Bubi Est

8/10/2019 Bubi Est

1/13

July 10, 2013

o Home

o Contact

o Help

o Author Services

o Author Log In

o

Subscriber Serviceso Subscriber Log In

o Johns Hopins C!"

o About

o About the Author

Medical Specialties

Life Sciences

Species and Cell Types

Research Technology

Therapeutic Technology and Methodology

Pharmaceutical and Healthcare Industry

Article Published in the Author Account ofStephen T Holgate

A Look at the Pathogenesis of Asthma The !eed for aChange in "irection#ublishe$ on !ay 10, 2010

Author%Stephen T# HolgateSpecialty%Immunology, In&ectious 'iseasesInstitution% In&ection, In&lammation an$ Immunity 'ivision, Southampton (eneral Hospital, School o& !e$icine,)niversity o& SouthamptonA$$ress% Southampton, S*1+ +', )nite$ -ing$om

Access #'. as a Subscriber

#urchase/'o0nloa$ 1his #'.

elate$ Articles

"mail his Article

Share his Article

Abstract hile asthma is an in&lammatory $isor$er o& the con$ucting airays, most &re4uently

therapeutics $irecte$ speci&ically at components o& these pathays have ha$ limite$ or nosuccess in the clinic5 #art o& the problem lies in over6reliance on simple animal mo$els o& antigen

8/10/2019 Bubi Est

2/13

sensiti7ation an$ challenge to select therapeutic can$i$ates, an$ partly because allergic

mechanisms have been stu$ie$ out o& conte8t o& the &orme$ elements that mae up the structure

o& the airays such as the epithelium an$ un$erlying vasculature an$ mesenchyme5 his revie

covers recent e8perience ith some ne therapeutics that inclu$e biologics an$ conclu$es by

presenting a ne para$igm &or the $isease that embraces heterogeneity an$ greater

consi$eration o& the role playe$ by &unctionally active structural components5 Since asthma asoriginally $escribe$ in terms o& reversible air&lo obstruction, this moves aay &rom placing

in&lammation at the center o& the $isease more toar$s a parallel involvement o& the epithelial

mesenchymal trophic unit to provi$e the conte8t ithin hich the in&lammatory response occurs5

Asthma A Historical Perspecti$e

he term asthma as $erive$ &rom the (ree or$ &or shortness o& breath, hich encompasse$

many clinical con$itions o& the heart an$ lungs5 It as not until the mi$ 19 thcentury that the term

became more restricte$ to the $isease o& variable air&lo obstruction &olloing the care&ul clinical

an$ physiological observations o& 'r5 Henry Hy$e Salter ma$e on :0 patients he ha$ collecte$ in

Lon$on an$ publishe$ in his treatise On Asthma and Its Treatmentin 1;+0 5 It as

Salter ho $e&ine$ asthma ith remarable insight as ?#aro8ysmal $yspnoea o& a peculiar

character ith intervals o& healthy respiration beteen attacs5@ Salter also recogni7e$ that these

episo$es ere cause$ by contraction o& smooth muscle that $i&&erentiate$ it &rom ?bronchial

catarrh, recent bronchitis an$ ol$ bronchitis@ an$ that there ere unusual cellular elements in

asthmatic sputum5 His &in$ings ere some 30 years be&ore #aul "hrlich $iscovere$ aniline $yes

&or histochemical staining 5 By the early 19+0s, asthma as still regar$e$ as a

$isease o& episo$ic bronchospasm treate$ ith inhale$ broncho$ilators an$ systemic 8anthines5

Asthma Mechanisms %arly Concepts

By the early 19=0s our therapeutic options &or asthma as i$ening ith the intro$uction o&

inhale$corticosteroi$san$ so$ium cromoglycate 5 'uring the perio$ in the 19+0s hen

SC( as being $evelope$, #epys $escribe$ allergic responses in to phases% early an$ late

5 he early phase &olloing allergen provocation resulte$ &rom the local actions

o& mast cellme$iators such as histamine, prostanoi$s, heparin, an$ slo reacting substance o&

anaphyla8is 5 he late phase as thought to result &rom an in&lu8 o& in&lammatory

leuocytes especially eosinophils ith a secon$ ave o& me$iator release5 #rior to this perio$

theeosinophilas consi$ere$ to be a protective cell hose ob as to inactivate mast cell

$erive$ me$iators such as histamine, heparin, an$ SS6A 5 Hoever,

$uring the 19;0s the eosinophil as place$ as the central pro6in&lammatory cell o& asthma an$

other more chronic allergic $isor$ers ith release o& a range o& highly basic granule6associate$

proteins% maor basic protein, eosinophil cationic protein, an$ eosinophil6$erive$ neuroto8in

5 his perio$ o& asthma research also line$ activate$ lymphocytes to

the recruitment o& eosinophils ith &actors such as eosinophil chemotactic &actor o& anaphyla8is

5

hese &actors $escribe$ biological activities in the absence o& their structural i$enti&ication5 *ther

in&lammatory &actors associate$ ith the late allergic an$ relate$ immune responses inclu$e$

platelet activating &actor F#A., to be i$enti&ie$ later as an ether phospholipi$ G, high molecular eight neutrophil chemotactic &actor , lymphocyte inhibitory

&actor , macrophage/monocyteactivating an$ inhibitory &actors , to name but

a &e

8/10/2019 Bubi Est

3/13

&actors5 !osmann an$ colleagues $escribe$ to types o& lymphocyte base$ on their cytoine

repertoire an$ line$ them &unctionally to $i&&erent immune responses, h1 an$h2 5 hese &in$ings su$$enly opene$ up the entire &iel$ enabling

$etaile$ $issection o& immunological processes that ere line$ to the initiation an$ perpetuation

o& allergic6type tissue responses5 Although the cellha$ been incriminate$ in orchestrating theallergic in&lammatory response since the early 19;0s, un$erstan$ing that there ere selective

cytoines emanating &rom a particular subset o& cells provi$e$ a clearer un$erstan$ing o& ho

allergen e8posure in atopic subects coul$ initiate both an Ig" an$ a speci&ic e&&ector cell

response involving mast cells, basophils, an$ eosinophils 5 he

ey to this initiating set o& signals as the recognition, uptae, processing, an$ subse4uent !HC

Class II restricte$ presentation o& allergenic epitopes by pro&essional antigen presenting cells

along ith engagement o& co6stimulatory molecules on cells lea$ing to their

$i&&erentiation into a h2 subtype 5 Subse4uent e8posure to the same allergen

epitopes stimulate$ the secretion o& the h2 cytoines through the coor$inate activation o& a

cluster o& cytoine genes enco$ing IL63, 6D, 6:, 69, 613, an$ (!6CS. on chromosome :4316335

he i$enti&ication o& chemoines more or less selective &or the allergic e&&ector cells that inclu$e$the eota8ins, AC, !'C, A"S, an$ !C#s 163 provi$e$ the

necessary lin beteen cell activation an$ the chemoattraction o& e&&ector leuocytes that ere

engage$ by a$hesion molecules hose e8pression as enhance$ by release$ me$iators

interacting ith the microvascular en$othelium 5

Therapeutics %merging from the Allergic Cascade

By the mi$62000s, a pretty &ull picture o& the allergic casca$e ha$ been $escribe$5 !oreover, the

cellular an$ me$iator targets &or these $rugs ere reasonably ell establishe$5 he last 10 years

has itnesse$ some &urther embellishment o& these pathays ith the $iscovery o& a$$itional

cytoines such as the IL61= &amily, IL633,IL63:,an$ thymic stromal lymphopoietin , to

name but a &e, that orchestrate h2 an$ h1= immunological responses 5

Leukotrienemodifiersith this large increase in nole$ge o& the allergic pathays o& asthmatic in&lammation, it is

reasonable to as hether ne therapies have emerge$ as a result5 he $iscovery by

Samuelsson an$ colleagues o& leuotriene BDas the novel neutrophil chemoattractant generate$

&romarachi$onic aci$ an$ the subse4uent i$enti&ication o& cysteinyl

leuotrienes 5 he more

recent $iscovery o& the Cyst Lr1 as the receptor that me$iates the smooth muscle, vascular,

mucous, secretory, an$ neural aspects o& LCDan$ L'Das ell as activating both

monocyte/macrophages an$ eosinophils provi$e$ a rational e8planation &or hy bloca$e o& this

me$iator class is o& bene&it in asthma5 he $iscovery o& to other receptors, Cyst Lr2 an$ Cyst

Lr3

8/10/2019 Bubi Est

4/13

trimeric an$ he8americ immune comple8es &orme$ are rapi$ly remove$ ithout e&&ect, an$

&olloing inection o&omali7umab, &ree Ig" in the circulation &alls $ramatically5 he net result over

several ees is the removal o& Ig" &rom mast cells, basophils, an$ 'Cs ith subse4uent

internali7ation o& their .c1 receptors5 By interrupting the trigger mechanism &or the allergic

casca$e, omali7umab is anti6in&lammatory 5 Clinical trials establishe$ its

e&&icacy in severe corticosteroi$6re4uiringallergic asthma5Its e8pense an$ being an inecte$me$ication limit its use to the very severe en$ o& the asthma spectrum 5 It is a$ministere$ in a $ose commensurate ith the total serum Ig" level an$ bo$y eight,

an$ clinical e&&icacy is assesse$ at 1+ ees since there are respon$ers an$ non6respon$ers

that cannot be $istinguishe$ at baseline an$ only by a physicianKs &ull assessment a&ter therapy

&or 1+ ees5 *ne a$vantage o& omali7umab is its ability to bloc allergic pathays $istant &rom

the lung an$ is there&ore e&&ective against allergic co6morbi$ities that occur in severe asthma

such as rhinosinusitis an$ urticaria 5

Targeting the eosinophil

he $iscovery o& a selecte$ range o& cytoines associate$ ith the allergic casca$e has ma$e

them attractive therapeutic targets5 Beginning ith IL6D an$ IL69, a i$e range o& biologics have

been clinically investigate$ &or severe asthma ithout e&&icacy being shon

8/10/2019 Bubi Est

5/13

cell proli&eration an$ maturation5 .urthermore, animal mo$els in hich this molecule or its

receptors ere $elete$ or bloce$ e8hibite$ mare$ re$uctions in airay allergic

in&lammatory responses as ell as in aspects o& airay all remo$eling 5 A large

number o& humani7e$ or human blocing monoclonal antibo$ies against IL613 or the share$ IL6

DrO have been $evelope$5 Hoever, the initial positive results obtaine$ ith an IL6D $ouble

mutein that acts as a receptor antagonistan$ the monoclonal anti6IL613 antibo$y in allergen challenge shoing an attenuate$

late phase reaction have not translate$ to clinical e&&icacy in asthma trials in mo$erate6severe

$isease5 Another monoclonal antibo$y $irecte$ to the common IL6DrO has

also been teste$ in a 126ee clinical trial at 3 $oses an$ also &oun$ to be ine&&ective $espite

shoing evi$ence &or re$ucing circulating Ig" levels an$ eosinophils 5 In the

upper one thir$ o& $isease severity, there as a hint o& e&&icacy, but small numbers o& patients in

these subanalyses resulte$ in no signi&icant change in measure$ asthma outcomes5

hese somehat $isappointing clinical results coul$ still be e8plaine$ on the basis o& ina$e4uate

evi$ence &or involvement o& IL613 as a &unctionally important cytoine in the human $isease

asthma 5 In$ee$, a January 2010

literature !"'LI" revie &or IL613 i$enti&ie$ almost 3,000 peer6reviee$ publications on itspotential role as a ey cytoine in allergic an$ parasitic $iseases, but by the time the search as

limite$ to human asthma an$ $irect evi$ence, the number $roppe$ to + hich inclu$e$ 2

reviesP o o& the D publications came &rom a single laboratory in the )5-5 , $emonstrating the increase$ presence o& IL613 in sputum in :0M o& patients,

ith little or no lin to $isease severity5 hus a clinical trial base$ on a target that is only

e8presse$ in hal& the asthmatic patients is $estine$ to be challenging 5

.urther insight into the anti6IL613 respon$er/non6respon$er issue has been provi$e$ by an

attempt to sub6phenotype IL613Qasthma &rom those not e8pressing or utili7ing this cytoine as

part o& their $isease pathobiology5 )sing epithelial brushings, oo$ru&& et al5 has shonthat multiple gene e8pression reveale$ to $istinct subgroups% ?h26high@ an$ ?h26lo@ asthma ith appro8imately

hal& o& patients &alling into each group5 Interestingly, the to subgroups $i&&ere$ in their

e8pression o& IL6: an$ IL613 in bronchial biopsies an$ airay hyperresponsiveness, serum Ig",

bloo$ an$ airay eosinophilia, subepithelial &ibrosis , an$ airay

mucin gene e8pression5 he lung &unction improvements e8pecte$ ith inhale$ corticosteroi$s

ere restricte$ to the ?h26high@ asthma5 hey conclu$e$ that in humans, asthma can be $ivi$e$

into at least to $istinct molecular phenotypes $e&ine$ by the $egree o& h2 in&lammation5

.urthermore, current mo$els $o not a$e4uately e8plain non6h26$riven asthma, hich

represents a signi&icant proportion o& patients an$ respon$s poorly to current therapy5 Although

bronchial brushing to obtain a transcriptomic &ingerprint is not practical, this stu$y $oes illustratethe potential &or i$enti&ying biomarers in relevant pathays that impact on therapeutic

responses5

Tumor necrosis factor alpha,a pleiotropic target

Another cytoine that has attracte$ some attention in severe asthma is.6O5 Bloca$e o& .6

O has been o& maor signi&icance &or the treatment o& other chronic in&lammatory $isor$ers such

asrheumatoi$ arthritis, psoriasis,in&lammatory boel $isease, an$ sarcoi$osis

2009>5 here has accumulate$ substantial evi$ence in severe corticosteroi$ re&ractory asthma

that .6O is a ey can$i$ate me$iator5 hree small clinical trials using the .r1&usion

protein, etanercept, suggeste$ e&&icacy ith a particular e&&ect against airay

hyperresponsiveness 5 he stu$y

by Berry et al5 also i$enti&ie$ that anti6. respon$ers ha$ increase$ e8pression o&membrane6boun$ .6O, .6Or1, an$ .6O6converting en7yme on their peripheral6bloo$

8/10/2019 Bubi Est

6/13

monocytes that coul$ prove to be a use&ul in$icator o& those in hom this therapy is e&&icacious5

Subse4uently a large multi6$ose clinical trial o& the anti6.6O monoclonal

antibo$ygolimumabover 2+ ees &aile$ to con&irm e&&icacy 5 Hoever, in

subgroup analyses those patients ith more reversible air&lo obstruction an$ upper airay co6

morbi$ity $i$ respon$ in a $ose6$epen$ent manner5 )n&ortunately, severe a$verse e&&ects that

inclu$e$ in&ection an$ cancer stoppe$ &urther e8ploration o& this possibility5T lymphocytes at the heart of asthma

ith the a&orementione$ $isappointing results in targeting cytoines or their receptors, there

have been attempts to bloc cell activity5 hile small trials o& cytoto8ic an$ immunosuppressant

$rugs in$icate$ e&&icacy in some

patients, si$e e&&ects prove$ a real problem 5 Biologics have also

been use$, inclu$ing anti6C'D , anti6C'2: , an$

anti6C'23 , an$ again, hile some patients shoe$ evi$ence o&

a response, others clearly $i$ not or else the overall response as too ea to continue

$evelopment5 *verall, this is a $isappointing outcome consi$ering the suggeste$ sentinel role o&

cells in prevailing hypotheses o& asthma pathogenesis5 .inally, both in primary an$ secon$ary

prevention, allergen avoi$ance has proven not e&&ective hen single avoi$ance strategies ereuse$, but combination approaches looe$ more promising at least in mil$er $isease ith a strong

allergic component 5 Similarly, allergen immunotherapyusing subcutaneous

or sublingual allergens, hile help&ul in mil$ asthma associate$ ith rhinitis, seems &ar less

e&&ective in more severe $isease here there is also concern over anaphylactic si$e e&&ects

5

Time to Change Asthma Paradigms Asthma ' A "isorder of %pithelial Mesenchymal

Interaction

A&ter these overall negative results an$ against a bacgroun$ o& strong un$erpinning science, it

is legitimate to as i& the overall hypothesis &or asthma pathogenesis is correct5 hat has been

missing in much o& the mechanistic un$erpinning science in vitroor in animal mo$el systems is

an un$erstan$ing o& the chronic nature o& asthma, the importance o& smooth muscle changesthat $e&ine the human $isease, the i$e range o& environmental &actors beyon$ allergen

e8posure that $rive the inception, e8acerbation an$ persistence o& asthma, an$ lac o&

consi$eration o& the airay conte8t here these immunological an$ in&lammatory reactions occur

5 Simple allergen sensiti7ation an$ challenge in

animals &alls a long ay short o& real asthma as e8perience$ by patients 5 In$ee$, the only animal that e8periences naturally occurring asthma is the cat an$ yet this has never been e8plore$ as a potential mo$el system5 Apart &rom

improve$ animal mo$els that more closely re&lect the human $isease, greater attention shoul$ be

no given to the $evelopmental origins o& asthma, sub6phenotyping the $isease, an$ ho

$i&&erent environmental &actors beyon$ allergen e8posure interplay in $isease pathogenesis5

(igure )5 'iagrammatic representation o& the inter6relationship beteen immunological an$ in&lammatory

mechanisms an$ the structural elements o& the airays in asthma pathogenesis5

8/10/2019 Bubi Est

7/13

ecent research suggests a ey role &or respiratory viruses as an

initiating &actor that sets the airays in a state here sensiti7ation to allergens is more liely

5 Here an$ ith other environmental in&luences , the airay epithelium seems to be o& particular

relevance since this structure serves as a physical, metabolic, an$ innate immunological barrier

that is strongly in&luence$ by all these &actors 5 Since 'Cs are in intimate contact iththe epithelium it seems highly liely that epithelial cells play a particular role in their programming

as suggeste$ recently 5

he importance o& the airay smooth muscle, vascular be$, an$ neural netors has also been

un$erplaye$5 hese structures all play a critical role in the $evelopment o& the &etal airays an$

are programme$ to interact closely ith the epithelium as the epithelial mesenchymal trophic unit

%1136:, 200;5

Babu -S, Arsha$ SH, Holgate S5 *mali7umab, a novel anti6Ig" therapy in allergic

$isor$ers5 E#pert Opin Biol Ther1%10D96:;, 20015Berry !A, #arer ', eale , oo$man L, !organ A, !on #, Bra$$ing #, ar$la AJ, #avor$

I', Brightling C"5 Sputum an$ bronchial submucosal IL613 e8pression in asthma an$

eosinophilic bronchitis5 Allergy !lin Immunol11D%110+69, 200D5

Berry !A, Harga$on B, Shelley !, #arer ', Sha '", (reen H, Bra$$ing #, Brightling C",

ar$la AJ, #avor$ I'5 "vi$ence o& a role o& tumor necrosis &actoralpha in re&ractory asthma5 "

Engl $ed3:D%+9=6=0;, 200+5

Blease -5 herapeutics targeting IL613 &or the treatment o& pulmonary in&lammation an$ airay

remo$eling5 !urr Opin Investig %rugs9%11;06D, 200;5

Bullerotte ), iec7ore ', -app A, e$i B5 "&&ective treatment o& re&ractory severe heat

urticaria ith omali7umab5Allergy,epub ahea$ o& print, 20095

Busse , Israel ", elson HS, Baer J, Charous BL, oung ', e8ler , Shames SE'acli7umab Asthma Stu$y (roup5 'acli7umab improves asthma control in patients ith

8/10/2019 Bubi Est

8/13

mo$erate to severe persistent asthma% a ran$omi7e$, controlle$ trial5Am &espir !rit !are

$ed1=;%10026;, 200;5

Canonica (, Bous4uet J, Casale , Locey ., Baena6Cagnani C", #aanar , #otter #C,

Bous4uet #J, Co8 LS, 'urham S, elson HS, #assalac4ua (, yan '#, Bro7e JL, Compalati

", 'ahl , 'elga$o L, van i (, (oer (, Le$&or$ '-, et al5 Sub6lingual immunotherapy%

orl$ Allergy *rgani7ation #osition #aper 20095Allergy+D%16:9, 20095Cohen S(5 Asthma among the &amous5 Henry Hy$e Salter , British

physician5Allergy Asthma 'roc1;%2:+6;, 199=5

Corren J, Busse , !elt7er "*, !ans&iel$ L, Bensch (, .ahrenhol7 J, en7el S", Chon ,

'unn !, eng HH, Lin SL5 A ran$omi7e$, controlle$, phase 2 stu$y o& A!( 31=, an IL6Dalpha

antagonist, in patients ith asthma5Am &espir !rit !are $ed1;1%=;;69+, 20105

'ra7en J!5 Anti6leuotrienes as novel anti6in&lammatory treatments in asthma5Adv E#p $ed

Biol:0=%21=621, 20025

'umon$e 'C5 TLymphoinesK% molecular me$iators o& cellular immune responses in animals an$

man5'roc & (oc $ed+3%;996902, 19=05

'urou$ier #, ulah AS, Sayers I5 Leuotriene pathay genetics an$ pharmacogeneticsin

allergy5Allergy+D%;23639, 20095.ahy J5 I$enti&ying clinical phenotypes o& asthma% steps in the right $irection5Am &espir !rit

!are $ed1;1%29+6=, 20105

.loo$6#age #, !en7ies6(o A, -ay AB, obinson 'S5 "osinophilKs role remains uncertain as

anti6interleuin6: only partially $epletes numbers in asthmatic airay5Am &espir !rit !are

$ed1+=%199620D, 20035

.loo$6#age #, Senson C, .ai&erman I, !atthes J, illiams !, Brannic L, obinson ',

en7el S, Busse , Hansel , Barnes CE International !epoli7umab Stu$y (roup5 A stu$y to

evaluate sa&ety an$ e&&icacy o& mepoli7umab in patients ith mo$erate persistent asthma5Am

&espir !rit !are $ed1=+%10+26=1, 200=5

.rigas ", (leich (J5 he eosinophil an$ the pathophysiology o& asthma5 Allergy !lin

Immunol==%:2=63=, 19;+5(alli SJ, sai !, #iliponsy A!5 he $evelopment o& allergic

in&lammation5 "atureD:D%DD:6:D, 200;5

(o$&roi$ JJ, Heymans ., !ichel ", e$euilh C, Steiner ", Benveniste J5 #latelet activating &actor

% total synthesis o& 16*6octa$ecyl 26*6acetyl sn6glycero636phosphoryl

choline5 )EB( Lett11+%1+16D, 19;05

Hal$ar #, #avor$ I', Sha '", Berry !A, homas !, Brightling C", ar$la AJ, (reen H5

Cluster analysis an$ clinical asthma phenotypes5Am &espir !rit !are $ed1=;%21;62D,

200;5

Hal$ar #, Brightling C", Harga$on B, (upta S, !onteiro , Sousa A, !arshall #, Bra$$ing #,

(reen H, ar$la AJ, #avor$ I'5 !epoli7umab an$ e8acerbations o& re&ractory eosinophilic

asthma5 " Engl $ed3+0%9=36;D, 20095Holgate S, Casale , en7el S, Bous4uet J, 'eni7 , eisner C5 he anti6in&lammatory e&&ects o&

omali7umab con&irm the central role o& Ig" in allergic in&lammation5 Allergy !lin

Immunol 11:%D:96+:, 200:5

Holgate S, #olosa 5 he mechanisms, $iagnosis, an$ management o& severe asthma in

a$ults5Lancet3+;%=;0693, 200+5

Holgate S, 'avies '"5 ethining the pathogenesis o& asthma5 Immunity31%3+26=, 2009a5

Holgate S, oberts (, Arsha$ HS, Hoarth #H, 'avies '"5 he role o& the airay epithelium

an$ its interaction ith environmental &actors in asthma pathogenesis5 'roc Am Thorac

(oc+%+::69, 2009b5

Holgate S, Arsha$ HS, oberts (C, Hoarth #H, hurner #, 'avies '"5 A ne loo at the

pathogenesis o& asthma5 !lin (ci *Lond+11;%D396:0, 20095

8/10/2019 Bubi Est

9/13

Hoarth #H, Babu -S, Arsha$ HS, Lau L, Bucley !, !cConnell , Becett #, Al Ali !,

Chauhan A, ilson SJ, eynol$s A, 'avies '", Holgate S5 umournecrosis&actor

as a novel therapeutic target in symptomatic corticosteroi$ $epen$ent

asthma5 Thora#+0%10126;, 200:5

Iona S, omas7 (5 Antileuotriene treatment in chil$ren ith asthmaUne patents5 &ecent 'at

Inflamm Allergy %rug %iscov2%202611, 200;5Jacson 'J, (angnon ", "vans !', oberg -A, An$erson "L, #appas ", #rint7 !C, Lee

!, Shult #A, eis$or& ", Carlson6'aes -, Sala7ar L#, 'aSilva '., isler CJ, (ern J",

Lemanse . Jr5 hee7ing rhinovirusillnesses in early li&e pre$ict asthma $evelopment in high6

ris chil$ren5Am &espir !rit !are $ed1=;%++=6=2, 200;5

-line J, Hunninghae (5 6lymphocyte $ysregulation in asthma5 'roc (oc E#p Biol

$ed20=%2D36:3, 199D5

-on *!, Sihra BS, Compton CH, Leonar$ B, -ay AB, Barnes C5 an$omise$, $ose6ranging,

placebo6controlle$ stu$y o& chimeric antibo$y to C'D in chronic severe

asthma5 Lancet3:2%1109613, 199;5

Lecie !J, ten Brine A, -han J, 'iamant V, *KConnor BJ, alls C!, !athur A-, Coley HC,

Chung -., 'uanovic , Hansel , Holgate S, Ster #J, Barnes #J5 "&&ects o& an interleuin6:blocing monoclonal antibo$y on eosinophils, airay hyper6responsiveness, an$ the late

asthmatic response5Lancet3:+%21DD6;, 20005

Lee JJ, Jacobsen A", !c(arry !#, Schleimer #, LeeA5 "osinophils in health an$ $isease%

theLIA&hypothesis5!lin E#p AllergyD0%:+36=:, 20105

Liu L, Se$gic JB, Bates !", rtis ., (ern J", -ita H, Jarour , Busse , -elly "A5

'ecrease$ e8pression o& membrane IL6: receptor alpha on human eosinophils% I5 Loss o&

membrane IL6: receptor alpha on airay eosinophils an$ increase$ soluble IL6: receptor alpha

in the airay a&ter allergen challenge5 Immunol1+9%+D:26;, 20025

!arcus CL, Smith J, !anarious LA, Arens , !itchell (S, "lluru (, .orte , (ou$y S, Jabs

", -ane AA, -at7 ", #ay$ar&ar ', #ereira -, eeves H, ichtsmeier J, ui7 L, hach B,

unel '", hitsett JA, ootton ', Blais$ell CJ5 'evelopmental aspects o& the upper airay%report &rom an HLBI orshop, !arch :6+, 20095 'roc Am Thorac (oc+%:13620, 20095

!oraria JB, Chauhan AJ, Babu -S, #olosa , 'avies '", Holgate S5 he role o& a soluble

.alpha receptor &usion protein in corticosteroi$ re&ractory asthma% a $ouble blin$,

ran$omise$, placebo controlle$ trial5 Thora#+3%:;D691, 200;5

!osmann , Co&&man L5 H1 an$ H2 cells% $i&&erent patterns o& lymphoine secretion lea$ to

$i&&erent &unctional properties5Annu &ev Immunol=%1D:6=3, 19;95

!ur$aca (, Colombo B!, #uppo .5 Anti6.6alpha inhibitors% a ne therapeutic approach &or

in&lammatory immune6me$iate$ $iseases% an up$ate upon e&&icacy an$ a$verse events5 Int

Immunopathol 'harmacol22%::=6+:, 20095

air #, #i77ichini !!, -arsgaar$ !, Inman !', "&thimia$is A, #i77ichini ", Hargreave .",

*KByrne #!5 !epoli7umab &or pre$nisone6$epen$ent asthma ith sputum eosinophilia5 " Engl $ed3+0%9;:693, 20095

Fo authors liste$G !epoli7umab% 2D0:+3, anti6IL6: monoclonal antibo$y 6 (la8oSmith-line, anti6

interleuin6: monoclonal antibo$y 6 (la8oSmith-line, SB 2D0:+35 %rugs & %9%12:630, 200;5

*$emuyia S*, (hahary A, Li , #uttagunta L, Lee J", !usat6!arcu S, (hahary A, !o4bel 5

Cutting e$ge% human eosinophils regulate cell subset selection through in$oleamine 2,36

$io8ygenase5 Immunol1=3%:909613, 200D5

#ease J", illiams J5 he attraction o& chemoines as a target &or speci&ic anti6in&lammatory

therapy5 Br 'harmacol1D=%S212621, 200+5

#epys J5 e tests to assess lung &unction5 inhalation challenge tests in asthma5 " Engl

$ed293%=:;69, 19=:5

#olosa , Ben&atto (5 !anaging patients ith chronic severe asthma% rise to the challenge5 Eur Intern $ed20%11D62D, 20095

8/10/2019 Bubi Est

10/13

ate A, )pham J, Bosco A, !c-enna -L, Holt #(5 Airay epithelial cells regulate the

&unctional phenotype o& locally $i&&erentiating $en$ritic cells% implications &or the pathogenesis o&

in&ectious an$ allergic airay $isease5 Immunol1;2%=26;3, 2009

einero C, 'eClue A", abinoit7 #5 Asthma in humans an$ cats% is there a common

sensitivity to aeroallegens in share$ environments Environ &es109%+3D6D0, 20095

icci !, !atucci A, ossi *5 cells, cytoines, Ig" an$ allergic airays in&lammation5 InvestigAllergol !lin Immunol D%21D620, 199D5

othenberg !", -lion A', ou&osse .", -ahn J", eller #., Simon H), Schart7 LB,

osenasser LJ, ing J, (ri&&in "., Haig A", .reer #I, #arin J!, (leich (JE !epoli7umab

H"S Stu$y (roup5 reatment o& patients ith the hypereosinophilic syn$rome ith

mepoli7umab5 " Engl $ed3:;%121:62;, 200;5

osenasser LJ, !eng J5 Anti6C'235 !lin &ev Allergy Immunol29%+16=2, 200:5

Saha S-, Berry !A, #arer ', Si$$i4ui S, !organ A, !ay , !on #, Bra$$ing #, ar$la AJ,

#avor$ I', Brightling C"5 Increase$ sputum an$ bronchial biopsy IL613 e8pression in severe

asthma5 Allergy !lin Immunol121%+;:691, 200;5

Samuelsson B5 #rostaglan$ins, thrombo8anes, an$ leuotrienes% &ormation an$ biological

roles5arvey Lect=:%16D0, 19=9619;05Sly #', -usel !, Holt #(5 'o early6li&e viral in&ections cause asthma Allergy !lin

Immunol,epub ahea$ o& print, 20105

Spence '#, Johnston SL, Calverley #!, 'hillon #, Higgins C, amhama$any ", urner S,

inning A, inter J, Holgate S5 he e&&ect o& the orally active platelet6activating &actor

antagonist "B 20;+ in the treatment o& asthma5Am &espir !rit !are $ed1D9%11D26;,

199D5

horne -J, ichar$son BA, eith !C, ai #C, Spry CJ, Butterorth A"5 #artial puri&ication an$

biological properties o& an eosinophil6activating &actor5 Eur Immunol 1:%10;3691, 19;:5

yas H, -rishnasamy (5 #aul "hrlichKs ?!ast7ellen@ W &rom aniline $yes to 'A chip arrays% a

historical revie o& $evelopments in mast cell research5 $ethods $ol Biol31:%3611, 200+5

asserman SI, (oet7l "J, Austen -.5 #re&orme$ eosinophil chemotactic &actor o& anaphyla8is

8/10/2019 Bubi Est

11/13

Apr 2D, 2012 Inhibition o& Interleuin6: &or the reatment o& "osinophilic 'iseases

*ct 2:, 2010 Sublingual Speci&ic Immunotherapy

Jan 1D, 2011 he (enetics o& Asthma an$ Allergic 'isor$ers

Apr 2+, 2013Asthma #henotypes an$ "n$otypes% An "volving #ara$igm &or Classi&ication

!ar 20, 2010 Churg6Strauss Syn$rome% "volving Concepts

!ay 23, 2011Cytoines in the #athogenesis o& )lcerative Colitis

Jul 1D, 2009 e 'rugs &or Asthma

*ct 2+, 2012 ole o& the IL623/IL61= A8is in CrohnYs 'isease

!ore elate$ Articles

Access This P"( as a SubscriberZ

#urchase/'o0nloa$ 1his #'.

CategoriesAllergen Immunotherapy*Asthma* ChronicIn&lammation*Corticosteroi$s* "osinophil*"osinophilia*"osinophilic "sophagitis*HypereosinophilicSyn$rome* !epoli7umab*eutrophil* *mali7umab*hinovirus* ype 1 Helper Cell*ype 1= HelperCell*ype 2 Helper Cell*RolairTags epithelial mesenchymal interaction*IL613* IL6:*immunoglobulin "* immunosuppressive$rug* leuotriene*.6alpha

In a collaboration betweenDiscovery

Medicineand Johns Hopkins School of

Medicine CME, certain articles

published byDiscovery Medicinewill be

certified by Johns Hopkins as a Johns

Hopkins CME series. These articles will

be labeled "Hopkins CME."

Search

Search

Search ips/Help

+ournal Issues , Current - Archi$e .Part/

Current Issue* 0ol )1* !o 231* +un# 42)5Z o 0;D, !ay 2013Z o 0;3, Apr52013Z o 0;2, !ar5 2013Z o 0;1, .eb5 2013Z o 0;0, Jan5 2013Z o 0=9,'ec5 2012Z o 0=;, ov5 2012Z o 0==, *ct5 2012Z o 0=+, Sep5 2012Z o0=:, Aug5 2012Z o 0=D, Jul5 2012Z o 0=3, Jun5 2012Z o 0=2, !ay2012Z o 0=1, Apr5 2012Z o 0=0, !ar5 2012Z o 0+9, .eb5 2012Z o 0+;,Jan5 2012Z o 0+=, 'ec5 2011Z o 0++, ov5 2011Z o 0+:, *ct5 2011Z o0+D, Sep5 2011Z o 0+3, Aug5 2011Z o 0+2, Jul5 2011Z o 0+1, Jun52011Z o 0+0, !ay 2011Z o 0:9, Apr5 2011Z o 0:;, !ar5 2011Z o 0:=,.eb5 2011Z o 0:+, Jan5 2011Z

6lobal Categories

8/10/2019 Bubi Est

12/13

Medical Specialties

A$$iction !e$icineAgingAnesthesiologyBacteriologyCar$iologyCar$iologyan$ Circulation'ermatology'rug'iscovery"n$ocrinology"pi$emiology(astroenterology(enomic!e$icine(eriatrics(erontology(ynecologyHematologyHepatologyImmunol

ogyIn&ectious 'iseases!e$ical(enetics!icrobiology!ycologyephrologyeurologyeurosurgeryutrition*ncology*phthalmology*rthope$ics*tolaryngology#athology#e$iatrics#ersonali7e$!e$icine#harmacogenetics#harmacogenomics#harmacology#lastic an$econstructive !e$icine#reventive!e$icine#sychiatry#sychology#ulmonologya$iologyegenerative!e$icineepro$uctive !e$icineheumatologySurgeryo8icologyra$itionalChinese !e$icineranslational esearchransplantation)rologyirologyLife Sciences

AnatomyAnthropologyBiochemistryBioin&ormaticsBiologyBiophysicsCellBiologyChemistry'evelopmental Biology"cology"mbryology"nvironmentalScience"pigenetics(enetics(enomics(lycomics!olecularBiologyeuroscience#hysiology#lant Biology#roteomicsSpecies and Cell Types

Bacterium.ungusHuman*ther Species#arasiteo$entStreptococcusgor$oniiirusResearch Technology

Antibo$y #ro$uctionBiotin6Avi$in echnologyBispeci&icAntibo$yCarbohy$rateCell CultureCell .usionCell racing In ivoCellular

"lectrophysiologyChemiluminescenceCombinatorial Chemistry'isease (ene'iscovery'rug 'elivery.lo Cytometry(ene -nocout(ene argeting(enerans&er(enetic "ngineeringHigh hroughputScreeningImagingImmunotechnology!icroscopy!olecular"ngineering!olecular #ro&ilinganotechnologyuclear !agneticesonanceuclear rans&erucleic Aci$*rganism Cloning#roteinAInter&erenceStem Cell echnologyissue "ngineeringransgenicechnologyR6ay CrystallographyTherapeutic Technology and Methodology

'iagnosis"8perimental herapyherapyPharmaceutical and Healthcare Industry

BiotechnologyCommerciali7ation o& 'iscoveries.'A 'rugegulation#harmaceutical In$ustry

6lobal Tags

List of )22 Random Tags .or 0ie& All Tags/:6hy$ro8ytryptamine receptorAAactivate$ protein Cacute phasereactantA'Asa$iponectina$ipositya$renocorticotropin hormonealpha

&etoproteinangiotensin6converting en7ymeantithrombosisA#C geneApoA6I!ilanobacterial a$hesinbacterial translocationBC(BLySBotulinum

8/10/2019 Bubi Est

13/13

to8inB#Hc6!yc oncogenecalcium phosphosilicate nanoparticlescalciumpumpcar$iorespiratory &itnessC'22chromosomalinstabilitychromosomecoctail therapyCp( islan$CLCLA6DcyclinC#2C9$iet6in$uce$ thermogenesis'rugesistance$ystrophinearly $iagnosis"(.embryonic stemcell"osinophilia&actor RIIa&!I&oo$ allergen.*R#2&ri77le$ relate$proteingermline mutationglial cell line6$erive$ neurotrophic &actor(!&oo$(!!(nHgp120H'AChomeostasish"human leuocyteantigenhypo8iainhibitor o& apoptosisI[aryotypei$neytransplantationnocoutlactamaseL.A61longevitylo8#memoryloss!ICAmigraine trans&ormationmolecular evolution!Im*inhibitorneutrali7ing antibo$y-61 receptororphan$iseaseostreoti$ep21panobinostatphospho$iesterasepoliovirusgenomeprostaglan$in4uantitative trait locusA-Lretinoic aci$receptorritu8imabSBSCAS#S# mappingsnAsynaptic plasticitycell anergy6cell me$iate$immunitytelomerase!#trama$oltranschromosomictriple86&ormingoligonucleoti$etumorigenesisvascular en$othelial groth &actorvascularen$othelial groth &actor receptor1

Copyright 2013, 'iscovery !e$icine5All ights eserve$5