Stem Cell Biology and Regenerative Medicine
`
`Hossein Baharvand
`Nasser Aghdami Editors
`Advances in Stem
`Cell Research
`
`···~
`
`EXPENSIVE ITEM
`This item must be
`returned by
`recorded delivery
`
`

`

`Hossein Baharvand· • Nasser Aghdami
`Editors
`
`Advances in Stem Cell
`Research
`
`BRITISH LIBRARY
`DOCUMENT SUPPLY CENTRE
`
`0 2 AUG 2012
`
`·-·-····································
`••••••••••••••••••••••••••••••••••••••••
`
`p
`4-\II, H
`",,,~ umana ress
`
`

`

`Edirun
`Hcw,dn Baharvaml
`Rnyan ln-.titull:
`Univer .. ity nf S\.·icn..:l· n11d Culturt
`I ehran
`Iran
`
`:--:u,,c, Aghd.uni
`Rcgl'Jl\.·rat,ivc ~ ledii:tnc
`R,,) au ln,titulc fnr Stem Cdl 811,lof)
`.inli T cd111ology
`Tehrnn
`lrnn
`
`lSBN 973-1-61779-939-6
`DOI I0.1007!978-1-61779-9-40-2
`!)pringcr New Yori,. He1tldbc:rg U..,rdrccht London
`
`ISBN 978-1-6 I 779-940-2
`
`tcBookl
`
`Libra!) of Conire" Cunuol Nambcr. 2012937Ti9
`
`C .Sponger Scicn1."e • Ru,~ines t\kdia. LLC 201:!
`This 'Aorl.: i, ,ubject in oopynghl All rightS are re~rwd by the Pubh her, .,..hccher the whole or part of
`the maccnal 1, curn:~"Tncd. ~pccifically the righh of trart,;lation, rcprincing, reu-.e uf 11lu,tn1uons.
`rec11auon. broadc:i~tmg, repwducti1111 on mkmtilm~ or in any other phy!.ical way. and cran,m1~~ion llr
`1nfonnat1on ~toragc and retrit'\'al. elclU-unac adaptation. ~nrnputcr ",uv. are. ur by 5imilar or di~,imala,
`methodology now knc,wn or hereafter developed. E,cmptcd frorn 1h1-. legal re.;ervation are briel
`c\Cc:rph in connection "1th re, 1cw, or ,cholarl} analy,i~ or mJlerial ,upplied \J)Cc1hcall~ for the
`p111vo,l' uf being entered and c,ccu1ed ,u: a computer -.y,tem. tor c,du'IVC ll!>C by 1hc purcha.~cr of lht•
`\\l)rk. Duplication of thi, puhlk11uon or pans thereof is fll."TmitrcJ only under the pnl\ bion, ,,1
`the Copyrigh1 Law of the Publt,her's loca1ion, in 1h current vcmon, and J)l:mw,,11>n for U)C mu)I WWI!)
`be obtained from Sponger. Permi~1ons for use lllll)' be obtained through R1gh1~Llnk at the Copyright
`Clearance Center. \'iolJtion~ nre ltuble tu pro~cution under the n:sperllve Copyrigh1 La\11
`· Jbc u~e oi gcr.eral dcs.:rip1i,-e name
`registered names. trademark,;, SCl'\'IL'C mark,, l"lc
`in tl1is
`publication doe-. not imply, c,·en in the absence of n specific st .. 1emen1, that such names are e~cmpt
`lrom the re!e,·ant protccti,c law~ nnd regulation~ and therefore free for general u-.c,
`\Vh1le the advke and inf111m.1twn in tha" book are bclien-d t11 be.• uuc and accurate at the date ol
`puhlirntion, neither the author-. nor the ed11or-. 1111r th.: publhhcr c:m accept :tn) le!!!al re.,pon,itiilrty for
`un~ crrurs or or.ii,;-.ion\ th.,1 ma~ he made. Th1: puhli-;her makc-. m, \\arranty. c'tpre~s or 1mphcd. with
`rc~rect to the material contained herein.
`
`Pnntl'tl un ac1tl-fn:e paper
`
`Humana Pre-;\ i, n brand 01 Spnnger
`
`Spnnger h pan • •:' Sponger Sc 1eflC'c+Busine,, Media iw" w pringcr com i
`
`

`

`Contents
`
`1 ES Cell Lines from Tetraploid Mouse Blastocysts ............
`Martin J. Pfeiffer. Manin Stehling. Anna Jauch and Michele Boiani
`
`2 The Significance of Culture Adaptation of Embryonic Stem Cells
`,,:
`for Regenerative Medicine ............ . ................
`Neil J. Harrison. Duncan Baker and Peter W. Andrews
`
`3 Blomanufacturlng Human Pluripotent Stem Cells
`for Therapeutic Applications . ...........................
`Xiaojun Lian and Sean P. Palecek
`
`4
`
`hESC-Derived Hepatocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Iman Saramipoor Behbahan and Mark A. Zem
`s Advances in Induced Pluripotent Stem Cell Biology. . . . . . . . . . .
`Ali Seifinejad
`
`6
`
`IPS Cells: New Applications for Metabolic Liver Diseases . . . . . .
`Tobias Cantz. Abbas Beh-Pajooh and Malte Sgodda
`
`7 Vascular Differentiation of Human Plurlpotent Stem Cells. . . . . .
`Helena V azao. Mruio Graos and Lino Ferreira
`
`17
`
`29
`
`49
`
`67
`
`85
`
`97
`
`8 Mechanism of MicroRNA-Medlated Global DNA
`Demethylation In Human IPS Cells . . . . . . . . . . . . . . . . . . . . . . .
`Shi-Lung Lin
`
`117
`
`9 MicrotechnologicaJ Approaches in Stem Cell Science . ..... · .... 135
`Faramarz Edala~ Jae Min Cha. Hojae Bae. Sam Manoucheri,
`Sang Bok Kim and Ali Khademhosseini
`
`ix
`
`

`

`X
`
`Content!,
`
`16 7
`
`191 .
`
`2 I I
`
`227
`
`10 Application of Micro/Sanotechnol~· to Stem Cell Research
`and TKhnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Amir R. Aref
`11 Spermatogonial Stem Cells . . : . . . . . . . . . · . . . . . . . . . . . . . . . . .
`Hossein Azizi. Sabine Conrad. Thomas Skutella
`and Irma Virant-Klun
`12 Cellular Reprogramming and Fate Conversion . . . . . . . . . . . . . .
`Masaki Jeda
`13 Omics in Stem Cell Therapy: The Road Ahead . . . . . . . . . . . . . .
`Kyunghee Byun. Goo-Bo Jeong. Trevor N. Collingwood
`and Bonghee Lee
`14 Microglia: The Bodyguard and the Hunter
`of the Adult Neurogenlc Niche . . . . . . . . . . . . . . . . . . . . . . . . . .
`Jorge Valero, Maria Francisca Eiriz. Tiago Santos. Ismael Neiva.
`Raquel Ferreira and Joao 0. Malva
`lmmunosuppressive Properties of Mesenchymal Stromal Cells. . .
`Francesco Lanza, Diana Campioni. Endri Mauro.
`Annalisa Pa~ini and Roberta Rizzo
`16 Cellular Therapy for Hematology Malignancies: Allogeneic
`Hematopoietic Stem Tramplantatio~ Graft-Versus-Host Disease.
`and Graft Versus Leukemia Effects. . . . . . . . . . . . . . . . . . . . . . .
`James L. M. Ferrara and Pavan Reddy
`17 Cardiac Versus Non-Cardiac Stem Cells to Repair the Heart:
`The Role of Autocrlne/Paracrtne Signals . . . . . . . . . . . . . . . . . . . 367 ·
`Manlio Vinciguerm. Vincenzo Lionetti, Carlo Ventura
`and Nadia Rosenthal
`18 Adult Neurogenesis in Alzheimer's Disease and Therapies. . . . . . 383
`Philippe Taupin
`Author's Biography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
`Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
`
`15
`
`245
`
`281
`
`303
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Chapter 16
`ellular Therapy for Hematology
`alignancies: Allogeneic Hematopoietic
`tem Transplantation, Graft-Versus-Host
`Disease, and Graft Versus Leukemia
`Effects
`
`Jame L. ~I. Ferrara and Pavan Reddy
`
`Ab tract The ability of allogeneic hematopoietic cell tran . plantation (HCT) to
`cure hematologic malignancie . i widely recognized. An important therapeutic
`a: peel of HCT in erndicating malignant cells is the graft-, er 1-us-leukemia (GVL)
`effect. But the GVL effect is clo. el} associated with graft-ver u -ho t disease
`GVHD) the major compli auon of HCT. G HD remain the major barrier to the
`~,ider application of allogeneic HCT for a variety of disease . GVHD occurs in t,,o
`form., acute and chronic. and both are associated with GYL effects. Recent advance-;
`in th under tanding of genetic polymorphi. ms. the cherno-cytokinc networh,
`e\'eral novel cellular uhsct · indudmg r~gulator~ T cells. and of the dir·ct medi(cid:173)
`ators of ellular cytotoxicity have led to impro,ed under randing of these complex
`proce ses. nimal studie-, sho\.'- that modulating . everal mediator of the complex
`GVHD cascade ma} he able to reduce the undesimble inflammatory aspects of
`GVHD while pre. rving the benefitc; of GVL. However. most of the laboratory
`ob ervations remain to be tudied in well-controlled clinical trials. Multiple cellular
`effector; ma} be involved in GVL, although donor T cell re ognition of ho t anti(cid:173)
`gens is an important element of this proces .. Cellular immunotherapy uch a donor
`leuk yte infu ion offer a
`trat gy for . eparating GVHD and the GYL effect.
`Both e pcrimental and clinical data uggcst that post-tran5plantation cellular
`immunotherapy can be performed relatively ·afely and effectively, and optimization
`of patient election, cell do e. and tinting of admini tration may all . erve to limit
`toxicity and enhance the potential GVL ffect. .
`
`J. L. \1. Ferrara CU )
`led1cine and Pediatrics. Combined Bone Marro" Tramplant Program.
`Univer,;1ty of Michigan Cancer enter. nn Arbor. ~I. LSA
`e-mail: Ferrara@um1ch edu
`
`P. Reddy
`Department of Internal Me<l1cme. Bone Marrow Tran ·plam Program.
`·niver ity of 1ich1gan Cancer Center. Ann Arbor, Ml, CS
`
`H. Baharvand and N. Aghdam1 (eds.). Ad\'llt1ce1 in Stem Cell Re. earclt,
`tem Cell Biology and Regenerative Medicine, DOI: I0.I007/978-1 -6I779-9-W-2_ 16,
`- Spnnger Science + Bu,c;ine. vfedia, LLC 2012
`
`303
`
`

`

`16. l Introduction
`
`The ah1lity of allogenc1c hcmalopoietic n:11 trarn,plantation rHCT) 10 cure certain
`hematologic mahgnanue,; j.., widely ret'ognized. An import.int therapeutic a pect
`of HC'T in eradicating malignant cell, is the graft-ver,;th-leukemia 1GVL effect.
`The 1mponance of the GVL effect in allogcneic HCT ha ... bt:cn ri..·cngni1.ed since
`the earlic~t C.'{peruncnt-. in ... rem cell Iran ·planta11on. Forty year-,; ago Barnes and
`colleague.., noted that kui..emic mice trcate<l with a ,ubtherapeuuc do,e of radia(cid:173)
`tion and a 'i)'ngene1c ( 1<lentical rwm) graft tran,ptant were more likely to relapse
`tern cell tran..,plant 11. 2] They hypothc,ized that
`than mic~ given an allogcnc1c
`the allog ·ncic graft contained cell, w 1th immune rea~ti\'1ty nece ary for eradi(cid:173)
`cating re,idual leukemia cells. The) abo noted that recipients of allogcncic grafts.,
`though less hkely to relapse. died of a ·'\1.-a..,ting ~yndrome" nov. recognized as
`l'hus. m addition to describing GVL. these
`graft-\er us-host disca-;c (GVHD)
`experiments highlighted tor the first time the mtncate rclation .. h1p bctwc: n GVL
`and GVHD Smee these early experiment. hmh GVHD and the G\11.. effect have
`linical
`been studied exten ivcly [3). This chapter reviews the pathophys1ology.
`feature,. treatment of GYHD. and .. ummanzes cunent under-,tanding c>f the rel&•
`tionship., between GYHD and the GVL effect.
`
`16.2 Graft-Versus-Host Disease: Clinical
`and Pathologic Aspects
`
`Ten years after the work of Barne and Loutit. Billingham formulated the require(cid:173)
`ments for the development of GYHD: the graft must contain immunolugicaQy
`competent cell , the recipient mw,t ex pres-. ti,sue antigen" that are not present in the
`transplant donor. an<l the recipient must be incapable of mounting an effective
`response to destroy the tran planted cclb [➔ J. According to these criteria, GVHDcaJI
`devdop in rnrious clinical ~ttings when tis.,ues containing immunocompetcnt cells
`(blood products. bone marrow. and :ome solid organs) are transferred between
`persons. The most common setting for the development of GVHD 1s foUowi--,
`allogcncic HCT; without prophylactic immuno uppress1on, most aJlogencic HCTI
`\\ ill he complicated b> GVHD. GVHD occurs seconclar}, to mismatch between
`hi tocompatibility anugcn:-. between lhe donor and recipient Matching of the majot
`hi,tocompatibility complex (~IHC) amigi:ns peed engraftment and redu e tho
`severity ot GVHD 15 I. The .MHC contains the genes that encode tissue antigen and
`were fir t identified furn:llonally in murinc models as tran'>plantauon antig(cid:173)
`rcsponsibk for rejection ot tissue grafts. In humans. the MHC region lie on the hoit
`arm of chromo,ome 6 and 1s called the human leukocyte antigen (HLA) region I
`The HLA region indud , man)' genes. not all of which are involved in imm
`II, each con
`activation. ft 1. d1, ided into two classes, Class I and Cla
`· ·
`numerous gene loci that encode a large number of pol> morphic alleles. MHC class
`
`

`

`dlular Tht'rap) for lfrm.itolo!!)' ~1alignar1-·1 ~,
`
`le ulc arc imohc<l in the prc,cntution of peptide, 10 CD • T l·clL. ,mJ da" II
`ecuJe, prc.-.ent peptide, to CD-r T cell, f61 .
`Each MHC antigen i-. comp<),ed of rwo p<il) peptide l·hain, Cl,," I anllgt:n, arc
`e up of a hca\) chain that contains the pulymorph1~: rcimm, and the
`npolymorphic light chain. t>eta-2 microglllhulin
`'The cla" I HLA antigen,
`Jud' HLA A. B. and C antigens These a1e cxpre~~ed on alrno,t all l:dls of the
`y at \'arying tknsi11c, (6]. Both chain, of clu,, II antigen:-- 1:onta111 polymorphic .
`gion · and are encoded m the MHC. The la,~ II an1igen, are. iunher divided into
`R, DQ. and DP antigen-.. Cla:-, II antigens are expre 'Cd on B cells. dendritic cells.
`-IJl(I monocytes and their expre:-.sion can be induced nn man) other cell type,
`following inflammauon or mjury [6. 7 ]. ·1 he determinution of l lLA types has bcrnme
`$1JCh more accurate \'- ith molecular techniques lhat replace earlier erologic
`or cellular methods. In patients who-.e ancestry imohc, c:ten,ive interracial
`· ing. the chance of identifying an HLA-i<.kntical donor are diminished (8).
`Despite HLA identity between a patient and donor. suhstuntial number, of
`patients ~till develop GVHD due to difference, in minor hi tocompat1bility
`111tigen1.. that lie outside the HLA loci. Mo. t minor antigens are expres ed on the
`cell urface a., degraded peptides hound to specific HLA molecules. hut the precise
`elucidation of many human minor antigens is yet to be accompli,hed [9]
`In the
`United States, the average patient has a 250, chunc..: of haying an HLA match
`within his immediate family f8] . Patients who lack an HLA-idcntit.:al family
`snember donor must seek unrelated donor volunteers or cord blood donations.
`
`16.2.1 Acute Graft-Versus-Host Disease
`
`Acute GVHD can occur within days (in recipient. who are not HL. -matched with
`the donor or in patient. not given any prophylaxb) or as late a. 2 months after
`transplantation. The incidence range
`from k . ...s than IO to more than 8Q<'>l .
`depending on the degree of histomcompatibility b tween donor and recipient. the
`number of T celL in the graft. the patient·~ age. and thi: GVHD prophylactic
`~gimen [9]. The principal target organs include the immune sp,tem, skin. liver.
`and inte tine. G HD occurs first and mo~t commonly in the .skin as a pruritic
`maculopapular ra.'h, often involoving the palm , ~oles. and ears; it can progre .. to
`total-body erythroderma. with bullae formation. mptur along rhe epid ·m1al•
`dennaJ border. and de~quamation in severe cases 19). Ga. trointestinal (GI) and
`liver manife-,tations often appear later and rart.:ly rcpre. cnt th~ first and only
`finding . lnte tinal symptom
`include anort:xia. nausea, diarrhea ( omctimc.
`bloody). abdominal pain. and paralytic ileu 19J. Liver dysfunction includes
`hyperbilirubinemia and increased serum alkalini: pho,phatasc and aminotransfer(cid:173)
`value . Coagulation studies may become abnormal. and hepatic failure with
`ascites and encephalopathy may develop in evere case. [9-11 ]. Hepatic GVHD
`can be distinguished from hepatic veno-ocdusivc disease (VOD} by weight gain or
`pa.in in the right upper quadrant in the latter [ 11 }. Acute GVHD aJ-;o re ·ults in the
`
`

`

`J L :-..1 F~rr.uu and P. Reddy
`
`dcla1cd n:cmery ot 1mmunocom~tence 19). The clintcal re"ult 1s profound
`11nmunoddic1enq and ,usceptibility to infe tions. often fut1hcr, ccemuated by the
`inununo,upprc,. i\e ugcnt, u,cd to treat GVHD [9}.
`Pathologicall}. the ,in" qua n.._ n of acute GVHD is ,elccti\c epithelial damage
`of target ,rgans l 12. 13 I. The epidermi~ and hair follicle, are damaged and
`sometimes destroyed. Sm.ill hilc duch arc profoundly affected, with ,egmenta)
`d1:-.rupt1on. The de·'itrurtton of intc,tinal crypt, result, in muco,al ulccrattons that
`ma) be either patchy or diffuse Other cpithelial su1tace,. ,uch as the conjunctivae,
`vagina, and e. ophagus, arc !cs, common I) im olve<l. A peculiarity of GVHD
`hi,tology is the frequent paucity of mononuclear cell infiltrntcs: however. as the
`disea ·e progre ses the mtfommatory component may be ,ubstamial. Recent tudi
`have identified inflammatory cytokine a, ,oluble mediator of.GVHD and have
`,ugge,1cd that d•rcct contact bct\\'Ccn target celb an<l lymphocytes may not be
`required for target cell destrucuon (see following secuon~) G HD lesions are noc
`evenly distributed in the target tissues. In the ~kin. damagt! 1s prominent at the tip
`of rcte ridge,: in the intc,tinc. al the ba,t! of the crypts; and in the liver. 1n the
`penductular epithelium. 1 he,c areas contain a high proportion of stem cell ,
`giv111g nse to the idea that GVHD targets may be undifferentiated epithelial cells
`with primitive -.urfacc antigen, [ 141.
`1 he histologic severity of a given lesion is at best enuquantitative and
`consequently. the sevent)' of pathologic findings are not used in the grading of
`GVHD. As it b often difficult to obtain an adequate ti', uc h1op,y. the phy ician is
`left to use-clinical judgment It can be very d1fficult to dLtinguish GVHD from
`other post-81 IT complication, .such a drug eruption,. infectious l'Omplkation.
`even on histology.
`A re<.:ent multicenter pha ... e III trial u,ec.l an independent committee to a·. es the
`prc,ence and ,everity of GVHD. The mcidence of GYHD a, determined by
`inve. tigators was substantially higher than the review committee could confirm [ 15).
`C\ crtheless, for an expcricm:cd dinician a combination of phy,ical and laboratory
`findings in the appropriate context provides a working diJgnos1s of GVHD that i
`, atisfoctory to produce a meaningful prognm~tic scale ba cd on clinical grading
`,ystcm ( 12. 17) Standarc.l grading systems generally mclu<lc clinical changes in the
`skin. Gl tract, liver. and perfonnance tatu ( Table 16.2) [ 16 ]. Although the everity
`of GVHD i. ometime. difficult to quancify. the o, era II grade correlate, with disease
`out ome. WhJle mild G HD (izrade I or II) 1s as ociated with little morbidity and
`almost no mortality. higher g~ndes are a. ·ociated with -;ignificanrly decreased
`,urvival [16. 17]. With grade IV GVHD. the mortality is almost 100% [17).
`
`16.2.1.l Clinical Features of Acute GVHD
`
`·taging and grading of acute
`
`The clinical features,
`Tablc1, 16.1 and I 6.2.
`In a comprehen ive re\'iew of patient receiving therapy for acute GV~
`it wa., found that 81 % had skin invol\'cment. 5➔% had GI in olvemcnt. and
`
`

`

`16 Cellul..ir rhernp) for Hem tolu ') ~1arignanrn:~
`
`30'
`
`Tahl
`
`ltd CJ1111~·,1I manite 1,111nn
`
`,111d -.1a~111g uf acut · li\ HO
`
`tr~ thcrnatmh, maculopapula1 ra ... h St..1ge J • <'25"·, ra,h
`1nrnh rng palm, and ... oles ma~ Staee 2: -25- ,09c ra,h
`be~·om cnnrluent
`\Lage J: gene mh ,cd er~ troderma
`SeH:rc d1~:1,e: bullae
`S· .ige .!: bullac::
`Painkl, Jaundic:I! w11h con1uga1ed
`StaJe I: b1li 2 'mg/dL
`hyp rbthrubinemia and
`Sta.;c 2: bili J.1-6 mg/dL
`incrca cJ alka.ltne pho,phata',('
`St gc J: b1li 6.1- 15 mg/dl
`Stage ➔ - bil1 " l.'i rng/dL
`litage I: diarrhea > 51Xl mUday
`~l.tE,e 2: diarrhea > IOOO mUday
`Stage 3: diarrhe > I 00 mUday
`Stage -4: 1leu . hlccding
`
`Lower: diarrhea. abdominal
`crnmp • d1-.1cnt1on. 1leu , nd
`bleeding
`
`l 'pper· nau,ea. ,omitmg. anon:. 1.1
`
`Ga-;tro-inte,tm.11 !GI)
`tract
`
`()v era 11 grade
`
`II
`Ill
`I
`
`l.1ver
`0
`I
`l-4
`2
`
`(ilucksherg criteriu for ,taging of acute GVHlJ• ------------
`Skm
`..
`I ,
`1-3
`l-3
`2
`
`And/or
`And/or
`And/ur
`
`Gut
`()
`I
`2-3
`2-4
`
`• See Table 161 tor indmdu,11 organ sragmg Traditionully, indi\'idual organs are ,t,1gcd Mthout
`regard to uttnbut1on. The overall grade of GVHD. however. reflects the actuul extent of GVHD.
`To 1U:h1e-.e <!U-.h merall grade. ,km di,ea,;c plu, li\'er and/or gut involvement arc rc4u1red
`
`bad li,·er involvement at the initiation of lh ·rapy [ 18]. Atter high-inten ·ity
`(conventional) conditioning. acute GVHD generally occurs within 14-35 days of
`tern cdl inftl';ion The time of on. et may dept!nd upon the degree of hi,tocom(cid:173)
`patibility. the number of donor T cells infu-,cd. and the prophylactic regimen for
`G HD. . "hyperacute" form of GVHD may occur in patients with ~evcre HLA
`mi rnatche and in patient, who receive T cell replete tran~plant.: without or with
`inadequate in vivo G HD prophyla. i. [ 191 It is. howe,er. imponant ro note that
`this "hypcracute" fonn is pathoph)-'-tolocally distinct from the hyperacute rejec(cid:173)
`tion after solid organ allo-grafting. This fonn of GVHD i. manifested by fe'.er.
`generalized erythroderma and desquamation, ,md often edema. It typically occur
`about I week after ,tern cell infusion <1.nd may be rapidly fatal. In patient.
`receiving more convenaonal (in vivo) GVHD prophylaxi , ,uch a...: .1 combinat~on
`of cyclo ·porine (CSP) and mcthotre ate. the median onset of GVHD b typically
`21-25 da~., after tran plant 1tion: hm\ever. afrer in vitro T cell depletion of the
`graft the onset ma} be much later [ 19J. Thus. the findings of rnsh and diarrhea by
`J week after transplantation would very likely he hyperacute manifestations of
`GVHD if mmirnal or incff cctive prophylaxis were administered: the same kinetics
`would be \Cf}' unlikely with the u. e of calcineunn inhibitor or in \ 1tro T <:ell
`depletion of the stem cell inoculum. A le,., ominuu-, -,yndrome of fever. ra ·h, and
`
`

`

`flmJ retcnlmn nccurnng in lhL' hr-.t I -2 weeks atlt:r -.tern cell infusion i.
`··engraftment synJrome'' . The,e manife,tauon may he se~n with either lJ g
`or autolognu!'. tran,plantation. While the pathophysiology 1s poorly unJ rstood.
`i, thought lo be du to a wave of cytokrne produ lion a, the gratt ,tarts to recover_
`-This is related to. but c.Ji.,tinct from. the "rytokrnc ,tonn ·· that is thought to
`contribute to acute (iVHD in which then! is no concon11tant 1 cell-mediated ttack
`119. 201 This syndrome responds immediately 10 steroid, in mo,t patient andit
`typ1 ally pre cnt. ea her rhan acute GYHD [ 16) In autologou-. tran. plantation the'.
`dittcrent1ul diagnosis I ot little rde\ancc. but 111 allogcneic tran,planc recipients it
`must he d1 ttnguished lrom the hyperacutc m mfe,tauon\ of G\'HD. A promp(
`response to steroid" would argue in favor of an engraftmcnt -.~n<lromc, although
`, VHD will al. o respond.
`some patient... \\ith
`Skin is the mo. t commonly affected organ. In patients receiving cran plant after
`mycloablative conditioning. the skin 1s u. ually the first organ involved. and GVHD
`often coincides with ngraftmcnl. Howe\'cr. the presentation of GVI ID .is ~
`varied follo\\ing nonmyeloablatiYe tran!',plant 01 donor lymphoc) te infu. ion [21).
`The characteristic maculopapular ra<-h can ... pread throughout the rest of the body but
`usually spare, the calp. and 1 often de cnbed as feeling like a sunburn, tight, or
`pruritic. In -evcrc cases the ,km ma) blmer an<l ulc:crnte [22). Histologic c(lnfir(cid:173)
`nrntion i-. cntu;al to rule out drug reactions, viral infections. etc. Apoptu ·is at the
`j.., charactcd tiL Other feature, includ\! d. keratosis.
`ba l: of dennal er) pL
`exocytosis of lymphocytes. satellite lymphocytes adjacent to dyskeratotic epidermal
`keratinocytes, and d..:rmal pen va cular lymphocvtic infiltration I:! I, 23 ].
`Gastrointestinal tract 1molvemcnt of GVHD ma} presl!nt as nausea. vomiting,
`anore. ia. diarrhea .• md/or abdommal pain ( 23 ]. It p; a pan-rnie unal proce ·s, often
`"ith differences in seventy between thl! upper and lower GI tracts. Ga. tric
`involvement gt\e, rise to po.,tprandial vomiting that ts not a]\\-a)S preceded by
`nau,ca. Although gastropuresi-; is seen after bone marrow transplam. it is u. ually not
`a-sociated with GVHD The diarrhea 01 GVHD ts secretory anc.l -.ignificant GI blood
`loss ma} occur a, a re. ult of mucosa} ulceration and 1s a sociated with a poor
`prognosi (24]. In ad"anced di ·ea e. d1ffu c. severe abdominal pain and di ·tention
`.
`i accompanied by voluminous diarrhea (>2 Uday) fl 7,251
`Radiologic findings of the GI tract include lumcnal dilatation with thickening of
`the wall of the .,mall bowel and air/fluid level· ugge uve of an ileus on abdominal
`flat plates or small bowel serie~. Abdominal computed tomography may show the
`"ribbon·· sign of diffuse thickenmg of the ,mall bowel wall (22) Little correlatiall
`exists between the extent of dis~ase and the appearance of mucosa on endoscopy. but
`·c\erthcle · . me
`loughmg ,., pathognomonic for ~cvere dtS(!ase [26J.
`muco-.al
`tudies have shov.n that antraJ biopsies correlate well with the -.everiry of GVHD in
`the duodenum and in the colon e\en when the presenting }mptom is diarrhea [26).
`Hi,tologic analysis of tissue is imperative to estabhsh the d1agnos1s. The hi toloP:
`rypC
`feature of GI GVHD are the presence of apoptouc bod1e-. m the ba. c of crypts
`abscesses. crypt lo s. and flattenmg of the surface epithelium [25, 27].
`Lh·er function te. t abnormaht1c MC common after bone marro\\ tran plant and
`occur ,;econdary to VOD, drug toxicity, viral infection. sep'-1~. iron mcrload. and
`
`

`

`Cellular Thcrnp; tor Hcmatolog~ ~1altgnanc1e\
`
`309
`
`oth • · ~au-,e-, of extr::ihcpallc hiliaiy ohstrucuon f I l ). The exa~t in 1dencc or hcpati
`G HD is probably underreported bc<.'~m e many patients do not undergo li, er
`bi,>P ie~. The deYelopmcnt of jaundice or .in im.rea. e rn the alk~1l1111: pho,phata~e
`and bilirubin are the initial features of anltc GVHD ot the li,·cr. The hi-,tologic
`features of hepallt GVHD are endothcltalitis, l}mphocytic infiltration ot the portal
`arc
`. pericholangttJs. and bile dud dcstru1:tion and lo. s [ 19. 30).
`
`16,2. l.2 Other Or,~ans
`
`Whdher GVHD attect~ organs other .than the classic triad of skin. livc.:r. and gut
`bas remained a matter of debate. However. numerou reports suggest additional
`organ manifestatiom,. The most likely candidate i
`the lung. Lung tox1c1t).
`in luding interstitial pneumonms and d1ffu-,e alveolar hemorrhage. may occur in
`2 oa of allogeneic transplanc reup1cnt hut in fewer autologou
`trnn plant
`recipients. Cau es of pulmonary damage other than GVHD include engraftment
`ymlrome c ee below). infection. radiation pncumoniti ·. and ch~motherap,-relatcd
`to icity (e.g .. methotrcxatc. bw .. ulfan) f 19, 2 J.
`t least one retrospc t1ve analysis
`failed to link severe pulmonary complications to cli111cal acute GVHD per se [29).
`The m rtaliry due to pneumonia increases with the seventy of GVHD. but this
`iation doc· no1 nc~cssarily imply that G\ HD. a oppo ·ed to 1mmuno up(cid:173)
`855
`pre. ion given for therapy. j- causauve (191,
`particular histop..ithologi._ .. yn(cid:173)
`drom · of lymphocytic bronchiti has be ·n attributed dire<:tl. ro GVHD. although
`du a sociation has not been confirmed by othct , [2 j.
`D . pite the tact that kidneys and heart can be targets for allogenc1c damage as
`evidenced by their rejection after renal and cardiac tran plants rcspecuv ly, there
`is no convincing evidence for direct renal or ~ardiac damage from acute GVHD
`that b not secondaf) to drugs or infection. Similarly. neurologu .. complications are
`tlso ornmon after Lransplantallon but most. can be attnbuted m drug toxicit).
`
`infection. or va-;cular in,ults.
`
`6.2.1.3 Differential Diagno is
`
`ut GVHD ought to be di tingui hed from any proce s that cau. es a con tella(cid:173)
`of fever. erythem:itous kin rash \\/Ith/or without lo\\-pre ,sure. and pulmonary
`that may occur during neutrophil rcco CI). Thi picture ma} reflect the
`m
`sregulated production of inflammatory cytokines and cellular re ponse to these
`lecule , and ha been termed engraftment or capillary leak ·yndromc [30, 31 ).
`pi ture i. mo,t clearly recognized after autologou~ transplantation where.
`retically, GVHD ,hould not occur. In allogene1c transplanl recipient distinc(cid:173)
`from acute GVHD b difficult. This engruftment yndrome is thought to reflect
`lular and cytokmc actl\•it1e during early reco..,ef) of (donor-d •rived) blood cell
`t and/or homeo ta1ic proliferation of lymphoqte . but a pre i e delineanon
`the offending cell. and rnechani rn. h~ not been accompli hed. Engraftment
`
`

`

`310
`
`J L. ~1 Ferrarn and P. Reddy
`
`... yn<lromes ma} be assol'.iatcd \\-tlh increased mo11~1lit). primarily from pulmonary
`failure and also (other) mulu-organ dysfunction. Corticosteroid therap} may be
`treatment of pulmonary manifestation!> [321.
`the
`ctfoi.:tivc partkularly for
`The differential c..hagno-.1s of skin rashes. diarrhea. and liver function abnonnalitie
`can be difficult to re:olve. Skin rashe:, may reflect delayed react10ns to the con(cid:173)
`dirioning regimen. antihiotics. or infections and furthermore histopath0Jog1c ·kin
`change, consi'>tent with acute GVHD can be mimicked by· chemoradiotherapy and
`drug reactions ll9. 33). Diarrhea can be a consequence of 181. viral infodions,
`c_pecially with C ·fV and other herpe-; viruses. para ... itc-.. Clmtridium difficiltt
`non pec1fic gastnti . narcotic withdrawal. and drug reacuons, all of which mimic
`GVHD of the gut. Liver dysfunction can be due to parenteral nutrition, VOD. viral
`or drug-induced hepatitis.
`
`16.3 Pathophysiology of Acute Graft-Versu -Host Disease
`
`It is helpful to remember t\a.:o important principle when con idering the patho(cid:173)
`physiolog) of acute GVHD. First. acute GVHD represents exaggerated but nonnal
`inflammatory re ponses agam,t foreign antigens (allo-antigcns) that are uhiqui(cid:173)
`tou 'ly expressed m a setting where they are undesirable. The donor lymphocyte
`that have been infused into the recipient function appropriately, given the foreign
`\!cond. donor lymphocytes en ounter ti ·ue in the
`environment they encounter.
`recipiem that have been often profoundly damaged. The effects of the underlying
`disease. prior infections, and the inten. it) of conditioning regunen all re ult_ in
`ub~tanlial change, not only in the immune cell. but a)so in the endothelial and
`rapidly encounter not only a
`the allogeneic donor cell
`epithelial cells. Thu
`foreign environment bur one that has been altered to promote the activation and
`proliferation of inflammatory celL. Thus. the pathophysmlog)' of acute GVHD
`may be considered a distortion of the normal inflammatory cellular respon. es that,
`in addition to the ab olute requirement of donor T cells, involves multiple other
`innate and adaptjve cells and mediators [34 ]. The development and evolution of
`acute GVHD can be conceptualized in three equential pha-,es (Fig. 16.1) to
`pro..,idc a unified per:pcctivc on the comple cellular interaction and inflamma(cid:173)
`tory cascade that lead to a ute G HD: ( 1) activation of the antigen-presenting
`celb (APC ); (2) donor T cell acuvation, differentiation. and migration; and
`(3) effe tor phase [341 It i · important to note that the three-phase de.cription 81
`di cu ed below allow for a unified perspective in understanding the biology. It is.
`however, not meant to ~ugge t that all three phases are of equal importance or that
`GVHD occurs in a step-wise and sequential manner. The patio-temporal rela-(cid:173)
`tion hip between the biological processes described below, depending on the
`context. are more likely to be chaotic and of varying inten ity and relevance in tbi
`induction, everity, and maintenance of GVHD.
`
`

`

`lb Cdlular I hemp~ 1lll Hemat11logy 'vl,1lig11,rnc1c,
`
`GVHO
`pathology
`
`( I) Recipient conditioning
`tls!:iue damage
`
`Host
`
`Small
`int
`tine
`
`fig. 16.1 P thuphy'>iology of GVHD: during 1ep I, irradiation anJ d1cmotherapy hoth dam.1ge
`and nctivate ho,1 tw;ue,. including intestinal muco,a, liver. and the ,kin. ,\<.:tivated cell ho,1, then
`se rcte inflammatory cvtokine'> k.g .. TNr-l'. and IL• I). which can be mea .. ured in the "}"temic
`circul tion. The C)1okin~ relea e ha important eftC(;t on APC-. of the ho l. mcludmg inaea ed
`expre, 10n ot adhe,1on molecule, <e g .• IC M-1, VCA\1-1) and of~IHC dm,s 11 antigen<;. Thee
`chan e, in the APC-. enhance the n:cogrution of hO'il MHC amVur mmor H antigen, by mature
`donor I t:elk Dunng ,tep ::!, dunm T cell .ict1va1ion 1, chara.:teriud by prolifl!falion of G\'HO T
`cell and .. e ri:non of multiple cytokine,. inducting 11.-2 and I , ·-:x. lndtKllon of CrL and '\K
`cell responses, and the priming of mononudeur phagoc)'te,;. [n <.tep ~- mononuch!ur cclb pmned
`by l~-:x and possibly orh~r C)10kme" are tnggered by a ~cond ignal ,ul ha~ endotoxm rlPS)
`rele cytopathi .. dlllOUnt-. of It I and T 'F-:i. LPS can leak through the mte unal muco~a
`lo
`damaged b~ thl' conchtwning regimen to <,t1mulate gut-a,.,ociatcd lymphoid fr,,ue ur Kup!fer c:elh
`in the hvec LP
`that penetrate the epidenni, may ,timulatc kcratinoq1e,. dennal fibrobl.1.'.>t. anc.J
`Jun. Thi, mcchani,m re ulb m the
`macr; phage'> to produce
`,imilar C)1okine, in
`th
`amplificauon cf local ti .. ue injury and funher production of mftamm,1tory effecrol"i such th
`nitnc o,nde. which. together v. 1th C..1L and NK effector . h:ud, lo the ()h,erved turger ti, ue
`de Ir\. tJon 1ry the ,tern cdl tran plant ho I (Tl_ effector, u-,e Fa.s/Fa.,L. ~rtorin/gran,ymc:: B. and ·
`mcm rane-bound cyto ine-, to ly..c target cell,
`
`A. Phw;e I· Acrfrarivn of cmti}l.e11-pre\e11ting cell'i
`The earlic t pha-.c of acute GVHD 1 initiated by