Interactions Between the Brain and the Immune System

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Annu. Rev Pharmacol Toxio Cpyght b nnua Reews In. ghts eseed

INTRACTION BTWN TH

BRAI AD T IMMUN YTM

Robert Ader, David Felten and Nicholas Cohen

Departments of Psychiatry Neurobiology and natomy and Microbiology and m

munology niversity of Rochester Schoo of Medicine and Dentistry RochesterNew Yok 14642

KE pychneurun!gy, bran, behavir and uniy neuendrneune news aunc nervus syse & unysess and ny

TODTO

F reasons that are not enirely cle, the neurosciences and immunologyevolved wthout serously consderng the possblty of nteactons betweenthese systems that could mutually nuence the esectve functons Wthn he ast 0 ears research cnceed with the relatonshs amongban behavo and mmun has exanded adl. Exements haveelably documened he eecs of behavo on mune funcon and heexisence of unsuspected connections between the nervous and immune systems. Ou pupos hee s to povde a bief and hghly selected ovevew of

some of he edence ha behavol factos ae capable of nuencngimmune funcon and to descbe some of he neual and endocrne channelso communcao ha lnk he ban ad he mmune ssem. Alhough

systemac esech n psychoneuommunology s elatvely new he ngeof the phenomena that bea on ban-behavommune system nteactons s

qute boad. Thee s an old and contnung expemental and clncal lteatue suggestng tha mmune funcon can be aleed b psychologcal means

and thee ae povocave daa suggesng that affectve states and pesonalychacestcs re assocaed wth dffeences n mmune functon Staegcally and pactcally such sudes ae dffcult to mplement and uneuvocalevdence fo such assocatons does not yet exst. A dscusson of hese eas

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ADR AD

s beod he scope o his reie T prs ri cocras o hexprimal as opposd o he cliical lieraur coci h ecs obhaior icludi srss i h modulaio o mmu rsposs ad h

ieraci relaioships amo ural edocrie ad immue processes hacould lad o a explaaio o such pheomea ad a raer apprciaioad udrsadi o ieraed procsss o adpaio

EHA VIORA NUNES ON IMMUNE UNTON

Eects of Stressudies i humas ae implicaed psychosocial cors i he suscepibiliy oad/or rcoey rom sral iciou bacrial alric auoimmu ad

eoplasi diseases ha o a raer or lesser e iole alraios immuooc dese mchasms e xpmea suds aimals idicae ha h oucome o srssul simulaio depeds upo haur o h srssor ad pahophsioloical rocess o hich he ora-sm s exposed Tha s h same sressor ma ha diere ecs odire disease processes ad dier sressors ma er dire eecso a picl pahophsioloic process rsuabl he abili o prdich oucom o sudis o h pahophsioloic cs o srss dpds upoa more complee udersadi o he eecs codiioall licied bpoially pahoic simulaio ad he acu ad chroic psy-chophysioloical ecs icludi he immuolic cs o he sressulsimulaio upo hich hes are suprimposed lhouh such sudis docu-m h cs o psychosocal acors o alraios i suscepibiliy odsas h do proid dirc idce ha such cs are mdiad bpschosocal ducd araos mmu uco

Rcel aio has be direc o uaii e cas i immueucio ha rsul rom diere sressul circmsacs The dah o a

amil mmbr or xampl is raed hih o scales o srssul li sad has be associad ih dpressio ad a icrasd morbidi admorali i a arie o disass , ma o hich ar presumd oiole immue deese mechaisms us chas i immu uciomay cosiu a impoa li bee psycosocial acors o he ohad ad alerd suscpibiliy o or proressio o disas o h oherThouh his chai o psychophysioloical es has o y be sablishdchas i som eaurs o immuoloic reaciiy suh as a reduced lm-phoproerae rspos o moc smuao ) a mpaird a

ural killer (NK cell acii ( ae b obsrd amo he bereadll oer suds a documeed chaes mmue reacy assocaedih h aeci rsposs o ohr losses suc as maral separaio addiorc 2

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RANMMN SSM NRANS 563

Th ationship betwen beeament and dpession as een ommntedupon fqunty n t psyat iatu, and studies of th immunanges assoiated wit depression are just beginning. Lympocyte esponsesto mitogns are rdued in drg-fr hspitaizd dprssed patients Nouh din a vident in an ambulatoy popuation o patient withmao deprssie disorder As ypotesed the dsrepany oud bedue to dfens in th sit of th dsod andor the ag of thosptad and nonhosptaed patts In gnea te mted number ofstudies on the immunoogi effets o epssion hae yieldd an inonsistntpatten o esults Some instgatos ha osed a signifiant suppessionof one o anothe paamet of mmunity (13-1 others hae not addition to the parameter() of immun untion measured oneneeds to onsider the age and sex o te patient; the natu o the dpssion(endogenous s nonendogenous dexaethasone suppessos o nonsuppresso ee e e eee aut dpssion or ar in mission;te seerity and/or duration of deprsion whi may b reated to wheterpatients ae ospitalied o ambulator whether patients a drgre andor ow long) and/or th presene or asen and kind of trapy Theinial igniiane of te ange in immunoogi eatiity that aompanyeaemnt o depesson remans a prmay and as yet unrsoled on

O rated nteest and mpotane s t rapdly gowng tatur oneing th immunomoduating ts f psyotropi dgs 22drugs oaue a w a ho usd or hraput puo (g n he tratmnt odeprssion. Not supringly te mmunologi eet of psyhotopi agentsdepend upon te sps, te in to o n o mmune sponse studid thedos ando duaton o dg tatment and in expeimntal studis tetimng o dug admnstraton in latin to antigen stimuation Psyhotrop dg aton th ts of many otr pimna intentions asodepends on te psyopysioogia tate of te organism upon whi it issuprimposd For xamp aoprido edus antiody rsponss in noral i ut rtor huora imunity wen gin to tred (irowded animas

Wh te dath o a spous s ntutiely strssul hangs n immunefuntion an b obsed in umans usng ntuty ess se but nonetss efte naturaly oung stessu stmuation. Cangs in mmunefuntion n rspons to mpndng amnations in mdal studnts and tofootal gam n ootal payr (and een speators was rpotd y arisin 8 Th eel of distress during examinaton peiods is inariay

geate than that during ontrol periods and the Gases 2) ha oundtansnt impamnts in seea paamets of immune funtion in medialstudents at suh tms Relate to a nonstssu asline measurement



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5 D N ND N

exanaon erod are aocaed wih a decrease n ogen reonvene, NK cell acvy, ecenage of hele T-Imhocye, and nefenproducon by ulaed lyhocye. n uden who ae eropove oEpenBa vu (EBV) hee ae levaed anEBV anbody e nerreed a a ooe cellular une eone cnol ove the laent vudung eanaon han conol eod Th ncdence o eleoedyo o necou llne alo nceaed ung exanaon eod Peonaly e have no yelde deence beween he uden whovoluneered or hee ude and her claae and ohe le change hacould have nfluenced une eone wee no and dd no oelaewh he change n une uncon

Seaaon eeence (.e. loe) have alo been uded n anal nodeneodc neruon o ohler nacon and/o ealy weanng deceae lyhocye oleaon o ogenc ulaon and educehe laqueong eone o ubeuen challenge wh hee ed bloodcell (SRC) Whehe he unolog eec o eaue weanng etended aeal cae 29)ae abable o nuonal acoeeaure regulaon ando aealy daed odcaon o neual oendocne develoen o uncon ean o be deened.

nan onkey (and he oher) reond o earaton wh a anendeeon o n vo ogen eonene hle he ude o beeaveen n huan doe no aea o b elaed laa corol level 3031) Sepaaon o quel oney o he ohe eul n evealchange n unoloc eacvy; hee nclude a declne n copleenoen level (an eeco echan n huoal une eone) acohage uncon, and gG anbody eone unzaon wh a bengnbaceohage he agnude o one o anohe o he eec beng a uncono he ychoocal envonen n whch h aal wee houed ollowngepaaon ) o nee ha heu acaque oney whchhow enally he ae bhavoal one o eaaon o he ohebu de ubanally quel oney n he endocne eonehowed no change n une uncon ollong eaaon.

n adul anal a vaey o behavoal aulaon neeed a bengeul o he ogan ae caable o nfluencng a vaey o uneeone n a vaey o ece. A noed n he cae o deae ucebly, a dealed eanaon o he leaue would eveal ha he eec oe on unologc eacvy deend un he ualy a well a heuany o he eul ulaon eg and he unogenculaon 38), he eoal elaonh beween eul ulaon andunogenc ulaon eg 39 e une eone o coen) unde udy e.g 7424) and evel ho aco. One coellnglluaon vded by he ngle udy n whch ean hea and

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RAI-IMM YM IRAI 55

old all ondered tror) were ound to et derntal ct on thnducton and/or ron o deayedtye hyrntty DTH) and conact entity, two cellmdated ron Agan, redicting h outcom

o uch eermnt deend uon a mor comlete undertandng of thinteraction betwen th ct uncondtionay licitd by immunognitmulaton and th acue and chronc ychohyologal fect of thetreul tulaton uon whh thee ar urmod.

From behaora rsecti, the mt hiticatd erimnta aradgm nole noou enronmental circumtanc that are redictale orunredtabl, caable or ncaable, or aodale or unaodable, thuhoding contant the hyca and noou lement o the tr whie roidng om animal wh th ablity o ada to or control ther nronmnt.

Aute and hron moto o uh ermntal aradgm ha, thu ar,yded nteretng but inconitent immunoogic eect Prmnary reut a aa oot hock reent the uron o lncNK cell actty en in animal ubjeted to necaable hok (46) and thatneaa ut not ecaa oot ho rut in a ureion o mitognndud lymhorolifraton (7 Th latter reult howeer, cannot bontently redued (8 Othe tgato 45) ha eoted altration in mmunoog reactiity among anmal ubectd to lct hocwith and wthout a warnng gnal or in anmal that were or wr not ab to

aod the noou tmulaton Th tn and drecton o the dfrncewa a unction o the arameter o immne untion being meaured

Nurondocrn tate roide the internal milu within whch mmunreone occur Stmulatng anmal durng rnatal and arly l ayngocal ntracton among adut anma and ong anma to enron

mnal rcumsance or whch they he no contrl ar among the ycholocal manulaton hat nduce neuroendocrne chang that are mlcaedn th modulation o immune reon. A dicued ow ou knowedgeof intracton betwen neuroendocrne and mmune funcon under normaland trful condton howr i ncomlt lucocorcod for amle are uually immunouree t generally aumed, therefore,tha an eaton in adrenocorial teroid th mot common manietaonof th ect of tre, reonl or the quenly oerd urono mmunolog reatity aoiated with te Thee ae numeou eame o tre-inducd, adrenocortcay mdated ateration of mmunron, arulary n itro; yt ral other oraton o trnducd altraton n mmunolog reatty ar ndendnt o adrnoorca actaton (0 956 onnt wth te ct o adrnalectomyhyohysecomy oiate h effec of tr on ome maur of immunynumr of erhral lood and lenc leukoyte) but the tendudueon of mtogen reonty of rihera bood ymhoy o



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566 ADR LEN AND H

nid by hypophysoy (57 I ss vdn h h in vvo iunoog onsquns of sss nvov xy opx nul, ndo

n, and iun spons inons. Consdng ha h aon of

un sponss is isl pbl o ling lvs o iuling hoonsand nuonsis s inions so il o inud opfdba and fdfowd haniss

Cnditind Altratin f Immunlgic Rativi

Lng, h os opx of bn funons, s h pay ans bywhih hgh ognss dp o h nvonn A d nd opl

ng ilusion of h ol of h nvous sy in h oduion ofuny, hn, os fo sva donsaons ha iun sponssn b odifid by ondonng In h s suds of ondonng (.g.58 nul ondiiond siuus CS ws pd wih injons ongn nd psnaion of h S on was nully abl o lii on

dond nass n nonspf naaoy ponss nd n so ssnss n nbody lvs as w Ths xpns nd h nsuingonovs bou h nion hv bn vwd swh 60

Mod suds of ondiond ons of iun sponss bn wih sudy by Ad & Cohn 6 who usd a asvson ing padigIn hs passv voidan suaion, onsupn o novl, dsinivyflvod dnking soluion, h CS, is pid wih siulus h uss sonoxious in s h unondiiond sius (UCS) Fo xapl, asinjd wh ylophosphaid (o an nub of oh dugs) onsung shan-vod w a n ing o vod dnng sahanvod w. Usng s, onsupon o shn-vod wa wspd wh n npon njon of h unosuppsv dg ylophosphaid CY). Th days a, al anias w iunizd wihSRBC nd ondiiond nils w ando dvidd ino goups:

Goup CS was xposd o h shan souon pvousy pad wh hiunosuppssiv dug nd injd wih sin Goup CSo ono foh fs of ondonng p s, ws povdd wih pn w nd ws noohwis npuad and Goup US ws gin plin w bu injdwih CY o din h unondiiond iunosuppssiv s o h dgA nonondiiond goup oginlly ivd CY wihou xposu o shinbu, foowng unzon ws povdd wh shn souon whnv any subs ap of Goup CS wa xposd o sahan. A plbogoup ws ogny njd wh sn foowng h onsupon of pn

wAs xpd, h paing of sahan onsupion wh an non of CYpodud n avsion o sahainlvod w nd as hypohsid, on

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RN-MMN SSM NRNS 67

dtioned anmas eexposed to the CS showed an attenuated antbody responseto SRBC comped to nonconditioned nmals and condtoned nimls thatwere not eexposed to the S. These dt nd vericton of the resuts by

oh nvsgos 6 6 hv bn kn s vdnc of bhvoycondond sppsson of mmunologc actvty In on o nothe of suchstudies, the cquston nd xtncton of th condtiond suppssion oenhancement of antbody- nd cemdd mmune esponss s w snonspecc hostdfens eactons has been documented usng drnt CSsdiffeent Us diffeent ntgns nd dffent outcom mesures. Extndng hs sch condonng pcsss hv bn mpcd n he dvopment of toleanc o n mmnomodltng n 6 6 h boloicffects of condtoned mmunosppessve esponss hv ben boted n

ang the pogsson of autommun dsease n lupuspon me 66 67and moaty to a transpantd pasmcytom6 nd condond ncssn specfc mdato of mcosa ma c fncton hs bn demonsttd6 Most of ths eseach hs dopted tstevesion condtonng padgm n hch n mmnomodng du hs svd s th CS t s nocea howeve tha th phenomenon s not confined to condtoned mmunophmcologc sponss. h immnooc ects of stss hav bncondtoned (eg 7) and conditonng effects hve been obseved usngnns s uncondond smu 6 7)

ompnsto sponss chactze mny (bt not ll) condtonedphysoogc ects inducd by dgs. One mght theefore expect conditionedsponss h oppos n dcon o h uncondond ffcts of himmunophamcologic du used as the UCS he data how a almostotay unfo n ong cndnd sponss that mmc the uncondtond munophmacoogc sponss 6 cnt cptons 727 pemt only th nfenc of compnsato mchnsms. he dscpancs s mhodoogc nd mchnsc ssus ha nd o b sovd.Anothe ecung issue conces th pven use of vesv stmuus

ondtons a mitton tht so nds to b ddssd Hoev th notontht condtioned mmun sponss nxcaby nked wth condtonedavoidnce esponses o that thee s some diect eationshp between condtond bhvi nd mmnoogc sponss civs no sppo fom thexistng tetue o the exten tht he smpng of dieent paamtes ofmmune funcon und dffn xpmnt ondons s sunly psenttve taste avesons can be expessed without conomtn changs inimmun functon and condtond changes in immun functon can beobtned wthout obsebe condtoned vodanc esponss 6 on

sstent with the relatonshp between condtoned behvoal nd utonomic ondocne esponss th vb d suggs th dffnt mup on



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56 ADR N AND HN

dtonng pocesses and mechansms ae nvolvd n th condtonng ofbehavoral and mmue responss.

Th physoloc dton of condtond lttons n un uncton

ar not yet know So wrters howr h plcly or plclyassumd that the conditioed suppresion of iunooic rectiity is astress-nducd ffct nc lucocotod latons, qutd wth or tanas an ndex of stress can suppress mun rponses th hypothss sattractve bcause t povdes a ready "planaton of an uxplaned phoeno Th ll dt hower prod o suppor for strssnducdeatos stss horos oy drocortcl sterods s themedator of condtond altratons mune functon Indeed much of thdat stad drct cotrdiction to such hypothess Thre are proems i

nterpretng etrpaton eperets but s should be notd that n one study7 mmunosuppresson was not obsevd n adrenalectomzd mcHowr th stressdton hypohss cnt accout for th follownobservatons: no condtond suppresson of antody producton s osrvedwhn LC s usd as th UCS or whn strod lls ar lvatd y njectonsof LC or cortcostron t th t o uto ; codtoeduppresson ad/or ehaeet o aody ad/or cedated rsposesoccur n the prsumd asnc of or wth euvalent chags n cocosteron nd prsuly othr stss hoo les 7 778 prferncetstn procdur that uats ud consumpton and obats th conct tht occurs wh s r oly posd to th CS soluto codtond unosupprsson s osd n th antbody rspons to Tdependent and ndependent ntgens ( 9 graftshost reacton (),d i th whit ood cel respons to cycohosphid (0) and in adscrt codto pd oth th CS+ d th CS nducestrod ltons ut ony th S + nducs codtoned rlas of hsta ( 1) t s esol to sust tht codtoned ltertons of muoloc rctty y dted y ondiioned nurondocrn responses but the data collctd thus far are nconsstnt wth th hypothessthat such efcts are edated sply y nonspecf stressnduced chns horoe lls.

Th mchanss undrlyn th codtod odulto o uty rot kow ut ther s o shorte of potetl edtors d t s hhyunlly tht multpl procsss ar volved. ondtoned mmunosupprss rsponses ocur whn codtod ls r rposd to thCS befor as well as ftr munaton. Such effects could ply that th

mechanss do not nvolv antnndud munologc or neurondornechs; thy could lso dct tht dffrt chss r oldwh codto s superposd o est or o te-cttedsyste Aso diffrt iuoodut ts h dfrnt sits of

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RA-MME TEM TERATI 569

acio ad he same immuomodulaig drug may have differe effecs oacivaed or oacivaed lymphocyes. As described below, we ow kowtha he mmue yem is ervaed ha leuocyes ad euros hare

cerai europepde/euroramer recepor ha ymphocyes ca produce everal euedocre facor and ha cell of he mue yem adhe ervou yem ca poduce ad repod o he ame cyoie Thuscodioed chage he paer of creae or decreae of eural ad/oredocrie aciviy ha ca be reogized by acvaed lymphocye or coverey he eec o codioig o te releae o iue produc capbleo beig recogied by he ervou ye coue poeial pahwyuderlyig he codiioed modulaio of immue ucios

Immunologic Eects on BehavirJus as reciprocal relohip x w el d ue fucioad edocrie ad immue fucio ccumulaig daa sugge immuologc ifluece o behavor a wel behvoal iuece o imue fucio. The behavoral effec of (erl) viral feco he cogive ademoioal sequelae of auoimmue dsease ad he behvioral differecesbewee ormal ce ad hoe wih geeic uscepibliy o auoimmuediease are reviewed elsewhere 82-86).

Rece da furher ugge ha behavioal chge ocaed wih im

muologc dyfucios may acually e adapive i maiaiig or resorighoeoa wihi he imue sye Lupu-pe NZBNZW)FI icedo o cuire codiioed ase averio i repoe o dose of CY hiduce codiioed avoidace respoes i healhy corol C57BL6 mce(87). Siilarly Mrl-pr/lpr mice wih maife ymom of auoimmudieae lymphadeopahy ad elevaed auoaibody ier) do o avoidfvored oluo paired wh doe of CY ha iduce ae verio cogec Mrl+/) col ice hee diferece i behavior are ohe resul of leaig deci i he upusproe ice because ere re oubrai diferece pror o he developme of ympom of deae orwhe a oimmuouppreve drug i ued a he UC rlprlpr icewh ypom of uomue deae alo voluary coue more of CY-laced flavored driig ouio ha aympomaic corol ad heydri ufficie mou of he Y -ed ouio o euae yphdeopahy ad ai-sigleraded DNA abody ier 9 Alhough o previously described wih respec o he immue sysem hese daa are cosisewih a large lieraure o he bchavioral regulio o phyiologcal e85) Wheher he aiml is respodig o opecic immuologicallyduced pahophyiologcal chge oe or oher arge orga or cose wih he bidrecioal pahway ha l he CN d immue sysemhe b i capbe of receivig ad rocessig iformio emaaig from



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570 D N ND CH

he (dyseguaed) immune sysem diey emains o be deemned To heexen ha he ban s apabe of ang on inomaon povded by heimmune sysem behavoa poesses appea o hve he poenia o serve an

n vvo immunoeguaoy funon

ENDORNE SYSTEMMMUNE SYSTEMNTERTONS

Even hough poduve neaons among subss of T and B ymphoyesand aessoy es an esu n he poduon o anbody and efe T esin vio he neuoendone meu n whih hese es nomay ive and he

e sufae ando yopasmi eepos fo a divesiy of homones andneuopepdes hey epess 99, povide he oppouniy fo moduaoyad neave gnas om ousde wa has been adonay vewed as heimmune sysem. This seon hghighs some of he eensve esus ndang ha homones of he aneo piuiay and he adena gand ae m-mmlar; a lymhcye a accer cells eceve neuoendone ues; and ha podus of he eukoye omponens of he immunesysem an ommuniae wh and moduae enoine and nevous sysemesponses 995 (Fo a disuson of he immunomoduaoy oes of

homones podued by he poseio piuiay h hyoid gand he pineahe gonads and he hymus see 96-00

Ato Ptuta Homos

Eay sudes 101-03 epoed ha sans of piuiaydefiien dwaf medispay eain mmunoogia abnomaiies ndng invouon of he hymus ea hypopasa of he bone maow and seonday ymphod ssuesand depessed emediaed and humoa immuniy. Some subsequen sudeswh hypophyseomized (hypo) mie suppoed he poposion of an in-eeaonshp beween he puay and mmue funon These obseva-ons ed o a pehoa of sudes o deemine wih of he many homonespodued by o soed n he piuiay, and whh of he hypohaameeasng homones oud moduae mmuny.

Homones podued by he aneo obe of he puay (he adenohypoph-yss) an be gouped no hee majo asses aodng o he amno adsequene homoogy One goup nudes gowh homone (GH) and poan(P) Adenooioopin (ACTH) apha meanoopn and bea ipoopin

(PH) fom a seond group of pepdes deved fom he peuso poenpoopomeanoorin (MC). LH he pohoone fo he mophnekepepdes he endophns The hd group nues hyoidsimuan homone (TSH) and he gonadoopins uenng homone (LH) and oe-simuaing homones (SH)

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RNMMUN SSM NRONS

GROWTH HORMONE (H) G defienie ve een oied wiara lluariy of e one marow and ymu and depreed Telti (0 05) NK aiviy (0) nd aniody repone (0 08 for

reiew s 10 02 09) iistati GH t GH-iit aiasfford ome degree of immune reoniuion (02)GH alo immunologil effe wen dminiered o normal a well a

o ypo nimal or dded o ulure of leukoye reed from inaias xa agassiat ags i it [gTell miogenindued proliferaie reps a iti2 (2) sytsis a t aittr t ts ats av vs graing a piuiry umor ell line produe G nd PRL ( 02 0) trstigly iti ig ss vi GH ai o str tyi

istgy nd L2 ti i ged r u like e ell gr didagt tg ssivity ts ( ) GH rriy aug-mened e in iro poliraio of rnformed nd ra ypy(2 ) a inreaed aiviy of allonigenpeifi yooi T ellfrom ina animl () Ineion o ypo ra wi G efeed mrkedinree omparale o oe indued y inereron gamma IN insra pduion y eiden eritoel mopage ad imulaed wi ymoan (02) Moreoer periperal lood nd puriiedava apas av ativa i vitr y GH t r srx

ide anion a nonpeii ally killed ngeed aria (15 6) n effea wa iniied wi a peifi anody o G Ta ee laer oeraion were mde wi a igly puriied populaion o maropage uppo i a GH xs die arags s gt inered ymoye ranored and reing peripeal yts andmonocye epre igainiy rtrs r GH (02)

Te CN oer ormone produ o paogen and e immune yemielf all onriue o e imp of G on immuniy or emple virue117 or aerial endooin inreae ereion o G in uman 118

Mopgedeived ineleuin L n a ag yi as GH (9) iat f ni and tyi yytimmunoreaive r G (20) on t endorine a immune yem i juegiig t e deipered. Tymoi rion V group of low moleulrweig pepide ered rom ovine ymue ue piuiry ell oinree eir ereion oG and RL ( 2 ) i led o e onep of aeedk loop eween e ymu nd piuiry 102 Te reorion ofiity yx rats a atagi y H Fia t areen finding e immunomodulaory effe of rin leion re alo

medied le in pr y e piiry glnd (22 2).

PROLACIN (PR) PRL i involve in immunologil proee (2) well a wi mmmlian reproduion and lion Ngy e l (25) iniied



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R , H

ry PRL ecren n r e dne recer n rcne, nd eved reed ndy nd DH rene en ndclee (14, 16, 17 rered yrlcne ndced y

dferen ecn (rcrne r cyene HCL ced flre eecvely del cllene fLea ooyogee; dereed lecnndced ene f T nd B cll ndeenden L rdcn r L recer exren reed Tcelldeendencvn f cre; nd reed crlly ndced T-cellrdcn fF ' (14, 17 Exen PRL revered ee defec (4n vv nde PL ned lycye rlfern (18 nddnrn exen PRL r d nn ( leenden PRL relee reled n ncreed enc renvy f

lycye, ncreed DTH rene, nd revered e rfnd nren eeced y cycrin (14 29 0)

n cnr n vv eec v eec PRL n e lernr L rdcn f lycye r n lcenfree cell clre ven een een (14 . Hever, en c clr ere nced lcncenrn f n ndy r PRL DA yne nd cellrlern rkedly ned (14, 18 T, l e ervn e nry cvy f e ndy cd e red n PRLfny cln cld n e nd n ne deced n GH r er

rne (14, e e clred cell eelve ere rdcnrPRL T de een drecly red y ervn lecnled nrl lycye ( 7, 31 , e rne EL4 y, eCTLL cyxc e T cell lne (4 nd n yel cell lne(3 ec rdce fcr PRLlke cvy nd nrecvy.ndeed, n neru n PRL drclly ned e r L4nd CLL cell (4.

Te clexy nderlyn PRLne ye nercn j ennn e reced Te nercn nclde e dnerc yend cell f e ne ye elf Fr exle, n nly d lycyerdce rPRL, Ll le e n PRL relee nvr (133 nd n vv (4 Mrvr, PRL nerc er rdc fe endcre ye Crcln PRL nevel rele n relencr nd vcve nenl ede (VP rele PRL level (4, d e d (14, 130 Serd rne l fec crcln PRL n relee eleved y eren (34 nd ned y lccrcd(135 Exen r enden elevn PRL n ce e crne l eleved revered e (e en rnvy, n ll (elyd e ry e nreve efec f lccrcd (14 T, PRL y nc cner e f e reveefec f lccrcd Snce ce ycl r evrl rer ndce

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RN-MMNE SSM NRONS 57

a apid ise in PRL conentatons (24), PRL ike ACTH and the cateholame a te horone Uke AC howeve the esasoiatedR ncease s foowed b deceased R seetion ad then refratoines

to urhe stmuaton wth epetton of the treso 124 136.

CTH ND THE ENDOGENOUS OPIIDS, ENDORPHNS ND ENKEPH-

l ACH ad the edogeous opod peptde apha beta ad gammaendophn are geerated b enzmat poeng o the OMC peuomoecue (137 3 Beta edoh compoed o 3 amo acd; apaand gama endophn ae copised o the ist 16 and 17 ano acidsespetive that ake up beta endohin. A obe o the pituita gand theadenal edua (7) macophages ( antigen o mitogenatiated

mphocte 2 1 ad T ce cubated wth aCD3 atod 14podue endorph In addto orotopn eeaing fato CRF) indect nduces ces to poduce beta endophn appaent b timuatngonocte to poduce (14 141)

aetera admnsteed ACTH aects an nceased output o ucootod om the adenas and s mmunosuppesse n seea sstem egantbod tte Arthus tpe and aaphyat hpesenstt aograt ejecto (142 he eae pama coo aocated wth AC aue adecease o the hpothaac euopeptde CRF whh tu deceaes

ACH seceton and bings ccuatng cotso ees back to noma theocaed hpothaaopituitayadena axis) At least ome o thee andothe in o iunoodulato sequeae o exogenous ACTH e ceaattrutabe to the gucococod pdut o the tet adea ad dued beow athe than to a dect eot o the ptutadeved AC oce o the mmue stem. Howeve n ceutue stes ACH suppeses antbod poducton (143) nteee wth macophage tumodaatt (144 odulate e uncton (45) ad uppeses NF 'poduton 146).

Endophns (and enkephans) an mod antgepecc o mitogendepedent n vtro proerato o mphocte (147 14) NK actvt (141) antbod epone (143 15) NF poducton (152) and phagocteheotaxis (15). Whethe sh esponses ae depressed o increaed madepend on the amino acid euence bindng to the elevant opiod o onopioid eepto 54 55 an/o on he stage o actiation o deentiationo the pau mphote that bn the endohn ueto 3 Foeampe apha endohn and ACT nhbt (14 whereas beta endohethe ehae 1 151 o has o eet 143) o the pm atSRBCantbod esponse.

eea mechaniss hae been poposed to epan how deet endophis moduate mmune esposes Endorphs ad AC ma ate the



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57 AR A H

inooic reevn receor on e yocye o ic ey ind139 ndeed, Henen nd coee 10 ve deonred endorin nd ACTH ode e CD2 SRBC receor nd CD3 (r of

e Tce nen receor coex eoe on n erer ood ce A econd ecn y ree o e recn fndin y Hejnen ndcoee 0 ncon of PHAed T ce w endorin efec o dernce of L receor on T ce. Fny, endorn cn reny n refereny o cen HLA c nien 15, ein n inoeneic coonen of eec ofendorn on ne reone

Te enen (eonneenein or e-en nd ecineenen or een re enede orne fro e recror

oece, roenein A 13 138 Enein nd o ecific oioidreceor n rn ie nd on yocye nd e noodoy ireec o nody forion in viro nd in vivo; e ner of erierood eocye e ner of T ce R roee yc we,rence o vir nd or cene; eocye ron; nodydeenden ce-eded cyooxcy nd rodcon o L2 nd exreonof e L- receor 3 15 158 e doe nd nre of e enein,e doe nd roe of nien dnered nd e n of enendinirion reve o nen y roe n deernn e direcionnd exen of e noodon noewoy nce oodede re rer cy derded n ood, e nc eween erecreon nd co y e crc o e ec on ne fncon.

Leve o endon nd enen re increed y eior ec re nereny n rd nvoved eer nerennoxoneenive or oodeded or cono (noxonenenvefoo hoc re ennceen of or row w een ony en oodeded neen re (wc o dereed K cyooxcy nvoved 159 n oer ord, reor need no invove e eedor.

Glucocorticoid Hormon Producd by th Adrnal Gland

Foon ery deonron cococod ced yod nvoon nd exeed cncy on n-noy nd noreive effec, die of e ode nd ie of cion of eeeroid re exoneny dd n nderndn of e coexiy of eine ye 12 Soe of e doe n reienreed effec of

exoeno cococod n dfferen ece nde row rerdon ndin; yoen; increed co of inoon nd noced decreed concenron n e dereon of nody foion iniiion of djvn effec of oneacteiu pavu on M

Annu.Rev.



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RNMMN M NRCN 575

antibody formaton; poongaton of toeane nhbtion of skn and enalalogaft rejetion retaded DTH reation inhibition of ontact ensttynhbton of generaon of yoox effe es eduon of mxed eukoyte

raton redud generaton of hepe ataton n ymphoytereruation pathway and dprd NK eatvty (2 66

Guootods eet equaly pofound and mmunoogay eeant no and n to effet on monoyt and marophag Thee nlude a

suppesson of numbes o uatng monoytes ass II MC antgenepesson phagoytoss and ntaeua ng of ean moogansmsytone produton/rton ytototy by ntrrontratd maophages numbes of epidema Langehans els bosynthess of someompement omponnt F eeptor preion hmotai antigen pr

sentation and prodution of inflammto medatos suh a paminognaato easase, and oagenase

Many o hes obations we eied fom udes tha inod thnoduton of phamaooga athe han physooga onentatons ofgluoortods Evdene that these adena steods eay do pay an mpotant in vvo mmunorguator (phyooga) ro om from tud onstess and fom eent epeimens evealng the eets o gluootods onhe atty of munoeguato ytones It has ong been nown that stressatvates the hypothaamo-ptutaadrnal a and that th ffts of tess

ae assoated wth some ateatons of mmune funton In addton, at eastom form of str ar aoatd wth an atrd uptbty to nftonand nopat da. Dpit th fa that th gluoorodndued downeguato modultons of e mmune ssem e eense w bemplisti to attribute a immunooga onsequenes of aeed behaiorasats e. ses fe-een hanges onditonng soey to nreasd adenoora sterod At ow onenratons guoorods exert muatofft on rtan mmunoogi ron hghr onntraton routnelyappea nhbito Ao the et of opiod peptde and ateholamines that

ae podued n th denal medula e subet to hypothaam and pitutnuenes and ae mmunomoduato Fnay, as noted above stessndued mmunodpsson has ben obseed n adenaetomzed as wel asn ntat anma (2)

Beedovky and oleague 666 have epored a tranient elationof serm orosteone n m and rt dung th peak of the antbodyrepone and folowng admntraon of oue produt o Con tted els. They hae poposed 67 that the antgenindud nease nguootods reguates oepoduon of anbody and as suh may e

pan th phnomnon of "antigni ompetition th depreed primrantibody eponse o an antigen adnsteed wthn a few days aer theprm immunization of that anma wth an urguated atgn Adr



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7 ER, EN N CHE

nacm ara abs ann mn (7 an as as assca nanc -cU acv (18) Ts srans ss a mmun ssm sf can ua aam

ua-arna axs b mans f ckns rs fm acva mncs (19) s scuss abv s a as rcn rcv sncansur n a IL- smuas scrn f aamc CR (5 170) anncass cncnan f C n asma (71)

In an ckn IL- rucn a anscrn an ransanvs (774) cccs x ffcs n rcn f ckns (11 1) suc as mr ncrss facr (17) IL2 an IN '(118) an IL- an GMCSF (1) Cr s srans maxan man f mmunsurssv fcs uccrcs Hvr

surssn f ckn rucn m n rc rsns fr rffcs sc s srssn f N acv (80)

ATONOM NERVOS SYSTEMMMNE SYSTEMNTERATIONS

T CNS as avaab rus fr cnacn an ruan srucurs n rr r an ska msc a) nurncrn u an ()anmc rus a bc acv mcs n

rac cs mmn ssm an mua r rsnss (10918118) I as n bn knn a aunmc nrus ssmarcuar sannc smac nrarnrc nrs rvnnrvan vascar an casar/rabcuar sm musc n m rans (18 18) In 1970 xsnc f rnrc an rrcrs fr nuransmrs n mc mncs/macasan rancs as sas (18 187) rcn vr as aunmc nnrvan f m rans as sn b arncma nrv frs n rc cnac mcs (185 188) I naars a nrransmrs ar avaa as aracrn scrns ansnac mars fr nracn rcs n cs f mmnssm (18 189 190) In s sc br scuss nnvan rma an scna m ss an n scb n cnura rv susancs quaf as nurranmrs rsc m sss.

Innervan Lymp Organ

mar m rans (mus n mr) an scnr m rans (sn m n u-asca m ss (GLar nnva nrarnrc (N) sannc smac nrv

Annu.Rev.



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RNMMN SSM NRNS 577

fbrs (9. Ppdrg nr fbrs ls h bn fund n hyus splnlyph nds nd A (9

Ths nr fbrs y b: (a) prry snsry fbrs whs ll bds r

fund n snsry gngln suh s drslr gngln r ndsgngln prularly pssbly wh subsn P (S r ssnlrdy nn b prry snsry nsrs n hr syss fbrswhs nurppd s lzd wh nrpnphrn (N n psgngln syph n fbs s pps b h s h s f hnurppd (N rnls n spln c) un psgnglnppdrg npus h r ndpndn f h NA nnrn r fbrsfr nrns pdrg nurns wn h rgn slf prulrly n hs f GAT nwn pssss n bundn f ppdrg ll bds f

h nr nrus sys Inrns ppdrg nurns n h hr lyhd gns h n bn dnrd lkl ha eve fbennrng h hyus spln lyph nds nd bn arw r drdnly fr gngln lls f h syph hn r llrl gngl nh sr r fr snsr gngl

INNERVATON OF PRMAR LMPHOID ORGANS Nr fbrs h bnfund n h subsn f h bn w wh nls ndng flyng hp lns (996 sng hln hsfursn pluss f NA fbrs n b sn rl wh h sulur nh w nd furhr dsrbu n h prnh (1 1619 I s n lr prsn hhr ppdrg fbrs ls dsrbu nh rly suds suggsd rl fr N n bn funnsyph suln rlsd ll n h ln fr h arrw9 97 slr sndry lyphd rgns B drnpr suln rggrd s lls n yl r hrnd h ll yl (19 suggsng h y funns suh s prlfrn dffrnn nd grn

y rspnd NA nurdulnTh hyus rs NA nnrn (1 190 f nuns nh su rl gngln nd h uppr syph hn (03 06Ths fbrs nr h hyus wh h sulur dsrbu wh h psulnd ssd sp nd fllw h sulur n h r. brs rsrd hrughu h r wh h hghs dnsy ssd wh hsulur h rdullry unn S NA fbrs brnh wyfr h sulur n h prnhy nd nd ng hyys Thdull nd ssd phll ns nnd sprsly nly lng

h sulur Th NA nnrn f hyus urs prnlly n rlr hn NA nnrn sndary lyphd rgns suh s h spln.Thyys whh pssss b drnprs rspnd hlns

Annu.Rev.



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5 R O

by nhbtng plfrtn nd prssng ll surf drnttn ntgns nhnd n vt plftn rspnss f thyyts frl -dy ld ts sypthtzd t brth h bn rprtd 6

. hs sprs dt suggst tht prlfrtn ffrnttn nd grtn f thyyts y b undr syptht NA dultn Th NAnntn th gng nutd thyus s h bn nd Asth t shrns th NA fbs tn th prtnttn ndnutnstt ntnt nd b dnsly pt f N sssts nnhbtng prlfrtn nd nhnng drnttn thn th hngng dnsty nd nnttn f suh fbrs th turng nd gng thyus ynhn nutrnsttr vlblty r ths funtns

Bullh & 3 usng hrsdsh pds tgrd tng

thnqus ptd dt nnvtn f th thyus by nuns n th stln f nulus bguu nd by rl nurns tht rsbld ntr

h lls hs tng study upld th dn r tyhlnstrspstv Ah prfs n th rgn f th t-dullary untn ldt th l tht th thyus s nnrtd by hlnrg fbrs Snlyphyts pssss usarn hlnrg rptrs 23216 suh nnrvtn uld prd n ndgnus lgnd f ntrtng th thHv lthugh Nn nd hs lgus 6 dnsttd bundntnnrtn t thyus fr th supr rl d upp hn sypthtgng th tgrd tng thnus thy unb t nd brnst r gl nntn. Our ts t lbl ts putt n fbrs nhys ntrgdly fr th brn st hv nt t th suss W fndn sgnfnt hln tyltrnsfrs hAT tvty n thyus 7.Ah stnng s sstd nly th nn-nul strutus. Ah ls sllzd n NA nrs n th thyus nd n thr systs s th rpsn f Ah ds nt sgnfy hlnrg nnrtn Ths dt thn nt supp th stn f hlnrg nnrtn f th thyus 7

Svrl rprts h suggstd th prsn f nurpptds n th thyus Pl unt prfls r dntd n thy rt ytn nd spssn ppr t b prsnt n nn-nurl pnt f th thyus nt rprts sugst th prsn f SP ndltnn gn-rltd pptd G nd N lzd th NE nnv brs n th thyus 3 Thyys nd lyphyts pssssrptrs fr nurus nurpptds lnd th lssl sndssng systs suggstng tht nunstts lsd thsptdg ns y b lbl t ntrt th ths spns lls.

INNION O ON OI ON NA syptht bsars nly fr gngln lls n th suprr sntr/l gnglnpl whh rs ts pgngln nput fr ll bds n th

Annu.Rev.



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19/42

BR-MM SSM RCOS 579

62 nrmlaral cll clun n nal cr n ra ( 8 , 1 86 224). T onlioni N fir rvl wi lni nr nr ln a ilar rion aloni lnic vaculaur an iriu ino

vral 8 82 8 8 0 2 22-228): (a) cau b) racular of oo ucl a la a rol in conracilcaailii f ln; c lar vl f ln an ( lnicw ul Mo fir iriu wi racular an wiul In wi ul fir follow cnral arriolar anfurr ranc ino arnca in ajor i (87 227) (a) LS urrounin cnral arriolar wr o -lr anurr lc ar cac (b aln arinal inu wraninrnin acra ri an n arinal zon wr

acra an B lc ri ) arafllicular zn aln our o o clur N (roinrola oiivnr rinal or irc naicik conac wi loc anacra n LS ( 886 88 9 ) T a clr ainan nr rinal fr wi oo ucl cll in an coarn of ln

P fr ar fun n ln arun cnral arrl an larvnou inu in rcula an xnin ino o r ul an L ( 8 29) T a nor fir or a a f

auonoic innraion racin ui ar n o inif ir oriinGcnann fr ar fun a can an aconain colocaliz P W al un PY conainin nr r in ln fllwn canal iuion n for N nrv( 23 23) Our rn o of NPY iunoracivi icolocali wi H in (N nrv alou i alo rain o onra rnall nal aiv nurranir fun in ln inclu oaoain CK nurnn n VP an or( 8 3 233) IL- unracv al a n nf in nrv-lil n ln (23) ra clcali in N fr In viw f xniv arra of rcor for an or nuroranir foun onloc onoc/acra ranuloc an or cll oiilii for nurall riv nracn wi cifc rcr n cll f iun ra cr f a cl finracin rval nurrann n CN r ckn inracion in iun

N fir ari fro anlin cll n ir ac cain or incollaral ac anlia an iriu ino l no wi ilr vaculaur ( 8 8 8 86 9 23 23) T fir iruu ulla cr aln ullar inu n a corcoullar uncion in aracorcal zon an arorz aon T

Annu.Rev.



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20/42

80 AD LN, AND HN

lyphys A subpsulr plus f A fbs snds brnhs n hrl n. F f ny dsrbu n h fll Thus vrl pns f yph nds r nnrvd nludg h duly rds h

pr nd ubpulr h ubpsul snu nd h psul. Aprsn h h spln nnrvn shs nuus funnl slrs (a s f lyphy nry (spln-gnl n lyph ndrtdullry unn ( s f ngn pur (splnrgnln nu lyph ndubpul nu f ngn prnnnd lyphy vn T lls (splPAS lyph ndprr f ngn prsnn nd lyphy vn Bclls spln-paraollicular/marginal zon; lymph nodmdullary cords);(e S lyphy grss (splnur rgnl n lyph nd

dullry snus 186 187 22Th n sruurs sudd s rprnv f GAT hv bn h rbb

ppnd nd Pyr's phs n svrl sps Th bs p f nnrvn by NA fbrs r slr 181 182 8 186 191 27 28.Ths fbrs rs fr msnr gangla, nd drbu n pluss f fbrsha hr ravl wh h smooh mus and u radaly, or mov drtlydlly ds th usl surf Ths fbrs tvl bn h flls n n ndulr plus hu sndn rbrzns n h Blyphy n hn drly rvr h Tdpndn (Typhy

zon and ntr th lamna propra whr th ranch rly among thllulr nuns nludng lyphy pls s nrhrffn nd othr clls Th NA rs xnd u o h subphll rgnf pl lls bu n h lun

nv vdn s fr h prn f nurppds n h nrnvu y 29 Whhr h ppd nrbu duln fmmun uncton has n asrtand nly fr f. As an xamplOy nd llgu 20 hv dsrbd plu f I P fbr nr hposapllary nuls th st o nry o lymphocyts h IP rprs21 22 h nun h hng bhvr f hs lyphys 23 Th fbr prbbly ply rl n h ngr nd rnn fyphys n GAT. Sd nd gus 25 fund s ssnbtwn SP nd GP nv fbrs nd s ls n h gu suggsng nnrn h may rsul n oh nuroransmrs and compounds roms ls bng srd n h l nvrnn nd uulynluncng ach ohr

Crter for Neurotrnmon

In rdr fr nurlly dvd ubn qulfy nurrnr mus sasy our crra. As dtald low st no all f ths h n m or NE h lls o h mmun sysm srvng s ona d

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BRAINIMMUNE SYSTEM NTERACTION

g (6 Ahugh nuppd fuf fth h dn f yhn nun wk ng

Criterion Presence of chemicay specic nerve fibers and their compartmentation h brn h NA yph fb nnr pry nd ndry yphd u ndng ny n pn wh yphy nd ngnpnng phg pn nd ndng ng p n GA nd und B yphy dungdpn y fy h f n In ddn h uggn f ppdg (IP NP SP GP n fb n hyu ppdg SP NP GP VP nd h n fb n h pn nd

ppdg hng nd ng b n f guPpdg nr fb h n bn nd rfuy n yp nd ndbn w

Criterion 2 Release of neurotransmitter and avaiabiiy for interaction hng dn f f nun n yphd gn fh pn f N N dr uy f h nuprn f h pn n dpd by g hn 9% bydnrn wh gngny h ypy ( 6 0

Sun ud nd n dy nd h NE d nh u ud f h pn ( 6 uggng h pnby f NE nun n ddn h pb by d ynp- nn wh yphy n h PAS n d undnd h by f nun n h nnn f p yphd h pry f h n n nd h pn nnn f nun u bnwn Dnn ud nd h y f N nd nuppd n h yphd gn ugg h h gn u

pn nd pbby b f nn wh yphd f hw u b

Criterion 3 Receptors on target ces h pn f b dnpprury h b ub n yphy w nwn (09 n bf d nnn f yphy w upd B yphyp b dnp hn yphy -upp nd hp p ppy h nub Mny/phgnd gnuy p dnp dn f ph d

np n yphy h bn nd dpndng ny upn us fph b gn n h un f yphy funn 6 9 B dnp n yphy r pdy nkd hugh



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22/42

582 ADR, FN AND COHN

li M seonessener sste rovn ston evene for ninooltor role for N Sties tt ve evlte et renocetors on slenic loctes fon recetr reltion follon

enervton (23 6) s s te se t et enocetors on oter tretells in te ere (60) s ts rtero for nerotrnssson sestlse soll for et renocetors s restve for l renercreetors n roves snl trnston t for NE tt s stlte ost of oter ioctive oleles knn to e involve in inorltion (e 26) . Ts ont oes rse ton n sties ofloctes fro te erierl loo nerotrnier resonses it efferent fro resonses n slen or lne erve lotes.Slrl ote n ltre eontte rke ltertons n

reetors resonses ese te e reve ro teir norliroenvironent n rol cn reson to te stte of enervtiontro reltion ecse soe nerotrnsitters n ent or snerze tokine eets on taret ells n vtro stes tt reove nollresent nerotrnstters s s NE st e interrete tiosl

otes ossess reetors for VI sotsttn n n otereties (24 1 242 262266). oever soe ctions re in orer for otereties nn ste s not te eqvlnt of rl reetor nlessstrilit islilit n stereoseifiit n e eonstrte n

intelllr eets t rite seon-essener lnks n e ientfe Slrl te eonstrtion of cne n locte fnton follon te lton of neoete (oten n rolo oses) oes noten tt te neroete te to lssl reetor or exleonists or ents tt lter seotonin sntesis n roe ltertions inlekote fnctions este te lck of evence for lssl serotonin reetors. Te serotonn cts to ifnt tke stes n exerts itseffets ntrelllrl (67). Ts s tilrl ton n te ver olexnterctons of te oio etes t locts Te eonstrtion of neffect of rolol oses of ete tt evene for enoenosresence of vlilit relese n eetors o tret ells oes not onstitte evence for nerotrnssson Soe o te oio etes olve nontritionl oe of tion or oronl efet in ition to ornste of trtonl nerotrnster role Eiene for oo reetorson lotes s een srse n nonssten. Interctons eteen orones n reetors for nerotrnstters lso st e taken nto ont(268) Glcoortios n enne te exesson of et reetor on soeells n relte nerotrnstter ntertions on lotes nrect (697)

Reetors on lotes for oine etoline (sn) lonne n enoene ve een reote e resene of tese recetors

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BRAIN-IMMUNE SYSTEM INERACIONS 3

n n envrnen ere n e rre lgn n evlle fr recer cvn rses n neresn nnsere qesn e re exresse ers e fnn nl en ell s n

secf ren su s G sne les n ve ru y o o Php hy r oly p m uevelen O ers e e nl n eenenn f ene exressn nes e resene f er funnl pees o oes

Creron unona roe or he uae neuroranmer lu reensve reve (6 7 e nuerous eles f n unuly e NE yo e op f hs hpe fw usul e le NE s h opo o hyys

M sen essener n eness n ennceexressn f ell surfe fferenn nens ( 6 0 0 7477 slcl cnenrns f N ve een rere ennceh pmy o M SRBC po e lkers u n llers revene s ennee (9 7) e llreveyoo lymphoy C po o llo ll oul enne xe nss n e nss () n sresse elsec ( N s en rre n e snessf leen nens r lph mechanis (4 n o n

cvn croes n rcell lss el (44 el se ( l 6 3 74 3 h o wh sresse n vv DH resnse n enne n vv rlfern fles n se n ll l nes n ennce NK cely oh n vv n n vr In n s ren re eecs nluoy h o lymphoy om oy lrns ers e uner ool (

h uopp V omo S ow mly o hp o n e nervus sse ve reenl een sn lrs f ne fnn (66 90 S s fn nl nrr fferen nrns sul e skn e us ernes rens f e rc n nere ers sln e s n sleen nh wllow ol moulo of opo houh C fers S sl o o ll h ly n rel sle nlo S h ul pmly lolvsln effes enne e l f les re ere S rees ve een fun n eler suppressor and Bles (969 n moph(9 S s ell en nn enne ell lfern lens (64 6 99 ls ennesCo u pouo y lymphoy fom m lnes sleen n eers es (99 300 In n ennes

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584 ADR, FLN AND CH

mcrophe phocytoi polymorphoucler leuocyte chemotxi (292, 293). Be o oervtio tht tre y excerte rheumtoithriti tht relee y peripherl erve my rouce my tiue

che o cute ilmmtio uch timultio o phocyoi y Nt h ee propoe tht cotriute to th pthophyioloy o thiiorer (288, 289 301)

omtotti o ou i C ier mll myelite Aelt ierct throuh receptor or omtotti o lymphocyte pper to eihiitory to my o the ctio o (288, 290, 299 302 303) omtotti ihiit the relee o rom the peripherl termil o primryffere uo. o h rec reeporme effe o ymphoye moocyte vi receptor omtti exert ihiitory eect o

HA-iuce hum cell mitoeei uppree eotoxiiuceleuocytoi uppree the relee o coloy-timulti ctor ctivityy peic lymphocyte

I eerl VI lo ihiit vriety o immu uctio (242, 262, 263 ,304) VI i ou i peripherl erve (l8, 233 240 305) ocite withthe thyu the spleen ymh nodes and mucosal tissues such the Gtrct. lymphocyte poe hih-iity receptor or VI (3 , 242) VIecree the T-cell proliertive repoe to mitoe ut h o ect oBcell mitoe repoe (242, 262, 304) VI ctivtio i relte to cA

muo 6 eery ihory o prierve repoe o ymphocyte VI receptor c e owreulte y iteliztio ollowiicutio o lymphocyte with V (243, 244) The locliztio o thee Tlymphocyte with owreulte VI receptor w ecree retly i themeeteric lymph oe eyer pthe while lolitio to pleeitetie liver lu w ultere Thi ltertio i VI-receptorexpreio ect the itertio o lymphoyte with the pilize hiheothelium o the potcpillr veule where lymphocyte eter lymphoe eyer' ptche hu lymphocyte ric ito G epeupo the icte o hih-iity receptor or VI.

Potntia ntactions of uotansmitts with s of thmmun Systms

Te mcroenronmen of ces of e mmune ssem The preece o erveier i the prechym o lympoi or the vilility oeurotrmitter or iterctio with cell o th immue ytem ew

imeio to our uerti o the microeiromet o immue cell.he pleic microeviromet coti prcri eocrie utocrieecretio lo prouct o erve ier. he prrie evirometiclue cytoie well the ecretio o cceory or uppori cell

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BRN-MMUNE TEM NTERCTN 55

e. ertnn htamne ptaann) an mt prbab mphteerve euopept 3 3 30630) The ere vmt iue h iv fm th pituit TH eh GH P

H a SH TSH) 0) t taret an uti aa ti thri he a ther) r the immue tem itef thmpept) 3 3 2) Thee re b-be na that nt epen upnee nteratn fr ther eet. Neurtramitter rpret atar f ia meue iret twar e f th immue tem t ear that eutamittr uh a NE a vra f the urpepti arpet i phia aequate netati a paaie etir inteati with earb e The peene iret ee terminatat with mphte a marphae a a ew frm f napt-ie

mmuniatin that ma mre irete an irt than pararne mmuiati, an ma b uprmpe upn th pararin pr furtramittr. A a furthr fr f mmuiati th f thmmune tem ma erete mpu that infuene thei wn futiautrne ifuen nurtramtter eretin frm aaet erve temna

hee f f mmunatn t u ane but nteat wth eahth He ma ater the exprei f eurtramittr reeptr aiue abve Neutranmitter ma ater th repivene f hrmne

a ti iteati with mpht maphae 33 34) tkine ma nterat wth nere terna t ater neuotranmtter eeaen atn t the effet n f the mmun tem 337) It ethat there ae bth a hr fea p betwee the evu teman the mmune tem e 33) The p ma b rpretb th RFAT-urtii-mphi ti-N imbhpthaam) mmunatn hanne Intereuki ha bee prpe a ake tne in th p ba n t enta eet n CR eun an mamine metabm reate t the R-Aurii axi

70) The hrt p ma be epreente b a ret ehane uh a aerve tmia eret a euotramtter with 6 m f a mphte ath mpht tin a tine that ntrat with th termina t aternurtanmitte mtabim ) .

aitin t the prnip neurotamitter ientife i a fiber termather aze neutranmtter ften preent. The neutranmtterma be theze n that ame ner temina . NE a NP P anC) a be taen up b a hhant uptake ite epiephre frmhma ur tae it NA erve teia fr ubequet rae a a

eurtamitter) 322 r ma be tae up b a w-affiit upte it ..ertin uptae from a pateet ure r ubeuet reeae a aeurtramitter 323). he etet f eeae f the oai epte ma



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8 ADER, FELTEN, AND COHEN

een uon iffereni reuion of reee foowin orie hyioogic imui uo he viiiy o he oher humor ge uch einehrine erooni urig ricur ero o ime Thu he

ehvior evirome coiion uroui he orgnim my hve mre efec on he cone of ecreion fro ere ermin

Potentil mechnisms of interction etween nerotrnsmitters nd trget

cells of the immune system Wih he emh o he ieiicio oreceor eurrmier vie for oei iercio i ymhoior he mo righorwr form of communicion rooe beweenere ymhoi ce i cic i-receor inercion wihueuen inrceur erion h infuenc he funcio o he e

ce The numer n comeiy of irec inreceor inercion for ige neurrmier uch E o he my ue ofymhoi ce icoiere ( 8 8 87 90 eurormir o my c iirecyhrugh he reee o oher ign moecue m m eerochromin oroher ce h re inemeirie beween nerve emin n ymhocyeor mcrohe (25 2 25 hee in cou be ve comeeuornmier my er boo ow vcur emeiiy or ymhocye ric cr eciize region o he vcuure eurornmiermy moue he civiy ereio or cio o oher eurormier

homoe cyoine or heir receor hereby ci ue neuromouor (eur unce h hve miim eec hemve u oeiehe efec of oher neury cive moecue iny neurornmier myinerc irecy wih ech oher o moify or occuy cive ie o heemoecue (3) hee rocee my occur ingy or i cominioeeni uon he comeiy o he oc mioenviroen

If we ume he mo irec mechnim o commuicion forneurornmier he rec ignreceor inrcion hen we mu wh he re ce i cbe of oin in reon o h irec inercio Ihe ce of ymhocye he oeni reone of he re ce re mnya roierio ) iereiio (c civion or incivio ereereio o vrey o receor (eg igeecic receor o T nB ce cyoie receor receor for oher neurornmier e ecreio of ecific moecue uch iboie B ymhocye ymhoie( ymhocye monoine (mcroe or omone (enocine ce:i movemen mirio or ere ce rffic n g ureguio ofruc of he mor hiocomibiiy come Thee re ony omeof he oibe reoe h my occur iy or i combiio in numerou comrmen of my ymhoi org i reoe o ingeneurornmier When we oo he mny neurornmier h eree i he hymic eic or ymhoe micoenvironme he oi-

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RAMMUE YEM ERACO 587

xtnt and compty o modaton s consdab. otn ot tscompcatd ntactons pomss to vy bt as cann a task asxpoin t o o notansmitts n t ban, o cytokins in t

mmn sysm

SUMMARY

obsations and sac dscibd in tis commnication di om anontaditiona viw o t immn systm. t as bcom abndanty caat t a pobaby no oan systms o omostatic dns mcanismstat a ot, vvo, sbct to t c o itactions btw bavoa and pysooca vnts. compx mcansms ndyn ts

ntactons and t atonsp to at ad nss owv a mpcty ndstood. T most impct ndstood, pap, a taosps amo ban, bavo, and immn pocsss. Wtotatmptin to co a t tat, w a sd stss cts and con-ton poma as statos to pont ot tat bavio can nncimm ncto. a aso dscibd data ndicatn tat t immsystm can ci and spond to na and ndocin sinas Convsy,

baioa, na, and ndocn ponss sm to b inncd by anactatd immn systm. Ts a aditiona iw o immn ncton at is

coid to ca itactions occi witin ympoid tsss is n-scnt to accont o cans n mmty obsvd n sbman anmasad man nd a wod codtos.

Ts data qstion sosy t notion o an aonomo immn mMost o t sac on t atio o mm sposs as bn pdicat-d on t assmption tat sc ation s accompisd by t intactincomponnts o t imm systm its, .. intactions amo p andsppsso ympocyts, Bcs, and accssoy cs tat can st n tpodcto o antbody ad cto cs T mm sysm s nd

capab o considab sation, and immn sponss can b mado ak pac in it. T nctions o tat componnt o adapti pocsssknown as t mmn systm tat a o tmat coc, owv, a tostat tak pac i vvo. T a now compn asons to biv tat invvo mmoaty pocsss c ad a nlcd by tnondocn nvonmt n wc sc pocsss actay tak pacannvonmnt tat on t on and, an at sas tat stn and/oactiatd kocyts can ci, and, on t ot and, is xqisysnsiv to indida's pcption o ad capaty to adapt to t d-mads o t nionmnt. T immn systm appas to b modad, notony by back mcaisms mdatd to na and nocn pocsss, bt by dowad mcaisms as w. T immnooc cts o

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588 ADR, AD OH

lerig, eil feeforwr mchim, gge h, lie irec erl ocri proc hvior c r ppropri circmcerve immorglory fcio i vivo oceplly, h cpciy o

pp or hc imm poe y coioi h i iml io o h oml opio moifiiliy of he immeym vi l ocri poc

We o o ye ow h re of ll h chel of commiciowee he ri he imme ym or he fciol igificce of heel ocri irreliohip h hve lih eileview o lev cerl eroocri ciciry i eyo he cope ohi viw, if mmy c povi i o fh i rerch oomic prgglioic ro rcve irec ir pro

jecio from ri m cli cl oliri, phe cli, egmelorreergic cli hypohlmic clei prvrivlr cle oxyoci vopi ro ll hypohlm poerio hypohlm or- l hypohlm, limic oi c cl myloi cle io o f h cl co (fol cil il coricl mily o of "limic co iio ic relio ofhe ye rie om reio ch he rrchi cei, crlgry reiclr formio of h ri m mro hypohlmicclei cell rop limic oreri re ch h hippocml

ormio pm coicl ociio . Th c icoc wih he hypohlm he rcre h lie he croro ofh limic foi i m cli

hi iegre circiry h exeive ceig eceig coecio mo he eio cie The regio lo h my imilriie.Thy r i iimely ivolv i vicrl oomic, eoocrilio Th coicl limic oi io mi oh civ cogiive procee my e ivolve i he rpo o reor, ifciv io ch epeio i veriv coiioig i he emoiol coex of eor ip from he oie well heii wol om immoloic ppciv h io h i iwhich leio el i lere epo of cell of h imme yem heyre h reio h repo o immiio o cyoie y lee rolciviy o l moomi molim hy h io hpoe he highe coceio of glcocoricoi cpor li omeocr ym wih o oow o h ooic roocri yem Th, hi circiry i h mor yem of he pec oply y rol i rpoi o imm igl li oowo he mme ym.

Wiho ig le o pcify h pci mchim w hve cricovgig eech fom i lvl of ioloicl oiio, ll of

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NMMN M NN 58

which suppo a nontadtonal, ntegated appoach to an eaboaton of thdpiv union o h mun ym. Th data umazd provdcompelng evdence tht the mmune sytem lke ny other ytem oertng

n h n of hoota ntgatd wth oth pychophyologalpoc and tho nuncd b and caabl fuencng the brn

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RAINIMMNE SYSTEM INTERACTIONS 59

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9 AE EEN AN OEN

cyclophosphmdenduced suppressono antibody poduction in ice Pyobiolog 6229-35

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90 Bost K 988 Horone ndneuroeptide ecetor on ononulearleukoytes Pro Allry 43:68-83

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