toexplore the immune responses during an extendedperiod of life. Thus, Balb/c mice were immunizedwith envelope proteins of SV in three different antigenpresentation systems including ISCOMs with capacity

to enhance Th1 response, Th2 adjuvanted micelles byadsorbtion to Al(OH)3 and non-adjuvanted micellesformulation. The ISCOM formulation (SV-ISC)induced a Th1 prole, i.e. a prominent IFN-g response

after a neonatal priming. Further the ISCOM modu-lated a neonatally induced primary Th2 immuneresponse towards Th1 when given as a subsequentimmunization. The Al(OH)3 formulation (SV-alMIC)induced in newborns a primary Th2 response withproduction of IL-5 and a detectable IgG1 antibodyresponse and it modulated a neonatally induced Th1response towards Th2. The non-adjuvanted micelleformulation (SV-MIC), requiring a 20-fold higherdose than adjuvanted formulations, induced Th1 sup-pression, which was overcome by a subsequent SV-ISC immunization. It is notable that only the Th2driving adjuvant could induce detectable antibody

response in 2-days-old mice conned to the IgG1subclass. Others have reported that 1-week-old micecan respond with a primary specic IgG2a. It shouldbe noted that Al(OH)3 has a depot effect which mightextend the antigen release for several days. A singleimmunization with the Al(OH)3 formulation inducedan immune response lasting as long as the micewere kept alive (up to 68 months). Thus, our ndingsshow that neonatal immunization to a large extentpaves the way for a geared postnatal immunity but alsothat later immunizations do have potential to modify aneonatally polarized immune response. The immuneresponses induced lasted as long as the mice were keptalive (up to 68 months). Furthermore, the Th1Th2

Table 1Ratio of SV specic IgG2a and IgG1 serum antibodies of mice 8weeks and 68 months after neonatal priming at 48 h of age andboost at 6 weeks of age

Priming Boosting n IgG2a/IgG1 ratio

6 Weeks

SV-ISCSV-ISCSV-ISCSV-MICSV-MICSV-MICSV-alMICSV-alMICSV-alMIC

SV-ISCSV-MICSV-alMICSV-ISCSV-MICSV-alMICSV-ISCSV-MICSV-alMIC

344555544

0.880.810.500.560.360.140.760.520.57

8 Weeks68 months

0.920.890.740.840.710.510.850.670.70


5/7

B. Morein et al. / Veterinary Immunology and Immunopathology 87 (2002) 207213 211

prole was kept, but with a more prominent increaseof the IgG2a antibodies (Table 1). Our results do notsupport the proposal that re-exposure to antigen after aneonatal priming generally results in a Th2 dominated

immune response (Barrios et al., 1996; Adkins andDu, 1998).

6. Maternal immunity inuences the antibodyand cell mediated immune responsesafter immunization of the offspring

The inuence of the presence of maternal anti-bodies on the immune responses in offspring after

neonatal immunization with SV envelope proteins inISCOMs was analyzed. It was found that maternalimmunity of mothers immunized with Al(OH)3 adju-vanted micelles of SV suppressed an endogenous SV

specic antibody production regardless the offspringwas immunized at neonatal (2 days) of age or as adults(6 weeks of age). In contrast, a signicant suppressionof the Th1 cell response, measured as IFN-g produc-tion was recorded after neonatal but not after adultimmunization. The inhibition of the IL-5 productionwas on the other hand insignicant. These suppressiveeffects by maternal immunity was only partial, sincethe neonatal immunization primed for both IgG2aantibody and T cell (IFN-g) responses recorded as

Fig. 3. The maternal immune status caused by vaccination inuences the T cell immune response of the offspring to the ISCOM vaccinemeasured by IFN-g/IL-5 ratio.


6/7

212 B. Morein et al. / Veterinary Immunology and Immunopathology 87 (2002) 207213

Table 2Experimental vaccines in neonates

Viral antigen

Herpes Equi 2Parvovirus

Canine distemperRotavirus (oral)

Sendai virus

Subject

10-Days-old foals3-Weeks-old dogs

Day old seals1-Week-old lambs

2-Days-old mice

Outcome

ProtectionHigh levels of HIantibodyProtectionImmuneresponse/protection?T and B cell responses

Can lymphatic organ architecture be influenced andestablished earlier e.g. by proinflammatory cyto-kines?Potent adjuvants can overcome some of these

problems.

References

Adkins, B., 1999. T-cell function in newborn mice and humans.Immunol. Today 20 (7), 330335.

Adkins, B., Du, R.Q., 1998. Newborn mice develop balanced Th1/Th2 primary effector responses in vivo but are biased to Th2secondary responses. J. Immunol. 160, 42174224.

Adkins, B., Ghanei, A., Hamilton, K., 1994. Up-regulation ofmurine neonatal T helper cell responses by accessory cellfactors. J. Immunol. 153 (8), 33783385.

Astori, M., Finke, D., Karapetian, O., Acha-Orbea, H., 1998.Development of TB cell collaboration in neonatal mice. Int.Immunol. 11, 445451.

Barrios, C., Brandt, C., Berney, M., Lambert, P.H., Siegrist, C.A.,1996. Partial correction of the TH2/TH1 imbalance in neonatalmurine responses to vaccine antigens through selectiveadjuvant effects. Eur. J. Immunol. 26, 26662670.

Billingham, R.E., Brent, L., Medawar, P.B., 1953. Activelyacquired tolerance of foreign cells. Nature 172, 603606.

De Carli, M., Elios, M.M.D., Zancuoghi, G., Romagnani, S., DelPrete, G., 1994. Human Th1 and Th2 cells: functionalproperties regulation of development and role in autoimmunity.Autoimmunity 18, 301308.

Delespesse, G., Yang, L.P., Ohshima, Y., Demeure, C., Shu, U.,Byun, D.G., Sarfati, M., 1998. Maturation of human neonatalCD4 and CD8 T lymphocytes into Th1/Th2 effectors.Vaccine 16, 14151419.

Forsthuber, T., Yip, H.C., Lehmann, P.V., 1996. Induction ofTH1 and TH2 immunity in neonatal mice. Science 271,17281730.

Grewe, M., Bruijnzeel-Koomen, C.A.F.M.,Schopf, E., Thepen, T.,

Langeveld-Wildschut, A.G., Ruzicka, T., Krutmann, J., 1998. Arole for Th1 and Th2 cells in the immunopathogenesis of atopicdermatitis. Immunol. Today 19 (8), 359361.

Kovarik, J., Siegrist, C.A., 1998. Immunity in early life. Immunol.Today 19 (4), 150152.

Marshall-Clarke, S., Reen, D., Tasker, L., Hassan, J., 2000.Neonatal immunity: how well has it grown up? Immunol.Today 21 (1), 3541.

Martinez, X., Brandt, C., Saddallah, F., Tougne, C., Barrios, C.,Wild, F., Dougan, G., Lambert, P.H., Siegrist, C.A., 1997. DNAimmunization circumvents decient induction of T helper type1 and cytotoxic T lymphocyte responses in neonates and duringearly life. Proc. Natl. Acad. Sci. USA 94 (16), 87268731.

Mosmann, T.R., Sad, S., 1996. The expanding universe of T-cellsubsets: Th1, Th2 and more. Immunol. Today 17 (3), 138146.

Nossal, G.J., 1983. Cellular mechanisms of immunologic tolerance.Ann. Rev. Immunol. 1, 3362.

clear cut boost effects by the subsequent adult immu-nization.

When the quotas of spleen cell production of IFN-g

vs IL-5 of neonatally immunized mice born to mothersimmunized with the three different delivery systemsdescribed above of SV-antigen were compared, asignicant correlation (r 0:997 at a p < 0:05)between the IgG2a/IgG1 quotas of the mothers andthe IFN-g/IL-5 levels of the offspring was recorded(Fig. 3).These results suggest a maternal inuence onthe development of Th1/Th2 immunity in neonates.

7. Experimental vaccines have induced potent

immune responses in neonates

InTable 2 a number of experimental vaccines arelisted which have induced potent immune responses inneonates. It should be noted that six different antigensand ve different species are included which indicatesa generality i.e. that potent adjuvant can be used toovercome at least some conceived difculties to ef-ciently induce immune protection in neonates.

8. Conclusions and question marks

Maternal immunity is an obstacle for vaccination ofnewborns.To what an extent is the immature immune systemof newborns a consequence of immunologicalunexperience?MHC class II expression and costimulation (e.g.CD86) can be upregulated in T cell responses innewborns.Can Ig switch be established earlier?


7/7

B. Morein et al. / Veterinary Immunology and Immunopathology 87 (2002) 207213

Raghupathy, R., 1997. Th1-type immunity is incompatible withsuccessful pregnancy. Immunol. Today 18 (10), 478482.

Rook, G.A.W., Stanford, J.L., 1998. Give us this day our dailygerms. Immunol. Today 19 (3), 113116.

Rukavina, D., Podack, E.R., 2000. Abundant perforin expression at

the maternalfetal interface: guarding the semiallogeneictransplant? Immunol. Today 21 (4), 160163.Sacks, G., Sargent, I., Redman, C., 1999. An innate view of human

pregnancy. Immunol. Today 20 (3), 114118.Sarzotti, M., Robbins, D.S., Hoffman, P.M., 1996. Induction of

protective CTL responses in newborn mice by a murineretrovirus. Science 271, 17261728.

Schurmans, S., Heusse, C.H., Qin, H., Merino, J., Brighouse, G.,Lambert, P.H., 1990. In vivo effects of anti-IL-4 monoclonalantibody on neonatal induction of tolerance and on an

213

associated autoimmune syndrome. J. Immunol. 160,24652473.

Singh, R.R., Hahn, B.H., Sercarz, E.E., 1996. Neonatal peptideexposure can prime T cells and, upon subsequent immunizationinduce their immune deviation: implications for antibody vs. T

cell-mediated autoimmunity. J. Exp. Med. 183 (4), 16131621.van Binnendijk, R.S., Peolen, M.C.M., van Amerongen, G., deVries, P., Osterhaus, A.D.M.E., 1997. Protective immunity inmacaques vaccinated with live attenuated, recombinant andsubunit measles vaccine in the presence of passively acquiredantibodies. J. Infect. Dis. 175, 534542.

Wegmann, T.G., Lin, H., Guilbert, L., Mosmann, T.R., 1993.Bidirectional cytokine interactions in the maternalfetalrelationship is successful pregnancy a TH2 phenomenon?Immunol. Today 14 (7), 353356.

6inmunidadenneonatosperez-mena

Documents