Natural Health Products, Modulation of Immune Function and Prevention

To view this page ensure that Adobe Flash Player version 9.0.124 or greater is installed.

Please login or register to make a comment!

...Description...... more. less.

9theappropri- ateaccessorycell,anditisthelatterthatthendeliversthe cytolyticblow.Th1cellsarethetargetoftheAIDSvirus, andwhenthevitalTh1cellsarecrippledthroughoutthe body(advancedAIDS),opportunistinfectionsultimatelykill theinfectedhost(humanoranimal).Th2lymphocytesactivate Blymphocyteswhosefunctionistoproduceanappropriate antibodyagainsttheoffensiveantigen,leadingtoitsdestruc- tionandelimination. Theinnateandadaptivesystemsarehighlyintegratedand interdependent(21).Inadditiontobeingarequisiteforadap- tiveimmunity,theinnatesystemisresponsiblefortheearly killingandclearanceofinfectiouspathogensandtheresolu- tionoftheinflammatoryresponse.Themostimportantmeans bywhichtheimmunesystemcommunicatesinternallyand externallyisthroughtheuseofcytokines,smallsolublesignal- ingmolecules.Cytokinesplayacrucialroleintheselection, initiationandmodulationofanappropriateimmuneresponse. Thesignalingnetworkofcytokinesischaracterizedbyits complexity(synergyandantagonism)andbyitsredundancy (parallelism)thatensurethespeedandflexibilityrequiredfor aneffectiveimmuneresponse. Theimmunesystemcangiverisetoseveraldisorderswhen itisweakenedoroveractivated(Table1).Forinstance,adefec- tiveadaptiveimmuneresponsecanleadtorecurrentinfection despitepreviousencounterswithantigens,toloweredtoler- ancetoself-organsandtissuesleadingtoorgan-specific autoimmunity,andtofaultyrecognitionandeliminationof transformedcellsleadingtocancer.However,anoveractivated innateimmuneresponsecancausechronicinfectionbecause ofinefficientclearingofpathogenorchronicinflammation duetoaninefficientregulationorresolutionoftheinflamma- toryresponse.Chronicinflammationcanleadtoextensive non-specificdestructionofneighboringtissue.Infact,inflam- mationandtheimmunesystemareintimatelytied.Inaddition, Table1. Healtheffectsofimbalancesoftheimmunesystem ImmunesystemstatusAttributablepathologies WeakPronetoopportunisticinfectiousdiseases Pronetocancerestablishmentandtumorescape OveractivatedChronicinflammationandautoimmunity (e.g.Type1diabetes) Heartdisease,cancer(e.g.lymphoid) Skindisease,allergiesandasthma Jointandtissuedestruction 514 NHPmediatedpreventionofchronicdiseases by on July 21, 2010 http://ecam.oxfordjournals.org Downloaded from inflammationisincreasinglyfoundtobeinvolvedinthe developmentofseveralchronicdiseasessuchasarterioscler- osis,diabetes,neurodegenerativediseasesandevencancer. Immunedysfunctionhasalsobeenlinkedtoconditions suchaschronicpain,anxietyanddepression,albeit sometimesasaconsequenceratherthanacause,andmaybe involvedinotherdiseaseprocessesinamannerthatiscur- rentlynotfullyunderstood(22).Indeed,itsdiverseinfluence uponhealthmaybeinpartduetoitsevolutionasadefence mechanismandinpartduetoitsorigins,possiblyasasensory organ(23). IstheImmuneSystemaGoodTargetto AimatInOrdertoPreventChronicDisease? Yes,But ... Afirstquestiontoaddressiswhethertheimmunesystemis agoodtargettoselectinthefighttopreventchronicdiseases. Consensusisgenerallypositivewithsomeimportantreserva- tionsbeingbroughtforward.Infact,itisacceptedthatthe immunesystemrepresentsourarsenaltocombatinfection anddisease.Asmentioned,anunderactivatedimmunesystem increasesrisksofopportunisticinfectionanduncontrolledneo- plastictissuegrowth,whileanoveractivatedimmunesystem leadstomanyafflictions,includinginflammation,allergy andautoimmunity.Hence,anuncheckedandunbalanced immunesystemhampersgoodhealthandqualityoflife.This explainstheconsensus 8Yes 9givenasananswerbytheexperts regardingthepertinenceoftargetingtheimmunesystemto preventchronicdisease. However,itmustbenotedthattheimmunesystemcarries outitsimportantdefensivefunctioninintimateandcoordi- natedinteractionwiththenervousandendocrinesystems (24,25).Theinnatecomplexityoftheimmunesystemandof itscommunicationtool,thecytokines,isthusfurthercompli- catedbytheseinteractionswiththenervousandendocrinesys- tems.Someconcernalsoariseswhenconsideringthat targetingtheimmunesystemmaybetooreductionistan approach,particularlywhendealingwithcomplexpathologies likecancer.Theseconsiderationsformthebasisofthe 8but ... 9 partoftheanswergiveninthetitletothissubsection. PromisingResearchAvenuesandMarkers Itisimportanttoconsiderthatinvertebratespecieslackadap- tiveimmunitybutareclearlyabletodealeffectivelywith infections.Itisalsointerestingtonotethattheseorganisms donotappeartodevelopcancerorautoimmunedisease(at leastnotinanyreadilyrecognizableform),buttheydodemon- stratesenescence(26 328).Therefore,theapparentabsenceof theseage-relateddiseasesininvertebratescouldsupportan evolutionaryargumenttofocusdiseasepreventionuponmain- tenanceofefficientandequilibratedinnateimmunity. Ifthislineofreasoningiscorrect,thentheimmunecellsof greatestinterestareonesoftheNKcelllineagedescribed above.Theseimmunecellsarepresentininvertebrateand vertebratespeciesandserveasalinkbetweeninnateandadap- tiveimmunityinvertebrates,asmentioned(25).Indeed,NK cellfunctionhasbeenidentifiedasareliablemeasureof immunotoxicityforuseinpharmaceuticalsafetytesting(29) andcouldperhapsprovideameanstomonitorimmunesystem equilibrium. Anotherimportantpointtoconsiderrelatestotheproblemof markersforimmunesystemfunction.Itisdifficulttoreach aconsensusontheappropriatemarkerstouseinordertomoni- torthemaintenanceofahealthyimmunesystem,primarily becausebiologicalheterogeneityprecludesreadilyidentifiable thresholdsforconcerninthepreventionofchronicdisease. However,thereexistpotentialnovelavenuestoexplore, includingtheuseofNKcellactivity,asmentionedabove,or theuseofaconstellationofmarkers,ofwhichcytokinesand cytokinereceptorswouldbeamajorpart.Muchhasbeenwrit- tenaboutthevalidityandvalidationofbiomarkersforhealth monitoring(30).Whileitisbeyondthescopeofthispaperto discusstheseissuesatlength,itisworthhighlightingsome generalconsiderations.Firstly,biomarkersmustberelevant tothequestionbeingaskedandpracticaltouseinthedesired settingsinceadvancesinanalyticalsensitivitycannowpro- videdetectionlimitsatconcentrationsoftenbelowthosethat havebiologicalimportance(31).Secondly,itisgenerallyeas- iertodefinethresholdsforintervention(i.e.whenadisease requirestreatment)thanforearlydetectionorprevention(i.e. beforeonsetofthedisease).Indeed,thresholdsfordiseasepre- ventionrequireagooddefinitionofwhatconstitutesthe 8nor- mal 9condition.However,biologicalheterogeneityandthe redundancypresentwithintheimmunesystemmakesthe establishmentofprecise 8normalranges 9especiallydifficult. Therefore,althoughNKcellactivityandcytokineassayscan beusedasreliablemeasuresfortreatmentintervention (32,33)theyhaveyettobeshowntobepracticalbiomarkers fordefiningathresholdfortheearlydetectionofchronic illnesses. Finally,oneinterestingalternativetoconventionalimmune systembiomarkersisthepresenceandqualityofmicroparti- clespresentintheblood.Suchmicroparticles,includingexo- somes,originatefromseveralcells,includingsome prominentimmunecells,andmayrepresentanoveltypeof intercellularsignalingmechanism(34,35).Hence,research intothedevelopmentofnovelandpertinentbiomarkerswill certainlycontributetofindingwaystomodulatetheimmune systemandpreventcertainchronicdiseases. ToolstoStudytheImmuneSystemandNHPs Inthissectionwebrieflyreviewseveralexperimentalmodels andapproachesthathavebeenusedtostudyimmunomodula- toryNHPs.Table2summarizestheadvantagesandlimitations ofeachmodality.Humanclinicalstudiesremainthegoldstan- darduponwhichscientistsandhealthcareprofessionalscan relytodeterminetheusefulnessandefficacyofagiven NHP.Nonetheless,animalmodels, invitro bioassays,and eCAM2005;2(4) 515 by on July 21, 2010 http://ecam.oxfordjournals.org Downloaded from modernproteomicandgenomictechnologiescanbemost helpfulindelineatingthemodeofactionofNHPs.Finally,epi- demiologicalstudiesbringawealthofinformationonthe influenceofgenetic(germline)andenvironmentalfactorson healthoutcomesinthegeneralpopulationandpertinent subgroups. Inaddition,itisgenerallyrecognizedthatagreateffort shouldbeplacedonthestandardizationofmethodsusedto studyimmunemodulationbyNHPs.Intermsofherbals,this alsoincludesacrucialcomponentofstandardizationofthe herbalpreparationsthemselves.AsmentionedinTable2 above,thegreatestinconsistenciesofclinicalresearchrelated toimmunomodulatoryNHPsarecausedinmajorpartbythe lackofqualitycontrolofthesourcematerialsused(36).The USagencyNCCAMcametoasimilarconclusionafteritsfirst 5yearsoffunctioningandisnowfocusingonmorepreclinical studiestopreparebetterclinicalstudies,notablywithherbal products(http://nccam.nih.gov/about/plans/2005/index.htm). NHPshavingImmunomodulatoryActivity Duringthelastcentury,modernmedicinehascontributed majoradvancementstosanitationandpublichealthinitiatives anddiscoverieslikeantibioticsandvaccination.Theseeffi- cientlyhinderedtheprogressionofinfectiousdiseasesthrough thepopulation.Infact,modernmedicinehassucceededbestin treatingacuteillnesses.Itisintherealmofchronicdiseases thatmodernmedicineanddrugshavebeenmoredisappointing andthatNHPshaveelicitedresurgentinterest.Inthissection, wereviewtheevidencefortheimmunomodulatoryactionof severalNHPs,includingprobiotics,productsofanimalorigin (principallymilkandthymicextracts),nutritionalfactors (especiallyvitamins,mineralsandfattyacids)andherbal products.Table3summarizesthestrongestevidencebrought forwardforsomeofthemostpromisingNHPs.Readersare alsoorientedtorecentreviews(37,38)forcomplementary information. Thegastrointestinal(GI)tractandtheskinepidermisarethe majorbarriershumanspossesstoconfronttheexternalenvi- ronment.Bothareresponsibleformaintainingsystemic integrityanduselymphnodesasefficientimmunecheck- points.TheGItractdistinguishesitselfbyholdingthegreatest numberoflymphnodes,andalsobybeingthemostintricate andcompleximmuneorgan.Probioticsarelivebacteriathat colonizetheGItract.Theyhavereceivedalotofresearch attention,particularlyinclinicalstudiesinchildrenandthe elderly(39 342).Indeed,theypositivelyaffectgeneralhealth goingfromthedevelopmentoftheimmunesystemininfants rightafterbirthtotheenhancementofgeneralimmunityin theelderly(criticallyexposedtoimmunosenescence).Pro- bioticsoffermuchpromisebecausetheyappearnotonlyto helpwiththematurationofthevisceralimmunesystembut alsotoequilibratethebody 9sdefencemechanisms.Inthat sense,theyactastrueimmunomodulatingagents,enhancing immunitywhenitisweakenedordeveloping,and bufferingexaggeratedreactions(e.g.allergiesandinflamma- toryboweldisease).TheyalsorepresenttheonlyNHPcate- gorythatresearchhasshowntohavewellestablishedcuring Table2. ToolstostudyNHPsasrelatedtotheimmunesystem Experimentalmodels/toolsProsCons Invitro measurementon cellculture Cantargetspecificeffectsofthestudiedproducton specificcelltypes Simplisticmodel,systemiceffectsnottakeninto consideration Veryhelpfulforinvestigatingcellularandmolecular mechanisms NHPadministrationgenerallynotphysiological Largenumberofverywellcharacterizedsystemswith efficientmarkersofactivation/inhibition Genomics/proteomicsNewanalyticaltoolsCostofutilization VerypreciseresultsAvailabilityofsourcematerial Canbeusedinfundamentalresearchaswellasclinicaltrials AnimalmodelsMousehasaverywellcharacterizedgenomeDespitehighsimilaritieswithman,uncertaintywhether miceandmenreactthesameway CompletelivingorganismDifficultyinmeasuringenvironmentalcomponents onamouse Geneticallymodifiable(transgenicandknockoutmice) Largenumberofwellcharacterizedmodelsfor severalhumanpathologies ClinicaltrialsGoldstandardforsafetyandefficacyWeaknessorlackofpropermarkerstoevaluatesuccess ofintervention DirectandsystemiceffectsmeasuredonhealthImproperadministration/standardizationofNHPs EpidemiologicalstudiesLarge-scalestudiesonthepopulationChallengeinscientificallymeasuringdietaryexposurein thepopulation Canincludeboththeenvironmentalandgerm linecomponentsofdisease Largecohortsneededforsignificantconclusions 516 NHPmediatedpreventionofchronicdiseases by on July 21, 2010 http://ecam.oxfordjournals.org Downloaded from aswellaspreventiveproperties.Probioticsexerttheiractions principallyby 1.Improvingtheintestinalimmunologicbarrierfunction throughspatialexclusionofotherpathogenicmicrobial thatcouldotherwisecolonizethegut(43,44). 2.Restoringnormalintestinalpermeability(45)inthe faceofinflammatoryorallergicdiseasesbystillill- definedmechanismsthatincludecellwallandDNA componentsplayingtheroleofimmunomodulatory products(46)andbyloweringtheproductionofpro- inflammatorycytokines(47,48). 3.Synthesizingvitamins(folicacid,biotinandothergroup Bvitamins,vitaminKandsoon)(116). Suggestionshavebeenmadethatprobioticsmayabsorbheavy metals(49 351)andthushelptheireliminationthroughthe feces.Probioticsmayalsopromotetheproductionofenzymes thathelpdecreasetheseverityofcertainfoodintolerances/ allergies(52).However,theseactionshavenotbeenfully documented. Dataonmilkpeptides,bovinecolostrumandthymicextracts arelessconvincingintermsofimmunemodulation,mostof theresearchhavingbeendoneincellularmodels invitro and showingcontradictingresults(53 364).Severalpeptides releasedfromenzymatichydrolysisofmilkproteinswere reportedtomodulateimmunefunctionssuchasphagocytosis, lymphocyteproliferationandcytokineproduction.Thetype ofenzymatictreatmenthasaninfluenceontheimmunomodu- latoryfunctionsofpeptidesgeneratedfrommilkproteinsand, withoutstandardizedprocedures,itisdifficulttodrawncon- clusionsfromthosestudies.Furtherresearch,especiallyclini- caltrials,willberequiredtoidentifytheimpactofthose productsontheimmunesysteminhumans. However,strongerevidencewaspresentedtosupportthe usefulnessofanumberofmicronutrientstopreventcertain chronicillnesses.Anewtermcoined 8nutraprevention 9is appliedtotheuseofempiricalcombinationsoffoods,spices andotherfood-gradeherbalsinthefightagainstcancer(65). Sofar,thisapproachisbasedonepidemiologicalstudies clearlyshowingrelationshipsbetweencancerprevalenceand foodconsumptionindifferentpopulationsaroundtheworld. Moreover,researchisnowshowingpotentantiangiogenic activityforpolyphenoliccomponentsofgreentea(66 368); angiogenesisbeingtheprocessbywhichgrowingtumorspro- motethedevelopmentofnewbloodvesselstoensuretheirsur- vival.Severalplantconstituents,includingsoyisoflavones (69,70)andcompoundsincruciferousvegetables(71,72),are alsoknowntomodulateenzymesinvolvedinxenobioticbio- transformation,namely,theactivationordetoxificationof 8foreign 9,pro-carcinogenicchemicals.VitaminChasbeen clearlylinkedtothemodulationofimmunefunction,particu- larlyinthecontextofnovelresearchshowingimprovedcogni- tivestatusinpatientswithneurodegenerativedisorders(73), whichareincreasinglyshowntoinvolveanimmunedysfunc- tioncomponent.Similarly,polyunsaturatedfattyacids,inpar- ticularthenowfamous w -3fattyacids,havebeenused successfullyinthemanagementandpreventionofseveral inflammatoryandallergicdiseases(74 376).However,clinical researchonlipidshasyieldedinconsistentresultsconcerning theirpotentialtomodulateimmunesystemfunction.Thisstate ofaffairsisrelatedtopoorstudydesignandtothegreatvari- abilityinimmunecellsselectedandmethodsusedtoassess immunefunction. Intakeofgreentea, Brassica vegetables(e.g.broccoli,cab- bageandothers)andsoyfoodshasbeenshowntobeassoci- atedwithlowerriskofseveralcancersinepidemiologic studies[reviewedin(77 382)].Furthermore,datafromexperi- mentalstudiessuggestthatgreenteaanditsconstituents,such asisoflavones,maymodulatemarkersofinflammationand immunefunction(83 387).Alimitednumberofherbalprod- uctsalsoshowpromiseintherealmofimmunemodulation. Table3. PromisingNHPsexhibitingmodulatoryeffectsontheimmunesystem NHPsourcePreventionTreatment ProbioticsHelpsimmunesystemmaturation(96)Helpsmanageatopiceczema/dermatitis(97) Helpspreventallergies(96),atopicdiseaseand hypersensitivitiesininfants(98,99) Promiseintreatinginflammatoryboweldisease(IBD) throughimmunemodulation(100,101) Enhancesimmunityintheelderly(102,96) GreenTea(EGCG,flavonoids ... )Dailyintakecouldpreventtumor growth(65,103,104) Potentantiangiogeniceffect(66 368) Potentanti-inflammatoryeffect(105,106) VitaminsCandE,n-3fattyacidsAntioxidant:decreaseoxidativestressinseveral chronicdiseases(73) Helpsmanagearthritis,asthmaandIBD(76,75) Anti-inflammatory:n-3fattyacids(74) Echinacea Enhanceantitumorimmunity(mouseNKcells)(107)Mayhelptreatupperrespiratorytractinfection(108) EnhanceNKcellimmunityinagedmice(107)Putativeantifungalproperties(109)andantiviralproperties(110) Ginseng(ginsenosides)Immunosuppressantproperties(111)Mayhavebenefitasanadjuncttocancertherapy(112) Anti-inflammatoryproperties(113) Ginseng(polysaccharides)Immunestimulatingproperties(NK,macrophages andantibodyproduction)(114) Helpsclearinfectionsagentslike Staphylococcusaureus , Pseudomonasaeruginosa and Candidaalbicans inmice(115) eCAM2005;2(4) 517 by on July 21, 2010 http://ecam.oxfordjournals.org Downloaded from Itisnotablythecasewith Echinacea thathasreceivedsignifi- cantscientificattentioninthepasttwodecades,particularlyin studiesonupperrespiratorytractinfections(36,88,89).Among itsmanyimmunemodulatingactivitiesreported,activationof macrophageshasbeendemonstratedmostconvincingly.How- ever,novelmechanismsofactionincludeeffectsonBandT lymphocytesaswellasNKcells(90,91).Inparticular,Currier andMiller(90)observedthatuponincorporating Echinacea in thedailydietofelderlymiceforonly14daysNKcellproduc- tioninthebonemarrow,aswellasthenumberofmaturefunc- tionalNKcellsreachingthespleen,increasedtolevelsfound inyoungadults(92).BrousseauandMiller(93)havealso revealedthatdailydietaryintakeof Echinacea throughout life,beginninginyouth,increasedthenumberofindividuals reachingoldageto74%asopposedto46%incontrolanimals. Thus,anyherbaltreatmentthatwouldaugmentNKcells wouldclearlybeworthyofinvestigationforitstherapeutic/ prophylacticpotential,especiallyintherealmofimmune modulation. Ginsengistheotherherbalthatshowsmuchpromiseasan immunemodulatingNHP.Indeed,itappearstohaveboth immunostimulantandimmunosuppressantactivities,which wouldlendcredencetotheviewthatginsengisan 8adapto- genic 9NHP.Immunostimulantactivitieshavebeenattributed topolysaccharidefractions,notablyactingonbothmacro- phagesandBlymphocytes(94,95).However,ginsenosides displayimmunosuppressantactivity invitro byinhibiting cytokinereleaseinactivatedmacrophages(I.Lemaire,unpub- lishedresults).Hence,furtherresearchiswarrantedonginseng andotheradaptogenicherbalstodefinetheirpotentialusein preventingchronicdiseasesrelatedtoimmunedysfunction. SummaryandConclusion Dysfunctionoftheimmunesystemisclearlyimplicatedinthe developmentofseveralchronicdiseases.Hence,attemptingto maintainanefficientandequilibratedimmunesystemisavalid approachtopreventcertainchronicillnesses.However,this approachislimitedbythegreatcomplexityoftheimmunesys- temanditscloseinteractionswiththenervousandendocrine functions.Thisisfurtherhamperedbythedifficultyinidenti- fyingreliableandconvenientanalyticaltoolstoassessimmune functionanditsmodulation.Inthatcontext,interestingareas forfutureresearchincludeNKcells,constellationofcytokine markersandreceptorsandassessmentofblood-borne microparticles.Despitetheselimitations,researchonNHPs hasshownthatcertainproductsoffernovelavenuestomodu- latetheimmunesystemandhelppreventchronicdiseases. Themostpromisingonesareprobiotics,nutraprevention (combinationsofbiologically-activefruits,vegetablesand spices)andso-calledadaptogenicplants(e.g.echinaceaand ginseng).Notwithstandingtheseencouragingresults,future researcheffortswithNHPswillneedtoaddresstheimportant issuesofstandardizationinbothproductqualityandresearch methodology.Amongareastofavorintheresearchagenda onNHPsandimmunemodulation,thisreviewhighlightsthe followingneeds:(i)studiesontheinteractionbetweenNHPs andimmunecells,particularlytheinfluenceofNHPsonthe innateimmunesystem;(ii)epidemiologicalstudiesandclini- calstudieswithNHPsinchronicillnesseswhereimmunedys- functionmayplayarole.Finally,social/economicimpactof NHPsinhealthcaremustalsobeconsidered. Acknowledgements ThisreviewisbasedondiscussionsheldinSeptember2004 duringa2daysymposiumorganizedandfundedbytheLucie etAndre ´ ChagnonFoundationinMontreal,Canada.Thesym- posiumistheobjectofashortmeetingreportin eCAM (1). Theauthorsexpresstheirgratitudetoallparticipantsfor valuablecommentsandsuggestions.Specialthanksgoto YvanBoutin(Le ´ vis-LauzonCollege,Le ´ vis,Canada),Edwin Cooper(UCLA,LosAngeles,CA,USA),JohannaLampe (FredHutchisonCancerResearchCenter,Seattle,WA, USA),SandraMiller(McGillUniversity,Montreal,Canada) andDenisRoy(LavalUniversity,QuebecCity,Canada). MsGenevie ` veCo Æ te ´ andGenevie ` veBeauchampareheartfully thankedfordevotingtheirtimeandinnovativeideastomake thesymposiumorganizationsuchasuccess.Wegratefully acknowledgetheexpertsecretarialhelpofMsLaurePinto. References 1.HaddadPS,BeauchampG,Co Æ te ´ G,BoivinM.Maintenanceofaneffici- ent,equilibratedimmunesystemthroughthenoveluseofnaturalhealth products:synopsisofasymposium. eCAM 2005;2:237 38. 2.CooperE.CommentaryonCAMandNKcellsbyKazuyoshiTakedaand KoOkumura. eCAM 2004;1:29 334. 3.KeisslingR,KleinE,ProssH,WigzellH.Naturalkillercellsinthe mouse.II.CytotoxiccellswithspecificityformouseMoloneyleukemia cells:characteristicsofthekillercell. EurJImmunol 1975;5:117 321. 4.HerbermanRB,NunnME,LarvinDH.Naturalcytotoxicreactivityof mouselymphoidcellsagainstsyngeneicandallogeneictumors.I.Distri- butionofreactivityandspecificity. IntJCancer 1975;16:216 329. 5.MillerSC.Geneticallydeterminedresistancetoforeignbonemarrow transplantationinmice:characterizationoftheeffectorcells. JImmunol 1983;131:92 37. 6.HackettJ,TuttM,LipscombM,BennettM,KooG,KumarV.Originand differentiationofnaturalkillercells.II.Functionalandmorphologic studiesofpurifiedNK1.1 þ cells. JImmunol 1986;136:3124 331. 7.KrishnarajR.ImmunosenescenceofhumanNKcells:effectsontumor targetrecognition,lethalhitandinterferonsensitivity. ImmunolLett 1992;34:79 384. 8.KutzaJ,MuraskoDM.Effectsofagingonnaturalkillercellactivityand activationbyinterleukin-2andIFN-a. CellImmunol 1994;155:195 3204. 9.HallerO,WigzellH.Suppressionofnaturalkillercellactivitywith radioactivestrontium:effectorcellsaremarrowdependent. JImmunol 1977;118:1503 36. 10.SeamanWE,BlackmanMA,GindhartTD,RoubinianJR,LoebJM, TalalN.Estradiolreducesnaturalkillercellsinmice. JImmunol 1978;121:2193 38. 11.RiccardiC,BarlozzariT,SantoniA,HerbermanRB,CesariniC.Trans- fertocyclophosphamide-treatedmiceofnaturalkiller(NK)cellsandin vivonaturalreactivityagainsttumors. JImmunol 1981;126:1284 37. 12.KooGC,CayreY,MittlLR.Comparativestudyofsplenicnaturalkiller cellsandprothymocytes. CellImmunol 1981;62:164 371. 13.KooGC,ManyakCL.Generationofcytotoxiccellsfrommurinebone marrowbyhumanrecombinantIL-2. JImmunol 1986;137:1751 36. 14.KallandT.Interleukin3isamajornegativeregulatorofthegenerationof naturalkillercellsfrommousebonemarrowprecursors. JImmunol 1986;137:2268 371. 518 NHPmediatedpreventionofchronicdiseases by on July 21, 2010 http://ecam.oxfordjournals.org Downloaded from 15.PollackSB,RosseC.Theprimaryroleofmurinebonemarrowinthepro- ductionofnaturalkillercells. JImmunol 1987;139:2149 356. 16.DussaultI,MillerSC.Declineinnaturalkillercell-mediatedimmuno- surveillanceinagedmice 4aconsequenceofreducedcellproduction andtumorbindingcapacity. MechAgeingDev 1994;75:115 329. 17.DussaultI,MillerSC.Theeffectivenessofimmunotherapyinagedleu- kemicmice. Gerontology 1995;41:195 3204. 18.DussaultI,MillerSC.Effectonleukemiacellnumbersofinvivoadmin- istrationofimmunotherapeuticagentsisage-dependent. Oncology 1996;53:241 36. 19.RoittIM,DelvesPJ(eds). EncyclopediaofImmunology ,3rdedition. London/SanDiegoAcademicPress,1992. 20.PaulWE(ed). FundamentalImmunology ,4thedition.Philadelphia: LippincottWilliams&WilkinsPublishers,1998. 21.HoebeK,JanssenE,BeutlerB.Theinterfacebetweeninnateandadap- tiveimmunity. NatImmunol 2004;5:971 34. 22.EwaldPW.Plaguetime:howstealthinfectionscausecancers,heartdis- easeandotherdeadlyailments.NewYork:TheFreePress,2002,282. 23.BlalockJE.Theimmunesystemasasensoryorgan. JImmunol 1984;132:1067 370. 24.HaddadJJ,SaadeNE,Safieh-GarabedianB.Cytokinesandneuro- immune-endocrineinteractions:aroleforthehypothalamic-pituitary- adrenalrevolvingaxis. JNeuroimmunol 2002;133:1 319. 25.TakedaK,OkumuraK.CAMandNKcells. eCAM 2004;1:17 327. 26.FlattT.AssessingnaturalvariationingenesaffectingDrosophilalife- span. MechAgeingDev 2004;125:155 39. 27.LuoY.Long-livedwormsandaging. RedoxRep 2004;9:65 39. 28.SinghK.Mitochondrialdysfunctionisacommonphenotypeinagingand cancer. AnnNYAcadSci 2004;1019:260 34. 29.USFDA.Immunotoxicologyevaluationofinvestigationalnewdrugs, GuidanceforIndustryDocumentissuedbytheCenterforDrugEvalu- ationandResearch.35. 30.WorldHealthOrganization.EnvironmentalHealthCriteria222: BiomarkersInRiskAssessment:ValidityAndValidation,Reportpub- lishedunderthejointsponsorshipoftheUnitedNationsEnvironment Program,theInternationalLaborOrganization,andtheWorldHealth Organization,andproducedwithintheframeworkoftheInter- OrganizationProgramfortheSoundManagementofChemicals. 31.PritzkerKPH.Cancerbiomarkers:easiersaidthandone. ClinChem 2002;48:1147 350. 32.KelleyDS,TaylorPC,NelsonGJ,SchmidtPC,MackeyBE,KyleD. Effectsofdietaryarachidonicacidonhumanimmuneresponse. Lipids 1997;32:449 356. 33.KelleyDS,TaylorPC,NelsonGJ,MackeyBE.Dietarydocosahexaenoic acidandimmunocompetenceinyounghealthymen. Lipids 1998;33: 559 366. 34.DenzerK,KleijmeerMJ,HeijnenHF,StoorvogelW,GeuzeHJ.Exo- some:frominternalvesicleofthemultivesicularbodytointercellular signallingdevice. JCellSci 2000;113:3365 374. 35.FreyssinetJM.Cellularmicroparticles:whataretheybadorgoodfor? JThrombHaemost 2003;1:1655 362. 36.GoelV,LovlinR,BartonR,LyonMR,BauerR,LeeTD,etal.Efficacy ofastandardizedEchinaceapreparation(Echinilin)forthetreatmentof thecommoncold:arandomized,doubled-blind,placebo-controlledtrial. JClinPharmTher 2004;29:75 383. 37.PlaegerSF.Clinicalimmunologyandtraditionalherbalmedicines. Clin DiagnLabImmunol 2003;10:337 38. 38.PatwardhanB,GautamM.Botanicalimmuodrugs:scopeandopportuni- ties. DrugDiscovToday 2005;10:495 3502. 39.ShiHN,WalkerA.Bacterialcolonizationandthedevelopmentofintesti- naldefence. CanJGastroenterol 2004;18:493 3500. 40.MarteauP,SeksikP,LepageP,DoreJ.Cellularandphysiologicaleffects ofprobioticsandprebiotics. MiniRevMedChem 2004;4:889 396. 41.BrownAC,ValiereA.Probioticsandmedicalnutritiontherapy. Nutr ClinCare 2004;7:56 368. 42.BruzzeseE,CananiRB,DeMarcoG,GuarinoA.Microfloraininflam- matoryboweldiseases:apediatricperspective. JClinGastroenterol 2004;38:S91 33. 43.Resta-LenertS,BarrettKE.Liveprobioticsprotectintestinalepithelial cellsfromtheeffectsofinfectionwithenteroinvasive Escherichiacoli (EIEC). Gut 2003;52:988 397. 44.JenkinsB,HolstenS,BengmarkS,MartindaleR.Probiotics:apractical reviewoftheirroleinspecificclinicalscenarios. NutrClinPract 2005;20:262 370. 45.MadsenK,CornishA,SoperP,McKaigneyC,JijonH,YachimecC,etal. Probioticbacteriaenhancemurineandhumanintestinalepithelialbarrier function. Gastroenterology 2001;121:580 391. 46.JijonH,BackerJ,DiazH,YeungH,ThielD,McKaigneyC,etal.DNA fromprobioticbacteriamodulatesmurineandhumanepithelialand immunefunction. Gastroenterology 2004;126:1358 373. 47.MadsenKL,DoyleJS,JewellLD,TaverniniMM,FedorakRN.Lacto- bacillusspeciespreventscolitisininterleukin10gene-deficientmice. Gastroenterology 1999;116:1107 314. 48.LammersKM,HelwigU,SwennenE,RizzelloF,VenturiA,CaramelliE, etal.Effectofprobioticstrainsoninterleukin8productionbyHT29/19A cells. AmJGastroenterol 2002;97:1182 36. 49.SummersAO,WiremanJ,VimyMJ,LorscheiderFL,MarshallB, LevySB,etal.Mercuryreleasedfromdental 8 8silver 9 9fillingsprovokes anincreaseinmercury-andantibiotic-resistantbacteriainoraland intestinalflorasofprimates. AntimicrobAgentsChemother 1993;37: 825 334. 50.LorscheiderFL,VimyMJ,SummersAO,ZwiersH.Thedentalamalgam mercurycontroversy 4inorganicmercuryandtheCNS;geneticlinkage ofmercuryandantibioticresistancesinintestinalbacteria. Toxicology 1995;97:19 322. 51.BrudnakMA.Probioticsasanadjuvanttodetoxificationprotocols. Med Hypotheses 2002;58:382 35. 52.deVreseM,StegelmannA,RichterB,FenselauS,LaueC, SchrezenmeirJ.Probiotics 4compensationforlactaseinsufficiency. AmJClinNutr 2001;73:421S 39S. 53.Migliore-SamourD,Floc 9hF,JollesP.Biologicallyactivecasein peptidesimplicatedinimmunomodulation. JDairyRes 1989;56: 357 362. 54.TorrePM,OliverSP.Supressionofmitogenicresponseofperipheral bloodmononuclearcellsbybovinemammarysecretions. JDairySci 1989;72:219 327. 55.FiatAM,Migliore-SamourD,JollesP,DrouetL,BalditSollierC, CaenJ.Biologicallyactivepeptidesfrommilkproteinswithemphasis ontwoexamplesconcerningantithromboticandimmunomodulating activities. JDairySci 1993;76:301 310. 56.SchlimmeE,MeiselH.Bioactivepeptidesderivedfrommilkproteins. Structural,physiologicalandanalyticalaspects. Nahrung 1995;39:1 320. 57.LahovE,RegelsonW.Antibacterialandimmunostimulating,casein- derivedsusbstancesfrommilk:casecidin,isracidinpeptides. Food ChemToxicol 1996;34:131 345. 58.CrossML,GillHS.Immunomodulatorypropertiesofmilk. BrJNutr 2000;84:81. 59.ShahNP.Effectsofmilk-derivedbioactives:anoverview. BrJNutr 2000;84:S3 310. 60.LowPP,RutherfurdKJ,GillHS,CrossML.Effectofdietarywheypro- teinconcentrateonprimaryandsecondaryantibodyresponsesinimmu- nizedBALB/cmice. IntImmunopharmacol 2003;3:393 3401. 61.LegrandD,ElassE,PierceA,MazurierJ.Lactoferrinandhostdefence: anoverviewofitsimmuno-modulatingandanti-inflammatoryproperties. Biometals 2004;17:225 39. 62.LiEW,MineY.Immunoenhancingeffectsofbovineglycomacropeptide anditsderivativesontheproliferativeresponseandphogocyticactivities ofhumanmacrophagelikecells,U937. JAgricFoodChem 2004;52: 2704 38. 63.MarshallK.Therapeuticapplicationsofwheyprotein. AlternMedRev 2004;9:136 356. 64.MercierA,GauthierS,FlissI.Immunomodulatingeffectsofwheypro- teinsandtheirenzymaticdigests. IntDairyJ 2004;14:175. 65.BeliveauR,GingrasD.Greentea:preventionandtreatmentofcancerby nutraceuticals. Lancet 2004;364:1021 32. 66.LamyS,GingrasD,BeliveauR.Greenteacatechinsinhibitvascular endothelialgrowthfactorreceptorphosphorylation. CancerRes 2002;62:381 35. 67.CaoY,CaoR.Angiogenesisinhibitedbydrinkingtea. Nature 1999; 398:381. 68.CaoY,CaoR,BrakenhielmE.Antiangiogenicmechanismsofdiet- derivedpolyphenols. JNutrBiochem 2002;13:380 390. 69.KishidaT,BeppuM,NashikiK,IzumiT,EbiharaK.Effectofdietary soyisoflavoneaglyconesontheurinary16alpha-to-2-hydroxyestrone ratioinC3H/HeJmice. NutrCancer 2000;38:209 314. 70.ChanHY,LeungLK.Apotentialprotectivemechanismofsoyaisofla- vonesagainst7,12-dimethylbenz[a]anthracenetumourinitiation. BrJ Nutr 2003;90:457 365. eCAM2005;2(4) 519 by on July 21, 2010 http://ecam.oxfordjournals.org Downloaded from 71.GillCI,HaldarS,PorterS,MatthewsS,SullivanS,CoulterJ,etal.The effectofcruciferousandleguminoussproutsongenotoxicity,invitroand invivo. CancerEpidemiolBiomarkersPrev 2004;13:1199 3205. 72.ZhangY.Cancer-preventiveisothiocyanates:measurementofhuman exposureandmechanismofaction. MutatRes 2004;555:173 390. 73.MartinA.AntioxidantvitaminsEandCandriskofAlzheimer 9sdisease. NutrRev 2003;61:69 373. 74.KelleyDS.Modulationofhumanimmuneandinflammatoryresponses bydietaryfattyacids. Nutrition 2001;17:669 373. 75.SimopoulosAP.Omega-3fattyacidsininflammationandautoimmune diseases. JAmCollNutr 2002;21:495 3505. 76.EndresS,LorenzR.Loeschke.Lipidtreatmentofinflammatorybowel disease. CurrOpinClinNutrMetabCare 1999;2:117 320. 77.MurilloG,MehtaRG.Cruciferousvegetablesandcancerprevention. NutrCancer 2001;41:17 328. 78.KristalAR,LampeJW.Brassicavegetablesandprostatecancerrisk: areviewoftheepidemiologicalevidence. NutrCancer 2002;42:1 39. 79.LeMarchandL.Cancerpreventiveeffectsofflavonoids. Biomed Pharmacother 2002;56:296 3301. 80.SarkarFH,LiY.Soyisoflavonesandcancerprevention. CancerInvest 2003;21:744 357. 81.LimerJL,SpeirsV.Phyto-oestrogensandbreastcancerchemopreven- tion. BreastCancerRes 2004;6:119 327. 82.ParkOJ,SurhYJ.Chemopreventivepotentialofepigallocatechingallate andgenistein:evidencefromepidemiologicalandlaboratorystudies. ToxicolLett 2004;150:43 356. 83.ParadkarPN,BlumPS,BerhowMA,BaumannH,KuoSM.Dietaryiso- flavonessuppressendotoxin-inducedinflammatoryreactioninliverand intestine. CancerLett 2004;215:21 38. 84.VerdrenghM,JonssonIM,HolmdahlR,TarkowskiA.Genisteinasan anti-inflammatoryagent. InflammRes 2003;52:341 36. 85.SurhYJ,ChunKS,ChaHH,HanSS,KeumYS,ParkKK,etal.Molecu- larmechanismsunderlyingchemopreventiveactivitiesofanti- inflammatoryphytochemicals:down-regulationofCOX-2andiNOS throughsuppressionofNF-kappaBactivation. MutatRes 2001;480: 243 368. 86.KatiyarSK,ChallaA,McCormickTS,CooperKD,MukhtarH. PreventionofUVB-inducedimmunosuppressioninmicebythegreen teapolyphenol( À )-epigallocatechin-3-gallatemaybeassociatedwith alterationsinIL-10andIL-12production. Carcinogenesis 1999;20: 2117 324. 87.JenkinsDJ,KendallCW,ConnellyPW,JacksonCJ,ParkerT, FaulknerD,etal.Effectsofhigh-andlow-isoflavone(phytoestrogen) soyfoodsoninflammatorybiomarkersandproinflammatorycytokines inmiddle-agedmenandwomen. Metabolism 2002;51:919 324. 88.BlockKI,MeadMN.ImmunesystemeffectsofEchinacea,ginsengand astragalus:areview. IntegrCancerTher 2003;2:247 367. 89.BarrettB.MedicinalpropertiesofEchinacea:acriticalreview. Phy- tomedicine 2003;10:66 386. 90.CurrierNL,MillerSC.Naturalkillercellsfromagingmicetreatedwith extractsfrom Echinaceapurpurea arequantitativelyandfunctionally rejuvenated. ExpGerontol 2000;35:627 339. 91.CurrierNL,MillerSC. Echinaceapurpurea andmelatoninaugment natural-killercellsinleukemicmiceandprolonglifespan. JAlternCom- plementMed 2001;7:241 351. 92.SunLZ-Y,CurrierNL,MillerSC.TheAmericanconeflower:aprophy- lacticroleinvolvingnonspecificimmunity. JAlternComplementMed 1999;5:437 346. 93.BrousseauM,MillerSC.Enhancementofnaturalkillercellsand increasedsurvivalofagingmicefeddailyEchinacearootextractfrom youth. Biogerontology 2005;6:157 3163. 94.WangM,GuilbertLJ,LingL,LiJ,WuY,XuS,etal.Immunomodulat- ingactivityofCVT-E002,aproprietaryextractfromNorth Americanginseng( Panaxquinquefolium ). JPharmPharmacol 2001;53:1515 323. 95.AssineweVA,AmasonJT,AubryA,MullinJ,LemaireI.Extractable polysaccharidesof Panaxquinquefolius L.(NorthAmericanginseng) rootstimulateTNFalphaproductionbyalveolarmacrophages. Phytomedicine 2002;9:398 3404. 96.CrossML.Immunoregulationbyprobioticlactobacilli:pro-Th1signals andtheirrelevancetohumanhealth. ClinApplImmunolRev 2002;3: 115 325. 97.ViljanenM,SavilahtiE,HaahtelaT,Juntunen-BackmanK,KorpelaR, PoussaT,etal.Probioticsinthetreatmentofatopiceczema/dermatitis syndromeininfants:adouble-blindplacebo-controlledtrial. Allergy 2005;60:494 3500. 98.MajamaaH,IsolauriE.Probiotics:anovelapproachinthemanagement offoodallergy. JAllergyClinImmunol 1997;99:179 385. 99.OgdenNS,BieloryL.Probiotics:acomplementaryapproachinthetreat- mentandpreventionofpediatricatopicdisease. CurrOpinAllergyClin Immunol 2005;5:179 384. 100.FedorakRN,MadsenKL.Probioticsandthemanagementofinflamma- toryboweldisease. InflammBowelDis 2004;10:286 399. 101.KanauchiO,MatsumotoY,MatsumuraM,FukuokaM,BambaT.The beneficialeffectsofmicroflora,especiallyobligateanaerobes,andtheir productsonthecolonicenvironmentininflammatoryboweldisease. CurrPharmDes 2005;11:1047 353. 102.GillHS,RutherfurdKJ,CrossML,GopalPK.Enhancementofimmunity intheelderlybydietarysupplementationwiththeprobiotic Bifidobac- teriumlactis HN019. AmJClinNutr 2001;74:833 39. 103.GreenwaldP.Clinicaltrialsincancerprevention:currentresultsandper- spectivesforthefuture. JNutr 2004;134:3507S 312S. 104.GaoYT,McLaughlinJK,BlotWJ,JiBT,DaiQ,FraumeniJF,Jr. Reducedriskofesophagealcancerassociatedwithgreenteaconsump- tion. JNatlCancerInst 1994;86:855 38. 105.AktasO,ProzorovskiT,SmorodchenkoA,SavaskanNE,LausterR, KloetzelPM,etal.Greenteaepigallocatechin-3-gallatemediatesTcel- lularNF-kappaBinhibitionandexertsneuroprotectioninautoimmune encephalomyelitis. JImmunol 2004;173:5794 3800. 106.TedeschiE,MenegazziM,YaoY,SuzukiH,ForstermannU,KleinertH. Greenteainhibitshumaninduciblenitric-oxidesynthaseexpressionby down-regulatingsignaltransducerandactivatoroftranscription-1alpha activation. MolPharmacol 2004;65:111 320. 107.CurrierNL,MillerSC.Theeffectofimmunizationwithkilledtumor cells,with/withoutfeedingof Echinaceapurpurea inanerythroleukemic mousemodel. JAlternComplementMed 2002;8:49 358. 108.BarrettB.Echinaceaforupperrespiratorytractinfection:anevidence- basedclinicalreview. JFamPract 1999;48:628 335. 109.BinnsSE,PurginaB,BergeronC,SmithML,BallL,BaumBR,etal. Light-mediatedantifungalactivityofEchinaceaextracts. PlantaMed 2000;66:241 34. 110.ThompsonKD.AntiviralactivityofViraceaagainstacyclovirsuscepti- bleandacyclovirresistantstrainsofherpessimplexvirus. AntiviralRes 1998;39:55 361. 111.LarsenMW,MoserC,HoibyN,SongZ,KharazmiA.Ginsengmodu- latestheimmuneresponsebyinductionofinterleukin-12production. APMIS 2004;112:369 373. 112.ChangYS,SeoEK,GyllenhaalC,BlockKI. Panaxginseng :arolein cancertherapy?. IntegrCancerTher 2003;2:13 333. 113.ParkEK,ChooMK,HanMJ,KimDH.GinsenosideRh1possesses antiallergicandanti-inflammatoryactivities. IntArchAllergyImmunol 2004;133:113 320. 114.KimTS,NaK,ChoiEM,ChungJY,HwangJK.Immunomodulating activitiesofpolysaccharidesisolatedfromPanaxginseng. JMedFood 2004;7:1 36. 115.SongZ,JohansenHK,FaberV,MoserC,KharazmiA,RygaardJ,etal. Ginsengtreatmentreducesbacterialloadandlungpathologyinchronic Pseudomonasaeruginosa pneumoniainrats. AntimicrobAgents Chemother 1997;41:961 34. 116.CrittendenRG,MartinezNR,PlayneMJ.Synthesisandutilisationof folatebyyoghurtstarterculturesandprobioticbacteria. IntJFood Microbiol 2003;15:217 322. ReceivedMarch3,2005;acceptedAugust26,2005 520 NHPmediatedpreventionofchronicdiseases by on July 21, 2010 http://ecam.oxfordjournals.org Downloaded from

less