과다호산구증가증-관련 질환과 개발 중인 치료 약물 · 2013-03-07 · remodeling·repair)”의 역할을 수행하는 세포로서 자리매김을 하 는데 일조하고

© 2013 Hanyang University College of Medicine 65http://www.e-hmr.org

Hypereosinophilia-associated Diseases and the Therapeutic Agents in Development Il Yup Chung

Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University

서 론

호산구(eosinophils)는말초혈액의백혈구중에서1-3%,골수의조혈모세포중약7%를차지한다.호산구는직경이12-15μm이고,핵은2열편으로되어있으며(bilobednucleus),세포질은과립(gra-nules)으로채워져있는과립구(granulocytes)이다.과립은산성염

료인eosin에의해서염색될때과립내에존재하는염기성단백질

(basicproteins)로인하여밝은심홍색을띠며,이렇게잘발달된과립으로인하여유세포분석기(flowcytometry)로분석할때호산구

는‘sidescatterhighcells’로나타나기때문에여러백혈구와확연하

게구별된다.호산구는4종의주요과립단백질을보유하고있다.majorbasicprotein(MBP),eosinophilperoxidase(EPX),eosino-

Hanyang Med Rev 2013;33:65-74http://dx.doi.org/10.7599/hmr.2013.33.1.65

pISSN 1738-429X eISSN 2234-4446

Eosinophil is one of the most enigmatic leukocytes that plays pleiotropic roles in initiation and propagation of inflammatory conditions, modulation of innate and adaptive immune responses, homeostasis, and remodeling and repair of diverse tissues in health and dis-ease. Eosinophils arise from CD34+ hematopoietic cells in the bone marrow under the in-fluence of transcription factors (C/EBPα and GATA-1) and hematopoietic cytokines (IL-5, IL-3, and GM-CSF). The unusually high numbers of eosinophils in blood and/or tissues, so-called hypereosinophilia, are often critically involved in pathophysiology of a wide variety of inflammatory diseases in many organs, including many allergic diseases (asthma, rhini-tis, conjunctivitis, atopic dermatitis), gastrointestinal diseases (eosinophilic eosophagitis, ulcerative colitis, Crohn’s disease, Duchenne’s muscular dystrophy, idiopathic myositis), cancers (pancreas, bladder, liver, kidney, breast, melanoma, colon, glioblastoma, gastric, uterine, oral/nasal, lung), infectious diseases (helminth, bacteria, virus, fungi), transplanta-tion rejection (lung, cardiac, corneal, skin, liver, and renal), reproduction, and autoimmune diseases. A dozen of therapeutic agents, notably including humanized anti-IL-5 monoclo-nal antibodies, that directly and indirectly target eosinophils have been developed and are studied extensively under clinical and preclinical trials. Some agents have been shown to have promising perspectives to hypereosinophilic diseases, especially against asthma ex-acerbations and hypereosinophilic syndromes. Further studies are required for discovery of the specific mechanisms of actions of the different eosinophil-targeted therapies, dos-ing strategies and treatment options with identification of biomarkers that can monitor and predict the responses.

Key Words: Asthma; Eosinophils; Interleukin-5; Hypereosinophilic Syndrome

과다호산구증가증-관련 질환과 개발 중인 치료 약물정일엽

한양대학교 과학기술대학 분자생명과학부

Correspondence to: Il Yup Chung우426-791, 경기도 안산시 상록구 한양대학로 55, 한양대학교 과학기술대학 분자생명과학부 Division of Molecular and Life Sciences, College of Science and Technology, Han-yang University, 55 Hanyangdaehak-ro, Sangnok-gu, Asan 426-791, Korea Tel: +82-31-400-5514 Fax: +82-31-419-1760 E-mail: [email protected]

Received 13 November 2012Revised 4 January 2013Accepted 11 January 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecom-mons.org/licenses/by-nc/3.0) which permits un-restricted non-commercial use, distribution, and reproduction in any medium, provided the origi-nal work is properly cited.

Hanyang Med Rev 2013;33:65-7466 http://www.e-hmr.org

Il Yup Chung • Eosinophil-associated Diseases and Their Therapeutic Interventions HMR

philcationicprotein(ECP),eosinophil-derivedneurotoxin(EDN)이이에속하며이들은호산구를다른세포와구별하게하는대표

적표지자이기도하다.호산구는다형의핵(polymorphonuclearcells)과과립정도에서유사한세포인호중구(neutrophils)와는다르게,CD14과CD16을매우적게발현하기때문에(즉,CD14lo/CD-16locells),자석에입혀진anti-CD16과의결합을이용하는방법인magneticactivatedcellsorter(MACS)로호산구는호중구로부터분리가가능하다(Fig.1).이와같이형태학적으로뚜렷하게식별될수있는호산구는현존하는모든척추동물에존재하며심지어일부무척추동물에서도호산구성세포(eosinophiliccells)가존재할정도로진화적으로보존된세포이다[1].포유동물내에서종특이

적으로호산구의형태적·기능적차이가분명하게존재함에도불구하고,대부분의경우종간에도호산구의공통적특성을공유하

고있기때문에,건강한상태에서그리고질병상태에서호산구의역할과기능을이해하는데실험동물로부터의결과가적극적으로반영되고있다[2].호산구는또한세포표면에IL-5Rα를발현하고있으나혈구세포의계통마커(lineagemarkers)인CD4,CD8,B220,CD19등은발현하지않는다.IL-5Rα이외에호산구를식별하는대표적마커로CCR3,Siglec-8,EMR1,CD11b등이있다.이중에서IL-5Rα와CCR3는혈구세포중에서호산구에서선택적으로발현

하거나호산구에서상대적으로훨씬풍부하게발현되기때문에,이들두분자를표적화하여(moleculartargets)호산구관련질환

에서호산구자체를제거하거나기능을제어하기위한약물이개발되어임상시험중이다.호산구는천식과같은유병률이높은질환과희귀질환의병태

생리에직·간접적으로관련되어있기때문에지난20년동안집중

적으로연구되어왔는데,질환과의관련성에대한다음의세가지주된임상적증상과징후에근거하고있다.첫째,호산구는다양한조직과세포에대해무차별적으로파괴적이며세포독성적이다.둘째,호산구는알레르기천식환자의폐에거의항상침윤되는혈구

세포유래의대표적염증세포로인식되어있다.셋째,호산구는장내기생충(helminthicparasites)의감염에대항하는숙주방어를구성하는주된세포로서진화된것으로인식되고있다[3,4].이러한질병과의연관성이외에도호산구는건강한사람의위장관계통의조직,흉선,난소,자궁내막등의조직에도존재하며,이러한조직과기관의항상성을유지및조절하는데기여할것으로추정하고있다.알레르기질환이발생할경우많은수의호산구는폐,피부,비강등으로침윤된다.정상상태에서혹은질병상태에서이든조직

에분포하는호산구를“조직호산구(tissueeosinophils)”라하며이는혈중에존재하는호산구(bloodeosinophils)의형태와생화학

적특성이거의유사하나일부기능적으로다른면을지닐수있다

[5].그동안여러질환의병태생리에서호산구는조직을파괴하는마지막단계의효과세포(end-stageeffectorcells),즉,“나쁜세포

(badcells)”로서인식하는보편적인시각에서가장최근에는“조직

A B20 μm

Fig. 1. Purified neutrophils and eosinophils from human peripheral blood. After RBC had been precipitated in 6% dextran-dextrose in 0.1 M EDTA (pH 7.4), the leukocyte-rich cell suspension was layered on a Percoll solution (1.070 g/mL) and centrifuged at 3,500× rpm for 30 min at 4°C. The enriched polymorphonuclear fraction were incubated with anti-CD16 monoclonal antibody-conjugated microbeads (Miltenyi Biotec), and neu-rophils (A) and eosinophils (B) were isolated through positively and negative selection, respectively, using a MACS (BD PharMingen).

Hanyang Med Rev 2013;33:65-74 http://www.e-hmr.org 67

정일엽 • 과다호산구증가증-관련 질환과 개발 중인 치료 약물 HMR

의개형과수선(tissueremodeling·repair)”이란역할을수행하는세포로재정립하는증거가드러나기시작하고있다[6].그럼에도불구하고호산구는만성적중증염증을동반하는난치성질환의병태 ·생리과정에서여전히중요한역할을수행하며,실제로호산구

를제거하거나호산구의활성을차단하는약물이상당한치료효

과를보이고있다.지난10여년간호산구만을선택적으로제거한mouselines와호산구에서선택적으로발현하는분자를제거한여러종류의knockout(KO)mice가제작되어호산구의역할을이해

하려는연구가진행되어왔다.이들유전적으로변형된mice를호산구관련질환의모델로이용하고또한사람의호산구의기능을차단하는약물의개발과임상·전임상실험결과로부터호산구관련질환에서호산구의역할을이해하는데기여하고있다.본종설

에서는호산구가직·간접적으로유발하거나관여하는인간의질환을소개하고,이중에서현재임상시험중이거나대기중인항-호산구약물과이들의임상적효과를기술하고자한다.

본 론

1. 호산구의 발생과 분화

호산구는다른혈구세포의발생과마찬가지로골수에서hema-topoieticCD34+stemcells로부터발생 ·분화한다.호산구의운명

을결정하는데핵심적인전사인자는CCAAT/enhancer-bindingproteins(C/EBPs)와GATA-1이다.C/EBPs는leucine-zipperdo-main을지닌전사인자인데,조혈모세포에발현시킬경우,호산구마커의발현과더불어호산구의생성과분화가유도된다[7].이와일치하여C/EBPα-KOmice는호산구가생성되지못하였기때문

에[8],C/EBPα가호산구계통으로운명결정에핵심역할을한다

고간주된다.GATA-1은두개의zincfingerdomains를지니며이들을통해DNA에결합하여표적유전자를활성화하는전사인자

로서,적혈구,골수거대세포(megakaryocytes),호산구,비만세포

(mastcells)에서발현된다[9].GATA-1을조혈모세포나제대혈유래CD34+cells에발현시키면전적으로호산구로분화가유도되며[10],결정적으로GATA1promoter에존재하는highaffinityGATA-bindingsites를제거하였을때혈구세포중에서유일하게호산구

만이제거된mice(ΔdblGATAmice)가만들어졌다[11].이러한증거는GATA-1이호산구의운명결정에중심적인역할을수행하는것을의미한다.일단호산구로운명이결정되어호산구전구세포인eosinophilprogenitor(EoP)가되면hematopoieticcytokines인IL-5,IL-3,GM-CSF가EoP를증식하고분화를촉진한다[12].이중에

서가장중요한cytokines은IL-5인데IL-5는호산구의분화,이동,활성화,생존을도모하는호산구전담cytokine으로작용한다.이러한이유로두개의humanizedanti-IL-5monoclonalantibodies로개발된“mepolizumab”와“reslizumab”는호산구관련다양한

질환에치료제로서적용되어임상시험중이다[13].한가지주목할점은호산구운명결정의masterregulators인C/EBPα와GATA-1는majorbasicprotein(MBP),eosinophil-derivedneurotoxin(EDN),CCR3등의호산구-특이유전자전사를활성화함에도불구하고[14,15],이들두개의masterregulators가호산구의핵심적

이며가장최초의분화마커라고간주되는IL-5Rα유전자의발현

에관여한다는결정적인증거가분자적수준에서아직밝혀지지않고있다.예를들어C/EBPα가IL-5Rαpromoter를invitro에서활성화하지만,IL-5Rαpromoter내에C/EBPα에의한전사활성을책임지는functionalsequencemotif(s)가아직동정되지않은상태

에있다.따라서두개의masterregulators에의한호산구운명결정

의분자적기전은여전히오리무중이다.

2. 과다호산구증가증 관련 질환(hypereosinophilia-associated diseases)

혈액이나조직혹은모두에서발생하는과다호산구증가증(bloodeosinophilia/tissueeosinophilia)은다양한질환의병태 ·생리과정

에직·간접적인관련하고있다.비록과다호산구를발생하게하는병인이다양하지만궁극적으로는골수에서조혈모생성과정을통해서호산구의발생분화(eosinophilopoiesis)가증가하고이에비례

하여혈액과조직으로이동이증가하기때문에과다호산구증가증

(hypereosinophilia)이발생한다.그러나일부호산구성염증질환

의경우,호산구의전구세포인CD34+IL-5Rα+cells이염증부위로이동하여그곳에서조성된미세환경에서분화가촉진될수도있다.아래의내용은호산구관련질환을사람을위주로기술한것이다.많은연구에서중복적으로관련사실을규명한관계로본종설의여백상대표적인참고문헌만을참조하여기술하고자한다.

1) 염증성 과민증(inflammatory hypersensitivity)

염증성과민증을지닌환자와정상인과비교할때염증부위에존재하지않았던호산구가유입되어현격하게증가하는공통된특징을나타낸다.

(1) 천식(asthma)

전통적으로알레르기천식환자의폐는호산구성염증이주도한

다는보편적인인식에도불구하고호산구와천식의가장중요한증상인기도과민성과의인과관계는상반된결과가도출되고있다

[16].그러나가쁜숨,기침,무호흡의정도가지속적이고심각하게재발하는천식발작(asthmaexacerbations)환자인경우,항-호산구치료는상당한개선효과가나타났다[17,18].이는호산구성기도염

증이최소한특정한소그룹의천식과병인관계를맺고있다는증거로서제시된다.천식은더이상단일질환이아니라다양한증상,원인,병태 ·생리적특성을나타내는매우이질적인질환(heteroge-



neousdiseases)임을고려할때,설득력이있다.

(2) 비염(rhinitis)

알레르기비염환자의비강상피조직에호산구와호산구의산물

인MBP가축적되어있고,비강조직의점막에손상을입히는것으로밝혀졌다.이는호산구가효과세포로서작용한다는것을암시하고있다[19].

(3) 아토피 피부염(atopic dermatitis)

아토피피부염을지닌환자의진피에MBP가과량으로존재하며이는호산구의탈과립(degranulation)이조직손상에적극적인역할을한다는것을의미한다[20].그러나mepolizumab를구강투여

하였을때말초혈액에호산구의수는감소하였으나치료개선효과

는없었기때문에[21],과다호산구가이질환의병인으로작용할것같지는않다.

(4) 결막염(conjunctivitis)

각결막염을지닌환자의결막조직에증가된호산구가비정상적

으로분포되어있으며호산구의과립단백질인ECP가염증부위에증가되었고혈청내에호산구의또다른과립단백질인EDN의양이증가되어있어알레르기성안질환에호산구의역할평가가이루

어져야한다[22].

2) 기타 염증성 질환

위장관조직에호산구의유입과축적은이질환의공통된특징

이다.호산구성위장관염증질환은혈중과다호산구(bloodeosin-ophilia)와는무관하며,호산구의수를조절하는독립적인기전이있을것으로예측된다.특히호산구가관련장기로유입되는과정

에서CCR3의리간드인eotaxin이주된역할을한다.

(1) 호산구성 식도염(eosinophilic eosophagitis)

호산구성식도염은식도의염증반응이다.호산구와IL-5,im-munoglobulinE(IgE)에의해서매개되는것으로보아이질환의병태 ·생리에호산구가주된역할을할것으로제시되었다.호산구

성식도염은아토피,연하곤란(dysphagia)및주로남자에서식도염등을보이며유병률이호산구성위식도역류(gastroesophagealre-flux)보다상대적으로높다는점에서호산구성위식도역류와구별

된다.Humanizedanti-IL-5치료법으로식도의호산구수를줄이

는데효과가있다[23].

(2) 궤양성 대장염(ulcerative colitis)

호산구는정상인의소장및대장의점막에항상존재하며오히려그수가혈액과골수에서보다더많이분포한다.IL-5R+cells이

궤양성대장염환자의점막에매우증가되어있고특히호산구에

서분비된과립단백질이많은양으로검출되었다[24].

(3) 크론병(Crohn’s disease, CD)

크론병은입에서항문에이르기까지위장관계에손상을일으키

는만성적인염증질환이며다양한증상을유발한다.정상적인사람의소장의점막에도많은수의호산구가존재하지만크론병환자인경우크게증가되어있다.최근에동물모델에서호산구를유입을차단하는anti-CCR3monoclonalantibody(mAb)를처리하

였을때,호산구의유입이차단되고주상세포(gobletcells)로의분화가억제되면서치료효과를나타낸보고가있다[25].

(4) 근위축증(Duchenne’s muscular dystrophy, DMD)

만성염증은일부근위측증의특징중에하나인데호산구의존재는calpain에의해서유발되는“limb-girdlemusculardystrophy1A(LGMD1A)”의특징이다.이러한유형의염증부위에거의호산

구가전적으로유입되어있음이관찰된다[26].

(5) 특발성 근염(idiopathic myositis)

특발성근염은골격근에호산구의유입과염증을지닌병리적특성을지니는데종종기생충감염과전신질환,약물복용과관련되어나타난다.진단은염증부위에호산구의유입유무로판단한다[27].

3) 장기이식거부반응(transplant rejection)

폐,심장,각막,피부,간,신장등의장기를이식할때와특히이들장기에대한거부반응이나타날때말초혈액과장기주변의체액에호산구의유입과호산구의활성화가관찰된다[13,28].이러한이유

는이식된장기의조직에서호산구를유입하는eotaxin등의신호분

자를분비하기때문일것이라고추정한다.주요관심은장기이식거

부반응에호산구의활성이어떻게작용하느냐하는것이다.호산구

가이식초기에면역억제적인개형·수선등의역할을할것이냐,아니면거부반응을책임지는alloreactiveTeffectorcells를유입하고활성화하는데에기여할것인가라는사실관계규명이필요하다.

4) 암(cancer)

오래전부터호산구는혈액암과고형암조직에과다호산구증가

증이관찰되었다.이렇게악성종양조직에호산구의침윤을“tu-mor-associatedtissueeosinophilia(TATE)”라하는데,좋은혹은나쁜예후를모두지니는것으로알려져있으나그관련기전은거의미지의세계이다[29].TATE는암의유형에따라호산구의유입여부가달라지는데일반적으로췌장,방광,간,신장,유방,피부에서발생한암조직은과다호산구의유입이거의항상관찰된다.반면

에대장,뇌,위,구강,비강,자궁,자궁경부,폐에암이발생하면호



산구가줄어들거나사라진다[13].전자나후자모두호산구가항암작용과암생성진행을촉진할수있다.그러나호산구는과립단백

질과기타면역조절물질을세포내과립에다량함유하고있기때문

에호산구의파괴적인‘end-stageeffector’기능을통해서암세포를파괴하거나성장을제한하는항암적인효과를지닐수있다.반면

에암세포를표적으로하는Th1반응을막거나,종양에의해매개

되는Th2반응을증가시키거나,Tregulatorycells(Tregs)의팽창

과활성화,Teffectorcellanergy를통해서종양을표적으로발생

하는면역반응을억제함으로써종양증식을촉진하는결과를초래할수도있다.따라서호산구와종양세포사이의분자적인상호

작용이규명되어야만호산구를표적으로하는새로운치료법을기대할수있을것이다[13,29].

5) 과다호산구증가증(hypereosinophilia)

과다호산구증가증은혈액이나조직혹은모두에서알레르기발생,기생충감염등의알려진원인이아닌이유로인하여호산구가병리과정에서일차적인역할을수행하는것으로생각되는증상이

며,상당히다양하고이질적인유형의질환으로서심장,위장관,중추신경계등에기능장애가발생한다[30].혈중호산구의수치가1,500/mm3이상으로6개월동안나타난다.

(1) 만성 호산구성 백혈병(chronic eosinophilic leukemia, CEL)

이질환은“t(1;4)(q44;q12)”형태의염색체상호전좌(reciprocalchromosomaltranslocation)가발생함으로인해F1P1L1과PDG-FRA의유전자가융합되고이로인하여proteintyrosinekinase(PTK)가활성화되기때문인것으로밝혀졌다[31].

(2) 과호산구성증후군(hypereosinophilic syndrome, HES)

알레르기질환,약물과민증,기생충감염,HIV감염,혈액암등의원인이아닌이유로과혈중호산구증(>1,500/mm3)을지니며이것

이주된이유로다양한장기에장애가나타나는질환이다.이증후

군은호산구의수를감소시키는약물에의해서상당한개선효과

를보인다.

6) 감염(infection)

호산구는전통적으로기생충감염뿐만아니라,바이러스,박테

리아,균류에의한감염에반응하여관련조직과혈중에그수가증가한다.호산구는toll-likereceptors(TLRs)의발현을통해서이들병원균을인지하고죽이며청소할수있는능력을지닌다[32].

(1) 장내기생충 감염(helminth infection)

흡충에속하는십이지장충인Necator americanus를자원자에

게감염시킬경우,혈중호산구수치가7-9주에정점에도달하며이

러한호산구증가는거의모든기생충의감염시나타난다[33].그리고호산구가보유하고있는세포독성적과립단백질은invitro에서기생충을죽이기활성을지니는이유로호산구의신체에서의주된역할이기생충감염으로부터보호해주는기능을지니는것으로오랫동안인식되어왔음에도불구하고,이러한역할이 invivo에서도일어날것이라는사실을뒷받침하는결정적인증거는없다.오히려최근에선충류(nematodes)계통인Trichinella spira-lis를감염시킨동물모델에서호산구는Th2immunity를증진하고반면에대식세포(macrophage)와호중구의역할을제한함으로써선충류기생충의성장과생존을증진한다는보고도있다[34].따라

서기생충에대한신체방어기전으로서호산구가다른백혈구와비교하여진화적으로늦게생성되었다는개념은재정립이필요한시점에와있다.

(2) 바이러스 감염(viral infection)

RNAvirus인respiratorysyncytialvirus(RSV)는영아와아동

의하부기도에가장흔하게감염하는바이러스로서RSV의감염시호산구의폐로유입이두드러지고cysteinylleukotrienes(CysLTs)와ECP와같은알레르기염증과관련되어있는데이러한분자는주로호산구에서유래되는것으로알려졌다[35].또한호산구의과립단백질중EDN은RNase활성을지니고있어직접RNAgenome을분해하는능력을지닌다[36].Rhinovirus는천식의중증도와발작에지대한영향을미치는일반감기바이러스로서호산구는기도상피조직과대식세포와더불어가장중요한면역반응을일으키

는세포이다.

(3) 박테리아 감염(bacterial infection)

호산구의과립단백질인MBP와ECP는항-박테리아강력한활성을지닌다.또한호산구는식세포작용(phagocytosis)을하지못하거나이러한능력이매우제한되어있기때문에,호산구의미토

콘드리아와MBP,ECP로구성된그물망인소위“eosinophilextra-cellulartraps(EETs)”라는방식으로항-박테리아활성을나타내는것으로알려졌다[37].

(4) 진균 감염(fungal infection)

진균성부비강염(fungalsinusitis)을앓고있는환자의기도와혈청에호산구의수와호산구과립단백질인ECP의생성이현격하게증가되어있는것으로보아호산구가진균의호흡기감염에대한면역반응의상당부분을차지한다고추정된다[38].

7) 생식(reproduction)

(1) 조기진통(pre-term labor)

양수에많은수의호산구를지니면서조기진통을겪는임산부



는적은수의호산구를지닌환자보다조기분만의위험성이높다

는보고가있다[39].이러한사실에근거하여호산구가양수의존재

하는주요백혈구일경우,호산구와조기진통/조기분만의인과관

계가추적되고있다.

(2) 자궁내막증(endometriosis)

자궁내막증은자궁강(uterinecavity)밖에서양성종양성격의자궁내막샘과중간엽조직이발생하는것을특징으로하고있다.호산구는정상적인자궁내막에생리전과생리동안에그수가증가하고또한자궁내막증의조직에서특히EPX를탈과립중인호산구

(degranulatingeosinophils)가증가되어있다.연구에따르면호산

구는자궁내막증에서조직을파괴하는역할이아니라관련조직의개형·수선에주로참여하는것으로알려졌다[40].이러한사실은앞서호산구가Lee등이제시하였던“조직의개형과수선(tissueremodeling·repair)”의역할을수행하는세포로서자리매김을하는데일조하고있다[2,6].

8) 자가면역 질환(autoimmune diseases)

(1) 자가면역 췌장염(autoimmune pancreatitis)

호산구성췌장염은지금까지10건미만으로보고된매우드문질환이다.이경우호산구성염증이췌장내여러조직내에서관찰

되며매우다양한병인을지닌다.호산구성췌장염을앓고있는환자는말초혈액의과다호산구증가증,증가된혈청IgE,특히위장관

계를비롯한다른장기에호산구의침윤등의징후를보인다[41].그러나최근보고에따르면만성췌장염에서과다호산구증의발생은특이한경우가아니며자가면역췌장염에서과다호산구증가증의발생빈도는비-자가면역췌장염의그것보다의미있게높게나타나

는것으로보아자가면역기전혹은췌장염과섬유화의진행과관련있을것으로추론된다[42].

(2) 시속신경수염(neuromyelitis optica)

시속신경수염환자의조직병리연구를통해서호산구가염증조

직의혈관주위에집중적으로분포하고있었는데이환자의뇌척수

액(cerebrospinalfluid,CSF)을보았더니호산구를유인하는che-mokines인eotaxin-2,eotaxin-3,호산구과립단백질인ECP의양이건강한사람,재발성다발성경화증환자,2차진행중인다발성경

화증환자보다훨씬높게나타나서CSF에는호산구를선별적으로활성화하는메커니즘이존재할것이라고암시하고있다[43].

(3) 피부경화증(scleroderma)

호산구성근막염(eosinophilicfasciitis,EF)라알려진피부경화

증은염증부위에호산구가과도하게침윤되어있는임상적징후를보인다[44].

3. 호산구 질환의 표적화된 치료법

호산구는핵의모양및특징적인과립의염색등형태학적으로독특한특색을지니는것이외에다른과립구와확연하게구별되

는독특한마커단백질을세포표면에발현한다.이러한세포표면

에존재하는호산구-특이적인마커를치료표적으로하여현재호산구관련질환이나호산구성염증치료를위한다양한약물이개발되고임상시험중에있다.대표적인마커로서IL-5Rα(CD125),CCR3(CD193),Siglec-8,EMR1,C3areceptor,cysteinylleukotri-enetypeIreceptor,platelet-activatingfactorreceptor,CRTH2(type2prostaglandinD2receptor)등이있다.이들마커단백질의기능을억제할때,호산구의생성과증식,이동,활성화,생존등을제어할수있다.우선임상시험중인항-호산구(anti-eosinophils)약물을Table1에소개하고,임상시험을기다리고있는후보약물

을기술하였다.다만본종설의제한된여백으로인하여약물의양,시기,기간등의‘administrationregime’은생략한다.

IL-5는호산구의증식,분화,이동,활성화,생존등호산구가생성

되면서죽을때까지전과정을책임지는유일한cytokine이다.따라

서IL-5는호산구관련질환과염증을치료하는데첫번째고려대

상이된물질이다.현재두종류의humanizedanti-IL-5antibodies가개발되어있다.

1) Mepolizumab

Mepolizumab는mousecomplementarity-determiningregion(CDR)과humanimmunoglobulinheavy/lightchain이연결된humanizedmAb(IgG1)이다.임상적지표에따른소그룹으로나누

지않은천식환자를대상으로진행되었던초기임상시험에서이약물은천식의가장중요한임상적지표인기도과민성을완화하지못하였다[16].그러나호산구성기도염증을앓고있는난치성천식환자를대상으로무작위배정비교임상시험(double-blind,placebo-controlledclinicaltrial)방식으로투여했을경우천식발작(asth-maexacerbations)을상당히완화하였고[18],최근에대규모로유치한호산구성염증/난치성환자를대상으로다중시설에서진행

한임상시험에서도유사한효과를보여호산구성난치성천식치료

제로서의전망을밝게하였다[17].Mepolizumab를F1P1L1-PDG-FRA-negativeHESs를지닌환자를대상으로무작위배정비교임상

시험방식으로투여하였을때코르티코스테로이드를덜사용하는효과를지닌약물(corticosteroid-sparingagent)로평가되었다[45].호산구성식도염(eosinophilicesophagitis,EoE)을지닌소규모의환자를대상으로특별한치료제가없는경우에이용하는동정적사용(compassionateuse)시험에서염증조직의호산구의수치가감소되었으며연하곤란과구토증세가상당히완화되었다.HESs에포함되는Churg-Strausssyndrome(CSS)을지닌환자를대상

으로시행한동정적사용시험에서mepolizumab는CSS발작을줄



이고corticosteroid-sparing효과를나타내었다[46].Mepolizumab는비용종증(nasalpolyposis,NP)인경우도비용종을감소시키는등난치성호산구성비염의치료제로서가치가있는것으로평가되

었다.그러나아토피성피부염에는증상을완화하는효과가없는결과가발표되었다[47].

2) Reslizumab

Reslizumab는다중시설에서진행한무작위배정비교임상시험에

서스테로이드약물이투여되는중증천식환자의폐기능을상당히호전시켰으며[48],비염을지닌환자인경우단한번의투여로비용

종을감소시켰다[49].HESs를지닌소수의환자를대상으로동정

적사용시험에서과다호산구증가증과임상적증상을완화시켰다

[50].또한호산구성식도염을지닌어린이를대상으로reslizumab의투여는식도의호산구를감소와더불어증상을호전시켰다[13].

3) Benralizumab

Benralizumab는humanizedanti-humanIL-5RαmAb로서IL-5R을통한신호전달과IL-5의결합을억제하는효과를지니며이항체에fucose가없는nonfucosylatedAb인관계로humanFcγIIIa에결합하여antibody-dependentcell-mediatedcytotoxicity(ADCC)를도모하는활성을지닌것으로알려졌다[51].임상1기시험에서benralizumab는혈중호산구와혈청ECP의양을감소시켰

으나백혈구의감소,인후염의발생,creatinephosphokinase(CPK)의혈중농도가증가하는부작용이발생함이보고되었다[52].Ben-

ralizumab는현재천식에한정하여임상시험중이지만곧HES환자를대상으로확대될것으로기대하고있다.

4) Alemtuzumab

Alemtuzumab는호산구를비롯하여Tcells,Bcells,단구(mono-cytes),대식세포,naturalkiller(NK)cells에존재하는CD52에대한항체이다.이약물은현재B-cellchroniclymphocyticleukemia(B-CLL)의치료제로서승인을받기는했지만미국FDA로부터심각한혈구세포감소증(cytopenia)을유발한다는경고를받은상태

이다.HES를소수의환자를대상으로한몇차례의증례보고(casereport)가있는데,호산구를감소시키는효과가있었다[53].

5) Alefacept

Alefacepts는CD58의첫번째extracellulardomain(ECD)과humanIgG1Fc와의fusionprotein이다.Tcells의CD2와FcγR에결합함으로써Tcells의활성화와세포사를유도한다.아토피피부

염환자에게투여되었을때혈중Tcells의수와활성화를감소시켰

으며동시에피부염증부위에IL-5,IL-13의양도감소되었고동시

에호산구의유입도감소되었다.Alefacept가호산구에직접작용

했다기보다Tcells의작용의억제로인한2차효과인것으로간주

된다[54].

6) Omalizumab

Omalizumab는IgE에대한항체로알레르기천식을치료하기

Table 1. Anti-eosinophil agents under clinical trials

Drug in clinical trials Target Company Disease of clinical trials Reference

Mepolizumab① Humanized GlaxoSmithKline Asthma 16-18anti-IL-5 mAb F1P1L1-PDGFRA-negative HESs 45

Eosinophilic esophagitis 13Churg-Strauss syndrome (CSS) 46Nasal polyposis 13Atopic dermatitis 13

Reslizumab Humanized Teva Asthma 48anti-IL-5 mAb Pharmaceuticals Nasal polyposis 49

Eosinophilic esophagitis 13HESs 50

Benralizumab Humanized MedImmune Asthma 52anti-IL-5Rα mAb

Alemtuzumab Anti-CD52 Bayer Eosinophilia 53HES 13

Alefacept Fusion protein of CD58 and human IgG1 Fc Astellas Pharma Atopic eczema 54Omalizumab Anti-IgE mAb Novartis/Genentech Asthma 55Pitrakintra IL-4/IL-13 receptor antagonist Aerovance Asthma 56TPI ASM8 Antisense CCR3 and common β chain Pharmaxis Asthma 57Imatinib Inhibitor of BCR-ABL protein tyrosine kinase Novartis F1P1L1-PDGFRA-positive HESs 31



위해승인된약물이다.비만세포,호염세포(basophil),그리고수지

상세포의FcεR1에작용을억제하는것으로알려졌지만호산구에대한효과는거의알려져있지않다.Omalizumab는혈중,객담,폐조직에서호산구수치의감소에효과가있는것으로보고되고있다[55].

7) Pitrakintra

Pitrakintra는두개의점돌연변이를지닌IL-4variant로서IL-4/IL-13receptor의antagonist로작용한다.천식환자를대상으로무작위배정비교임상시험결과폐기능의호전은있었으나혈중,객담,폐조직에서호산구수치를떨어뜨리지는못한것으로보고되었다

[56].

8) TPI ASM8

TPIASM8는CCR3mRNA와IL-3,IL-5,GM-CSFreceptor의commonβchain(βc)mRNAs에대한두종의phosphorothionateantisenseoligonucleotides이다.경증의천식환자를대상으로투여

하였을때초기및후기천식반응이현저히감소되었고또한CCR3및βc의발현감소와더불어혈중,객담,폐조직에서호산구수치가감소되었다[57].더구나별다른부작용이없었기때문에현재추가

적인임상연구가진행중이다.

9) Imatinib

Imatinib는Gleevec혹은Glivec(NovartisInc.,Switzerland)의상품명으로잘알려진만성골수성백혈병의치료제이다.이약물은염색체9와염색체22사이에상호맞교환으로발생한소위Phila-delphiachromosome(Ph)에서BCR-ABLfusiongene의proteintyrosinekinase(PTK)의rationaldrugdesign방식으로개발된저해제로1991년FDA에서승인되었다.Imatinib는차후에다른질환

의치료제로서도FDA승인받았는데,F1P1L1-PDGFRAfusiongene을지닌신생물질환도이에포함된다.동시에Imatinib는FDA가승인한최초의HES의치료제이기도하다.이fusiongene을지닌HES환자11명중10명이Imatinib에의해서완전히치유되었다

고보고되었다[31].

10) 전임상단계의 후보 약물

Anti-Siglec-8은호산구의세포사를유도하는능력을지니는데,호산구가특히위장관계통과같은조직에축적되면서과다호산구

증가증의병인으로서작용하기때문에호산구의세포사는중요한의미를지닌다.CCR3는리간드인eotaxin(CCL11)에반응하여호산구의이동과관련하여가장중요한Gprotein-coupledreceptor(GPCR)인데현재몇개의CCR3의antagonists가개발되었고[58],CCR3-eotaxin관계를끊는항체와소분자약물이임상시험중이

다.Verylateantigen4(VLA-4)는호산구가조직으로침윤하는과정에서내피세포에접착을책임지는호산구막단백질인데VLA-4의기능을차단하면호산구의침윤이차단되는전임상결과가있다

[59].VLA-4에대한mAb인Natalizumab(BiogenIdecCo)를다발

성경화증(multiplesclerosis,MS)환자에게투여시부작용이나타

났기때문에과다호산구증가증의치료에적용하는연구가지연되

고있다[60].마지막으로prostaglandinD2(PGD2)의수용체인CRTH2도역시골수밖으로호산구의이동과호산구의활성화에관여한다.현재CRTH2에대한다수의저해제가개발중이고[61]일부는호산구관련질환의치료를위한임상시험을기다리고있다[62].

결 론

호산구성염증은종종장기간의치료를필요로하는만성질환

과관련되어있으며사망률이높으며현재의치료법은그효과가제한적이다.이러한만성질환에서호산구역할의이해가증대와더불어호산구의표적화를타당화하는연구가병행되어야할것이다.한편으로호산구의생성,기능,이동을주관하는분자들이속속밝혀지면서항-호산구활성을지닌유망한새로운치료약물이개발

되고있다.대표적으로anti-IL-5와CCR3antagonist가있으며이들은다양한호산구성질환의치료를위해시험중이며,이들약물

은높은유병률을보이는천식의일부소그룹과과다호산구증가

증에대하여매우높은치료효과를보이고있다.그러나드문질환

인경우대규모로환자를유치하고또한약물도스와처리방식에따라서일관성있는결과를도출하는데어려움을겪고있다.앞으

로이러한점을개선하고동시에새로운표적혹은약물에대한반응을모니터하고예측할수있는마커의발굴이필요하다.

ACKNOWLEDGEMENTS

본연구는NationalResearchFoundation(2011-0014580)에서지원을받아수행하였다.사진을제공한한양대학교분자생명과학

부엄태기학생과편집을도와준강진현박사,그리고호산구분리

를위한혈액을공급한순천향대학교호흡기내과김도진교수에게감사의표시를전한다.

REFERENCES

1. LeeJJ,JacobsenEA,McGarryMP,SchleimerRP,LeeNA.Eosinophilsinhealthanddisease:theLIARhypothesis.ClinExpAllergy2010;40:563-75.

2. LeeJJ,JacobsenEA,OchkurSI,McGarryMP,CondjellaRM,DoyleAD,etal.Humanversusmouseeosinophils:“thatwhichwecallaneosino-



phil,byanyothernamewouldstainasred”.JAllergyClinImmunol.2012;130:572-84.

3. MeeusenEN,BalicA.Doeosinophilshavearoleinthekillingofhelminthparasites?.ParasitolToday2000;16:95-101.

4. GleichGJ.Theeosinophilandbronchialasthma:currentunderstanding.JAllergyClinImmunol1990;85:422-36.

5. LiuLY,SedgwickJB,BatesME,VrtisRF,GernJE,KitaH,etal.DecreasedexpressionofmembraneIL-5receptoralphaonhumaneosinophils:I.LossofmembraneIL-5receptoralphaonairwayeosinophilsandincrea-sedsolubleIL-5receptoralphaintheairwayafterallergenchallenge.JImmunol2002;169:6452-8.

6. JacobsenEA,HelmersRA,LeeJJ,LeeNA.Theexpandingrole(s)ofeo-sinophilsinhealthanddisease.Blood2012;120:3882-90.

7. MullerC,Kowenz-LeutzE,Grieser-AdeS,GrafT,LeutzA.NF-M(chickenC/EBPbeta)induceseosinophilicdifferentiationandapoptosisinahe-matopoieticprogenitorcellline.EMBOJ1995;14:6127-35.

8. ZhangDE,ZhangP,WangND,HetheringtonCJ,DarlingtonGJ,TenenDG.Absenceofgranulocytecolony-stimulatingfactorsignalingandneu-trophildevelopmentinCCAATenhancerbindingproteinalpha-deficientmice.ProcNatlAcadSciUSA1997;94:569-74.

9. TsaiFY,OrkinSH.TranscriptionfactorGATA-2isrequiredforprolifera-tion/survivalofearlyhematopoieticcellsandmastcellformation,butnotforerythroidandmyeloidterminaldifferentiation.Blood1997;89:3636-43.

10. HirasawaR,ShimizuR,TakahashiS,OsawaM,TakayanagiS,KatoY,etal.EssentialandinstructiverolesofGATAfactorsineosinophildevelop-ment.JExpMed2002;195:1379-86.

11. YuC,CantorAB,YangH,BrowneC,WellsRA,FujiwaraY,etal.Target-eddeletionofahigh-affinityGATA-bindingsiteintheGATA-1promot-erleadstoselectivelossoftheeosinophillineageinvivo.JExpMed2002;195:1387-95.

12. ClutterbuckEJ,HirstEM,SandersonCJ.Humaninterleukin-5(IL-5)regulatestheproductionofeosinophilsinhumanbonemarrowcultures:comparisonandinteractionwithIL-1,IL-3,IL-6,andGMCSF.Blood1989;73:1504-12.

13. WechslerME,FulkersonPC,BochnerBS,GauvreauGM,GleichGJ,Hen-kelT,etal.Noveltargetedtherapiesforeosinophilicdisorders.JAllergyClinImmunol2012;130:563-71.

14. YamaguchiY,ZonLI,AckermanSJ,YamamotoM,SudaT.ForcedGATA-1expressioninthemurinemyeloidcelllineM1:inductionofc-Mplex-pressionandmegakaryocytic/erythroiddifferentiation.Blood1998;91:450-7.

15. UhmTG,KimBS,ChungIY.Eosinophildevelopment,regulationofeo-sinophil-specificgenes,androleofeosinophilsinthepathogenesisofasth-ma.AllergyAsthmaImmunolRes2012;4:68-79.

16. LeckieMJ,tenBrinkeA,KhanJ,DiamantZ,O’ConnorBJ,WallsCM,etal.Effectsofaninterleukin-5blockingmonoclonalantibodyoneosino-phils,airwayhyper-responsiveness,andthelateasthmaticresponse.Lan-cet2000;356:2144-8.

17. PavordID,KornS,HowarthP,BleeckerER,BuhlR,KeeneON,etal.Mepolizumabforsevereeosinophilicasthma(DREAM):amulticentre,double-blind,placebo-controlledtrial.Lancet2012;380:651-9.

18. NairP,PizzichiniMM,KjarsgaardM,InmanMD,EfthimiadisA,Piz-zichiniE,etal.Mepolizumabforprednisone-dependentasthmawithsputumeosinophilia.NEnglJMed2009;360:985-93.

19. HarlinSL,AnselDG,LaneSR,MyersJ,KephartGM,GleichGJ.Aclini-calandpathologicstudyofchronicsinusitis:theroleoftheeosinophil.JAllergyClinImmunol1988;81:867-75.

20. LeifermanKM,AckermanSJ,SampsonHA,HaugenHS,VenenciePY,

GleichGJ.Dermaldepositionofeosinophil-granulemajorbasicproteininatopicdermatitis.Comparisonwithonchocerciasis.NEnglJMed1985;313:282-5.

21. OldhoffJM,DarsowU,WerfelT,KatzerK,WulfA,LaifaouiJ,etal.Anti-IL-5recombinanthumanizedmonoclonalantibody(mepolizumab)forthetreatmentofatopicdermatitis.Allergy2005;60:693-6.

22. BoniniS,MagriniL,RotirotiG,LambiaseA,TomassiniM,RumiC,etal.Theeosinophilandtheeye.Allergy1997;52:44-7.

23. ForbesE,SmartVE,D’AprileA,HenryP,YangM,MatthaeiKI,etal.Thelper-2immunityregulatesbronchialhyperresponsivenessineosino-phil-associatedgastrointestinaldiseaseinmice.Gastroenterology2004;127:105-18.

24. CarvalhoAT,EliaCC,deSouzaHS,EliasPR,PontesEL,LukashokHP,etal.Immunohistochemicalstudyofintestinaleosinophilsininflamma-toryboweldisease.JClinGastroenterol2003;36:120-5.

25. MastersonJC,McNameeEN,JedlickaP,FillonS,RuybalJ,HosfordL,etal.CCR3BlockadeAttenuatesEosinophilicIleitisandAssociatedRemo-deling.AmJPathol2011;179:2302-14.

26. SewryCA.Musculardystrophies:anupdateonpathologyanddiagnosis.ActaNeuropathol2010;120:343-58.

27. KrahnM,LopezdeMunainA,StreichenbergerN,BernardR,PécheuxC,TestardH,etal.CAPN3mutationsinpatientswithidiopathiceosino-philicmyositis.AnnNeurol2006;59:905-11.

28. RiiseGC,SchersténH,NilssonF,RydW,AnderssonBA.ActivationofeosinophilsandfibroblastsassessedbyeosinophilcationicproteinandhyaluronaninBAL.Associationwithacuterejectioninlungtransplantrecipients.Chest1996;110:89-96.

29. GataultS,LegrandF,DelbekeM,LoiseauS,CapronM.Involvementofeosinophilsintheanti-tumorresponse.CancerImmunolImmunother2012;61:1527-34.

30. SimonHU,RothenbergME,BochnerBS,WellerPF,WardlawAJ,WechslerME,etal.Refiningthedefinitionofhypereosinophilicsyndrome.JAllergyClinImmunol2010;126:45-9.

31. CoolsJ,DeAngeloDJ,GotlibJ,StoverEH,LegareRD,CortesJ,etal.AtyrosinekinasecreatedbyfusionofthePDGFRAandFIP1L1genesasatherapeutictargetofimatinibinidiopathichypereosinophilicsyndrome.NEnglJMed2003;348:1201-14.

32. WongCK,CheungPF,IpWK,LamCW.Intracellularsignalingmecha-nismsregulatingtoll-likereceptor-mediatedactivationofeosinophils.AmJRespirCellMolBiol2007;37:85-96.

33. KlionAD,NutmanTB.Theroleofeosinophilsinhostdefenseagainsthelminthparasites.JAllergyClinImmunol2004;113:30-7.

34. GebreselassieNG,MoorheadAR,FabreV,GagliardoLF,LeeNA,LeeJJ,etal.Eosinophilspreserveparasiticnematodelarvaebyregulatinglocalimmunity.JImmunol2012;188:417-25.

35. Dimova-YanevaD,RussellD,MainM,BrookerRJ,HelmsPJ.Eosinophilactivationandcysteinylleukotrieneproductionininfantswithrespirato-rysyncytialvirusbronchiolitis.ClinExpAllergy2004;34:555-8.

36. RosenbergHF,DomachowskeJB.Eosinophils,eosinophilribonucleases,andtheirroleinhostdefenseagainstrespiratoryviruspathogens.JLeu-kocBiol2001;70:691-8.

37. YousefiS,GoldJA,AndinaN,LeeJJ,KellyAM,KozlowskiE,etal.Cata-pult-likereleaseofmitochondrialDNAbyeosinophilscontributestoan-tibacterialdefense.NatMed2008;14:949-53.

38. FegerTA,RuppNT,KuhnFA,FordJL,DolenWK.Localandsystemiceosinophilactivationinallergicfungalsinusitis.AnnAllergyAsthmaImmunol1997;79:221-5.

39. RomeroR,KusanovicJP,GomezR,LamontR,BytautieneE,GarfieldRE,etal.TheClinicalsignificanceofeosinophilsintheamnioticfluidin



pretermlabor.JMaternFetalNeonatalMed2010;23:320-9.40. BlumenthalRD,SamoszukM,TaylorAP,BrownG,AlisauskasR,Gold-

enbergDM.Degranulatingeosinophilsinhumanendometriosis.AmJPathol2000;156:1581-8.

41. AbrahamSC,LeachS,YeoCJ,CameronJL,MurakataLA,BoitnottJK,etal.Eosinophilicpancreatitisandincreasedeosinophilsinthepancreas.AmJSurgPathol2003;27:334-42.

42. WangQ,LuCM,GuoT,QianJM.Eosinophiliaassociatedwithchronicpancreatitis.Pancreas2009;38:149-53.

43. CorrealeJFiolM.Activationofhumoralimmunityandeosinophilsinneutromyelitisoptica.Neurology2004;63:2363-70.

44. JarrattM,BybeeJD,RamsdellW.Eosinophilicfasciitis:anearlyvariantofsclerodermaJAmAcadDermatol1979;1:221-6.

45. RothenbergME,KlionAD,RoufosseFE,KahnJE,WellerPF,SimonHU,etal.Treatmentofpatientswiththehypereosinophilicsyndromewithmepolizumab.NEnglJMed2008;358:1215-28.

46. KimS,MarigowdaG,OrenE,IsraelE,WechslerME.Mepolizumabasasteroid-sparingtreatmentoptioninpatientswithChurg-Strausssyn-drome.JAllergyClinImmunol2010;125:1336-43.

47. OldhoffJM,DarsowU,WerfelT,BihariIC,KatzerK,LaifaouiJ,etal.Noeffectofanti-interleukin-5therapy(mepolizumab)ontheatopypatchtestinatopicdermatitispatients.IntArchAllergyImmunol2006;141:290-4.

48. KipsJC,O’ConnorBJ,LangleySJ,WoodcockA,KerstjensHA,PostmaDS,etal.EffectofSCH55700,ahumanizedanti-humaninterleukin-5antibody,inseverepersistentasthma:apilotstudy.AmJRespirCritCareMed2003;167:1655-9.

49. GevaertP,Lang-LoidoltD,LacknerA,StammbergerH,StaudingerH,VanZeleT,etal.NasalIL-5levelsdeterminetheresponsetoanti-IL-5treatmentinpatientswithnasalpolyps.JAllergyClinImmunol2006;118:1133-41.

50. KlionAD,LawMA,NoelP,KimYJ,HavertyTP,NutmanTB.Safetyandefficacyofthemonoclonalanti-interleukin-5antibodySCH55700inthetreatmentofpatientswithhypereosinophilicsyndrome.Blood2004;103:2939-41.

51. KolbeckR,KozhichA,KoikeM,PengL,AnderssonCK,DamschroderMM,etal.MEDI-563,ahumanizedanti-IL-5receptoralphamAbwithenhancedantibody-dependentcell-mediatedcytotoxicityfunction.JAl-lergyClinImmunol2010;125:1344-1353.

52. BusseWW,KatialR,GossageD,SariS,WangB,KolbeckR,etal.Safetyprofile,pharmacokinetics,andbiologicactivityofMEDI-563,ananti-IL-5receptoralphaantibody,inaphaseIstudyofsubjectswithmildasthma.JAllergyClinImmunol2010;125:1237-1244.

53. SefcickA,SowterD,DasGuptaE,RussellNH,ByrneJL.Alemtuzumabtherapyforrefractoryidiopathichypereosinophilicsyndrome.BrJHae-matol2004;124:558-9.

54. SimonD,WittwerJ,KostylinaG,BuettikerU,SimonHU,YawalkarN.Alefacept(lymphocytefunction-associatedmolecule3/IgGfusionpro-tein)treatmentforatopiceczema.JAllergyClinImmunol2008;122:423-4.

55. vanRensenEL,EvertseCE,vanSchadewijkWA,vanWijngaardenS,AyreG,MauadT,etal.Eosinophilsinbronchialmucosaofasthmaticsafterallergenchallenge:effectofanti-IgEtreatment.Allergy2009;64:72-80.

56. WenzelS,WilbrahamD,FullerR,GetzEB,LongphreM.Effectofanin-terleukin-4variantonlatephaseasthmaticresponsetoallergenchallengeinasthmaticpatients:resultsoftwophase2astudies.Lancet2007;370:1422-31.

57. GauvreauGM,BouletLP,CockcroftDW,BaatjesA,CoteJ,DeschesnesF,etal.AntisensetherapyagainstCCR3andthecommonbetachainatten-uatesallergen-inducedeosinophilicresponses.AmJRespirCritCareMed2008;177:952-8.

58. BlanchardC,WangN,StringerKF,MishraA,FulkersonPC,AboniaJP,etal.Eotaxin-3andauniquelyconservedgene-expressionprofileineo-sinophilicesophagitis.JClinInvest2006;116:536-47.

59. OkigamiH,TakeshitaK,TajimiM,KomuraH,AlbersM,LehmannTE,etal.Inhibitionofeosinophiliainvivobyasmallmoleculeinhibitorofverylateantigen(VLA)-4.EurJPharmacol2007;559:202-9.

60. BloomgrenG,RichmanS,HotermansC,SubramanyamM,GoelzS,Na-tarajanA,etal.Riskofnatalizumab-associatedprogressivemultifocalleukoencephalopathy.NEnglJMed2012;366:1870-80.

61. SugimotoH,ShichijoM,IinoT,ManabeY,WatanabeA,ShimazakiM,etal.AnorallybioavailablesmallmoleculeantagonistofCRTH2,rama-troban(BAYu3405),inhibitsprostaglandinD2-inducedeosinophilmi-grationinvitro.JPharmacolExpTher.2003;305:347-52.

62. SchuligoiR,SturmE,LuschnigP,KonyaV,PhiliposeS,SedejM,etal.CRTH2andD-typeprostanoidreceptorantagonistsasnoveltherapeuticagentsforinflammatorydiseases.Pharmacology2010;85:372-82.

Documents

과다호산구증가증-관련 질환과 개발 중인 치료 약물 · 2013-03-07 · remodeling·repair)”의 역할을 수행하는 세포로서 자리매김을 하 는데 일조하고