JonesThe prospects for in utero stem cell transplantation The prospects forin utero stem cell

transplantation

DRE Jones

Department of Immunology, University Hospital, Queen’s Medical Centre,Nottingham, NG7 2UH, UK

In utero transplantation of haematopoietic stem cells into the foetus, earlyin gestation, offers a new approach to genetic disorders. Immunologicalnaivete and the sterile uterine environment are perfect conditions fortransplantation, so that even mismatched cells will engraft. There havebeen notable successes world-wide, although numbers are small, whichgives encouragement to further work directed at means to enhance andsustain engraftment in a foetal recipient. For example, stem cells fortransplant can be obtained from various sources but these have differentproperties that can be exploited for therapy in specific disorders. However,some disorders may not be amenable to in utero transplantation and thereis need to achieve consensus in order to ensure that the procedure is usedappropriately, for the benefit of all.

Keywords:foetus, haematopoiesis, haematopoietic stem cells, immune system,transplantation

Exp. Opin. Invest. Drugs (1998)7(11):1819-1824

1. Introduction

Our ability to obtain an accurate diagnosis of a genetic disorder early inpregnancy has progressed rapidly within the past decade. Accurateprenatal diagnostic procedures can now give parents a welcome reassur-ance but it has also provided them with the option to terminate a pregnancyif a life-threatening condition is confirmed. With the current interest infoetal medicine, the prospect of therapeutic intervention early inpregnancy, to correct at least some of these disorders, has become a reality.One of the therapeutic options that has generated much enthusiasm is thatof stem cell transplantation into the foetus, in utero. The first trimesterhuman foetus is an ideal transplant recipient because the foetal immunesystem has not yet developed the ability to recognise foreign material (i.e.,‘non-self’) and to initiate a defensive response: a state of immunologicalnaiveté. Thus, even mismatched cells can engraft after a transplantprocedure in utero. This principle was demonstrated in 1945 by Owen, intwin cattle that shared a blood circulation but with no adverse effects [1]:one twin being tolerant to the other’s blood group type (haematologicalchimerism). The small size of the first trimester human foetus determinesthat relatively few cells (relative to, for example, a bone marrow transplantin postnatal life) can be infused in an in utero transplantation (IUT)procedure. The haematopoietic stem cell (HSC) is the ideal vehicle for inutero correction of a haematopoietic disorder diagnosed early in pregnancybecause it alone is able to generate all blood cell lineages; having beenaptly described as the mother of all cells [2]. The IUT procedure itself is

18191998 © Ashley Publications Ltd. ISSN 1354-3784

Review

1. Introduction

2. Why intervene in utero?

3. Targets for in uterotransplantation

4. Current strategies for inutero transplantation

4.1 Sources of haematopoieticstem cells

4.2 Transplant protocols

5. Expert opinion

6. Conclusion

Bibliography

http://www.ashley-pub.com

Expert Opinion on Investigational Drugs

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straightforward: cells are injected directly into thefoetal abdominal cavity under ultrasound guidance(infused HSC will home to the sites of haematopoieticactivity) and thereafter, the pregnancy is monitored inthe usual way. Already, there have been a number ofsuccesses reported after HSC transplantation in utero[3] and interest in using the procedure for a greatervariety of disorders is increasing [4]. However, thereare a number of questions remaining to be addressedbefore in utero transplantation (IUT) can be offeredroutinely and then move out of its current niche as anexperimental technique.

2. Why intervene in utero?

A confirmed diagnosis in a suspected genetic disordercan now be achieved at around 12 weeks gestation,by obtaining a small sample of tissue from thechorionic villi. Thus, parents are able to make an earlydecision regarding the future of their baby andwhether they wish to continue with the pregnancy.The timing of the diagnostic procedure is importantfor any potential therapeutic strategy being consid-ered. A number of haematopoietic disorders that canbe diagnosed at 12 weeks gestation may not yet havehad time to produce the pathological manifestationsthat ultimately could cause either severe disability orfoetal death. Thus, IUT has the potential to alter thecourse of a disorder and can be viewed as prevention,rather than a cure: this is the exciting challengeoffered by the procedure. A bone marrow transplantin postnatal life is performed after the recipient hasbeen conditioned: chemotherapy, perhaps inconjunction with radiotherapy/immunotherapy, isused not only to eradicate the underlying disease butalso to create space for the incoming donor cells.During the first trimester, spaces are developingwithin the foetal bone marrow, in readiness for futurehaematopoietic activity. If donor cells arrive to occupythese niches, haematopoietic development canproceed normally and depending on the nature of thegenetic defect, completely supplant the defectiverecipient cells. However, timing can be crucial. Up toapproximately 15 weeks gestational age, haemato-poiesis in the human foetus occurs solely within theliver and thereafter, migration of HSC to seed thespleen, thymus and bone marrow occurs [5].Throughout the first trimester, the liver is the engineroom of blood cell development and it continues toprovide all of the blood cells required for normalphysiological function until near to term, i.e., even

after haematopoiesis is actively proceeding within thebone marrow [6]. This requires different approachesto IUT for dyserythropoietic disorders (such as thethalassaemias) and for disorders of the myeloid orlymphoid lineage (such as some inherited metabolicdisorders and immunodeficiency states). Iftherapeutic intervention in utero is to be effective in,for example, a haemoglobinopathy the transplantedcells must engraft in the liver: they must go to thetissue that provides blood cells for the rapidlydeveloping foetus. Stem cells engrafting in thedeveloping bone marrow will not contribute tohaematopoiesis and the pathological sequelae of thedisorder will continue unabated. If a prenataldiagnosis can be obtained by the end of the 12th weekof a pregnancy, there is adequate time for donor HSCto be transplanted in utero before seeding of the bonemarrow begins. However, in the case of somemyeloid/lymphoid disorders, engraftment within thebone marrow can be efficacious because (undernormal circumstances) the foetus does not require themeans to fight infection until postnatal life. Thus,although the engrafted cells are not contributing tothe circulating blood cell pool they will developnormally and occupy niches within the bone marrowin preparation for the development of a fullyfunctional repertoire during the postnatal period.

3. Targets for in utero transplantation

The current status of IUT indicates that there are 2broad categories of disorder that are amenable to suchtherapeutic intervention: haemoglobinopathies andimmunodeficiencies. The metabolic disorders remainoutside the scope of IUT procedures, at least for thepresent. This is because such conditions represent awide spectrum of pathology, which can include veryearly onset and lesions in a variety of tissues.Currently, the most successful IUT procedures havebeen those performed in cases of severe combinedimmunodeficiency (SCID). There have been 6 cases ofIUT for SCID world-wide and of these, 5 were deemedsuccessful (one resulted in elective termination)[3,7,8]. These SCID cases are being seen as the successstory on which the future of IUT will rest. However, itmust be remembered that in these cases, the foetalrecipient is not only immunologically naive beyondthe first trimester but is also, through the very natureof the genetic defect, in a state of continued immuno-suppression. This gives the donor cells a distinctadvantage. The indigenous cells are unable to

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1820 The prospects for in utero stem cell transplantation

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proliferate and to occupy the thymic environment(and thence, to establish the immune repertoire)because a molecular defect does not enable cell-cellsignalling to be accomplished. The donor cells, withintact signalling mechanisms, are able to establishcommunication with each other and with the stromalmicroenvironment; proliferative signals areexchanged and engraftment proceeds. There is anempty niche to fill, because the indigenous(lymphoid) population is not able to develop. In thecase of haemoglobinopathies, there is a differentscenario. If a genetic defect prevents the assembly of afunctional haemoglobin molecule, the foetus cannotprovide oxygen for the rapidly growing tissues and toredress this deficiency there is vigorous compensatoryerythropoiesis. Thus, all of the spaces that donor cellscould use for engraftment are occupied and competi-tion is intense; there is little selective advantage overthe indigenous population. However, if the donorHSC are able to engraft, it is likely that they willgradually develop the selective advantage required tosustain sufficient numbers and be of therapeuticvalue, due to the normal lifespan of their progenyrelative to the (shorter-lived) indigenous cells. Dataobtained from adult bone marrow transplant recipi-ents suggest that 10 - 20% donor cell engraftmentmight be sufficient to achieve amelioration of thepathological sequelae of a serious haemoglobino-pathy [9]. Thus, and in contrast to the SCID patients,100% engraf tment is not essent ia l in thehaemoglobinopathies.

4. Current strategies for in uterotransplantation

4.1 Sources of haematopoietic stem cells

IUT procedures that have been performed thus farhave used HSC from either bone marrow (usuallypaternal, to avoid unnecessary trauma to the pregnantmother), or from foetal liver [3]. This latter sourceposes considerable ethical dilemmas, not leastbecause the tissue is retrieved from material obtainedafter termination of a (normal) pregnancy. However,HSC derived from different sources are likely to beuseful for different disorders because of the lineagecommitment inherent in the different cell types.Human foetal liver-derived HSC are committed toerythroid production until around the 14th or 15thgestational week, when there is a dramatic change inlineage commitment to encompass all cell types [5].

Thus, first trimester human foetal liver represents aunique source of HSC and the lineage commitmentmakes these cells ideal for IUT in a foetus diagnosedas having a serious haemoglobinopathy. The foetalHSC can be cryopreserved for long periods withoutloss of viability or growth characteristics [5,10]. IUT forSCID, however, does not require the donor cells to becommitted to the erythroid lineage, nor do the donorcells require engraftment within the recipient liver.The defective (recipient) immune system is notrequired to actively participate in host defence untilterm, so donor HSC engrafting within the developingbone marrow will gradually fill the expanding nicheswith normal progeny. Thymic education of thelymphoid cells produced will continue and a fullycompetent immune repertoire will be available at, orclose to, term.

There has been much criticism levelled at the use offoetal liver-derived HSC on scientific grounds. Thissource of HSC is non-renewable, so a repeattransplant from the same donor, if engraftment cannotbe demonstrated, is not possible. One of the goals ofstem cell biologists is to be able to expand stem cellsin vitro and, therefore, to provide an infinite source ofHSC from, for example, tissue culture systems.However, this has been fraught with problemsbecause HSC may lose their self-replicating abilitywhen cultured ex vivo for long periods [11] and thiswill result in a lack of sustained engraftment in foetalrecipients [12]. If the molecular events that commitfoetal liver HSC to erythroid production can beunravelled and thence manipulated in other sourcesof HSC, it may be possible to engineer stem cells tosatisfy the clinical application for which they areneeded. Clearly, the most useful source of HSC wouldbe those obtained from umbilical cord blood. This is avaluable resource, it is discarded at birth and its usedoes not generate the ethical dilemmas that surroundfoetal liver-derived HSC. Engineering umbilical cordblood HSC to alter lineage commitment is a worthygoal of the stem cell biologists and is currently thesubject of intense study. To date, umbilical cord HSChave not been used for human IUT, althoughoutcomes of postnatal transplants using this resourcehave been encouraging, particularly in paediatricmedicine [13]. It has recently been shown that evencells obtained from the CD34-negative fraction ofadult bone marrow can engraft in foetal recipients,providing CD34+ progeny and sustaining donor-derived haematopoiesis [14], thus revealing that weare still learning about the biology of stem cells.

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4.2 Transplant protocols

Because the number of IUT procedures world-wide islow (around 30, at time of writing) it is not possible tooffer opinion on the optimal procedure(s) to ensuresuccess in every case. Furthermore, differences suchas source and number of cells, transplant regimens,etc., make even comparisons between IUTprocedures for the same disorder at different centresimpossible. Certainly, the most outstanding successeshave been reported in those cases of SCID,transplanted in utero, where paternal bone marrow-derived HSC were used as the vehicle for engraftment[7,8,15]. One child, who is now over 3 years of age, isable to provide T-cell help (i.e., donor-derived) forclass-switching by indigenous B-cells and, thus, is notdependent on iv. immunoglobulin; in contrast to mostcases of SCID transplanted with bone marrow postna-tally [Flake A (1998); personal communication].However, these IUT cases have used a multipleinfusion regimen, i.e., HSC were infused on 2 or 3occasions over a 2 or 3 week period, in order toenhance the chances of engraftment occurring attherapeutic levels. The rationale for such multi-injections regimens is unclear but it has beenindicated that repeated injections of HSC will enablethe developing bone marrow niches to be filled withdonor cells, as they become available [16]. Definitiveevidence for this approach is sparse and because eachin utero injection will introduce a risk to the foetus,there is need to develop a standard protocol thatavoids the multi-injection regimen. Another approachto the enhancement of engraftment has been throughup-regulation of the donor HSC proliferative capacityby incubation in vitro, prior to transplant, with variouscytokines [17,18]. In this way, HSC could be investedwith a selective advantage over the indigenous cellpopulation by being primed for enhanced prolifera-tive capacity prior to the transplant. More work isneeded to determine the effects on long-term(sustained) engraftment, using animal models, beforesuch strategies can be used in human foetal recipients.Ethical constraints on the utilisation of specific growthfactors in a foetal patient might restrict the use of suchstrategies to experimental animal studies.

It is unlikely that bone marrow-derived HSC willprove efficacious for IUT in cases of haemoglobino-pathy. These cells will home to the developing foetalbone marrow, where they will become only arelatively minute proportion of the total HSC pool.This is insufficient to ameliorate the potentially lethaleffects of a serious haemoglobinopathy. Indeed, all of

the IUT procedures thus far described for thesedisorders have been unsuccessful [3], although furthercases continue to be reported [4,19]. Foetal liver-derived HSC hold great promise for IUT in thehaemoglobinopathies, due to their erythroid commit-ment [5] and their being sufficiently robust towithstand frozen storage for long periods withoutdetriment [10,20]. However, to date, human casereports are not encouraging: in few cases has therebeen any effect on the outcome of the disorder or,indeed, evidence of engraftment [3]. The animalmodels of IUT that use foetal HSC as the transplantvehicle are encouraging and indicate that functionaldonor-derived haematopoiesis is possible when thesecells are transplanted [4,21]. However, the vigorouscompensatory erythropoiesis in a human foetalrecipient with a haemoglobinopathy is a seriousimpediment to clinically relevant engraftment bydonor HSC and novel, but ethically acceptable strate-gies will be needed if a successful outcome is to beachieved.

When donor HSC have a selective advantage overindigenous cells, they will enter the cell cycle andtheir progeny occupy all available niches within thelymphohaematopoietic tissue of the recipient. Duringthe course of this engraftment process, donor-derivedhaematopoietic cells would be expected to proliferatemore rapidly than those of the recipient. Suchproliferative activity comes at a cost: there is a finitelimit to the number of cell divisions that can beundertaken. A recent report provided worryingevidence that this proliferative activity in a recipientcould result in long-term damage to the haemato-poietic effort due to increasing instability in DNArepair [22]. Cell division is influenced by telomeres:chromatin structures consisting of non-coding repeatsof the sequence, TTAGGG. During DNA synthesis, themost distal (telomeric) nucleotides in the laggingsingle-stranded end cannot be replicated and so,shorten with each cell cycle. This phenomenonconfers mortality on the cell [23]. It is of interest thatfoetal HSC possess telomeres that are significantlylonger than those found in stem cells obtained fromboth umbilical cord and adult bone marrow,suggesting enhanced proliferative potential over alonger time-period [24].

No metabolic disorders have yet been successfullytransplanted in utero, either with foetal liver-derivedor with bone marrow-derived HSC [3].

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1822 The prospects for in utero stem cell transplantation

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5. Expert opinion

The two categories of disorder that will determine theutility (and the future) of IUT procedures arehaemoglobinopathies and immunodeficiencies.Differences in the therapeutic approach to these twobroad categories serve to highlight the emphasis thatmust be placed on the source of stem cells for IUT.There must also be a consideration of protocols.Currently, procedures are empirical and for example,there appears to be little scientific basis for the use ofmultiple injections of donor cells into a foetal patient.A (postnatal) bone marrow transplant or infusion ofperipheral blood stem cells is conducted as a singleprocedure and the patient is conditioned in the sameway as the foetal recipient: an empty marrow awaits.

Immunodeficiency disorders are proving to beamenable to transplantation in utero, althoughnumbers of cases are small at present. The advantagesof therapy in utero for these cases includes the naturalsterile environment that precludes opportunisticinfection during immune reconstitution, posttransplant. If HSC are harvested from the paternalbone marrow donation, some of these cells can bestored frozen to provide material for a further(postnatal) transplant, should this prove necessary.However, established practice shows that a successrate of up to 90% for postnatal bone marrowtransplant in cases of SCID can be achieved, whichmakes it difficult to persuade clinicians that IUT is apractical therapeutic option. However, it must beremembered that such success can only be attained ifa full HLA-matched related donor is available and thisis all too rarely possible. Such a close match is notmandatory when performing the transplant in utero.

Therapeutic success in the haemoglobinopathiesmust be the great goal of IUT. These disorders can bediagnosed early in gestation (approximately 12weeks) and can be transplanted using HSC fromnormal donors. Complete (i.e., 100%) engraftment isnot necessary (as in SCID) because experience frompostnatal bone marrow transplantation indicates thatchimerism need only be partial. Therefore, earlytherapeutic intervention, with erythroid-committedHSC is the optimal strategy. However, caution must beexercised. Not all of the haemoglobinopathiesdiagnosed at 12 weeks gestation will be suitable forIUT. Sickle cell anaemia, whilst eliciting emotivereactions, does not have a predictable outcome andtherefore, may not be an appropriate first choice forIUT in a haemoglobinopathy. Gene therapy has been

suggested to be the ultimate goal for haemoglobino-pathy in utero but this strategy is a long way fromreality. The problems are legion: from obtaining anappropriate gene construct to inserting this into anon-dividing stem cell. The impediment to engraft-ment of such modified HSC are identical to thoseconfronting IUT with unmodified stem cells: how toovercome indigenous compensatory erythropoiesis.Some form of conditioning will be mandatory but notthe cytoablative regimens used in postnatal bonemarrow transplants. Clearly the fragile developingfoetus warrants a distinctly different approach andresearch must be undertaken in this area if futuresuccess is to be guaranteed.

6. Conclusion

In utero stem cell transplantation is being viewed as aviable alternative strategy for a growing number ofconditions that can now be diagnosed early inpregnancy. However, more research is needed beforeconsensus is reached on topics such as the optimalcell preparation, the timing of the transplant andconditioning of the foetal patient. There is a pressingneed to record all procedures carried out: thesuccesses as well as the perceived failures, so that allthose working in the field may benefit from previouswork. It is to be hoped that as IUT enters therepertoire of foetal medicine, its use will be extendedand that it will not be seen as just an esotericprocedure applicable in a few rare disorders. Asuccessful IUT procedure, with adequate andfunctional engraftment of donor cells can haveenormous cost benefit to health service providers.

Bibliography

Papes of special note have been highlighted as:• of interest•• of considerable interest

1. OWEN RD: Immunogenetic consequences of vascularanastomoses between bovine twins. Science (1945)102:400.

• Seminal paper that is often cited as one of the basic tenets ofimmunology.

2. KLING J: Gene transfer to the mothers of all cells. Na-ture Biotechnol. (1996) 14:269.

•• Good review article, indicating what problems lie ahead forgene therapy.

3. JONES DRE, BUI TH, ANDERSON EM et al.: In utero hae-matopoietic stem cell transplantation: current

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perspectives and future potential. Bone Marrow Trans-plant. (1996) 18:831-837.

•• Thorough review of the state of the art for in utero transplan-tation. All cases recorded by mid-1996 are reported in thisarticle and comment provided on the outcomes in each dis-ease category.

4. JONES DRE, BUI TH: Fetal therapy: prospects for trans-plantation early in pregnancy. Mol. Med. Today (1998)4:10-11.

• Report of the Second International Symposium on In UteroTransplantation and Gene Therapy, held in Nottingham,UK, in September 1997. An up-to-date account of cases andoutcomes and insights into current research in this area.

5. JONES DRE, ANDERSON EM, EVANS AA, LIU DTY: Long-term storage of human fetal hematopoietic progenitorcells and their subsequent reconstitution - implica-tions for in utero transplantation. Bone Marrow Trans-plant. (1995) 16:297-301.

6. ZANJANI ED, ASCENSAO JL, TAVASSOLI M: Liver-derivedfetal hematopoietic stem cells selectively and prefer-entially home to the fetal bone marrow. Blood (1993)81:399-404.

• Seminal paper showing the route of engraftment of cellstraansplanted in utero. Uses an animal model.

7. FLAKE AW, PUCK JM, ALMEIDA-PORADA G et al.: Treat-ment of X-linked severe combined immunodeficiencyby in utero transplantation of paternal bone marrow.New Engl. J. Med. (1996) 335:1806-1810.

• First report of 100% success using IUT for SCID.

8. LANFRANCHI AA, NEVA K, TETTONI R: In utero trans-plantations (IUT) of parental CD34+ cells in three pa-tients affected by primary immunodeficiencies. BoneMarrow Transplant. (1998) 21:S127.

• Three cases of SCID transplanted in utero, again reportingsuccess.

9. ANDREANI M, MANNA M, LUCARELLI G et al.: Persistenceof mixed chimerism in patients transplanted for thetreatment of thalassemia. Blood (1996) 87:3494-3499.

10. ANDERSON EM, JONES DRE, LIU DTY, EVANS AA: Gesta-tional age and cell viability determine the effect of fro-zen storage on human fetal hematopoietic progenitorcell preparations. Fetal Diagn. Ther. (1996) 11:427-432.

11. BREEMS DA, BLOKLAND EAW, SIEBEL KE et al.: Stroma-contact prevents loss of hematopoietic stem cell qual-ity during ex vivo expansion of CD34(+) mobilized pe-ripheral blood stem cells. Blood (1998) 91:111-117.

• Important paper discussing the impact of ex vivo expansionprotocols on the quality of stem cells (and by implication,the effects this will have on engraftment after a transplantprocedure).

12. SHIMIZU Y, OGAWA M, KOBAYASHI M, ALMEIDA-PORADA G, ZANJANI ED: Engraftment of cultured hu-man hematopoietic cells in sheep. Blood (1998)91:3688-3692.

13. GLUCKMAN E, ROCHA V, BOYER A et al.: Outcome ofcord-blood transplantation from related and unre-lated donors. New Engl. J. Med. (1997) 337:373-381.

14. ZANJANI ED, ALMEIDA-PORADA G, LIVINGSTON AG,FLAKE AW, OGAWA M: Human bone marrow CD34(-)

cells engraft in vivo and undergo multilineageexpression that includes giving rise to CD34(+) cells.Exp. Hematol. (1998) 26:353-360.

15. WENGLER GS, LANFRANCHI A, FRUSCA T: In utero trans-plantation of parental CD34 haemaopoietic progeni-tor cells in a patient with X-linked severe combinedimmunodeficiency (SCIDXI). Lancet (1996) 348:1484-1487.

• A successful foetal SCID patient transplanted in utero.

16. FLAKE AW, ZANJANI ED: In utero hematopoietic stemcell transplantation. A status report. J. Am. Med. Assoc.(1997) 278:932-937.

• A good review outlining the advantages and drawbacks ofthe various in utero protocols.

17. ZANJANI ED, ASCENSAO JL, HARRISON MR, TAVASSOLIM: Ex vivo incubation with growth factors enhancesthe engraftment of fetal hematopoietic cells trans-planted in sheep fetuses. Blood (1992) 79:3045-3049.

18. FLAKE AW, ZANJANI ED: In utero transplantation of he-matopoietic stem cells. Crit. Rev. Oncol. Hematol. (1993)15:35-48.

19. MONNI G, IBBA RM, ZOPPI MA, FLORIS M: In utero stemcell transplantation. Croat Med. J. (1998) 39:220-223.

20. MYCHALISKA GB, MUENCH MO, RICE HE et al.: The biol-ogy and ethics of banking fetal liver hematopoieticstem cells for in utero transplantation. J. Pediatr. Surg.(1998) 33:394-399.

21. JONES DRE, LIU DTY, ANDERSON EM, LAMMING GE:Transplantation of human fetal liver-derived haema-topoietic stem cells into sheep, in utero. In: Correctionof Genetic Disorders by Transplantation (Vol. IV). RingdonO, Hobbs JR, Steward CG (Eds.), COGENT Trust, London.(1997):130-136.

22. WYNN RF, CROSS MA, HATTON C et al.: Accelerated telo-mere shortening in young recipients of allogeneicbone-marrow transplants. Lancet (1998) 351:178-181.

•• Important data relating to the fate of stem cells after trans-plantation. Accelerated proliferation of these cells in the re-cipient could lead to their premature demise.

23. SHAY JW: Accelerated telomere shortening in bonemarrow recipients. Lancet (1998) 351:153-154.

•• Good review of the telomere theory: reasons why stem cellsare restricted to a finite number of cell divisions and howthis process could be accelerated in transplant recipients.

24. LANSDORP PM: Telomere length and proliferation po-tential of hematopoietic stem cells. J. Cell Sci. (1995)108:1-6.

•• Excellent report on telomeres in stem cells from varioussources and the implications for transplantation. The supe-rior qualities of foetal stem cells are clearly shown.

DRE JonesDepartment of Immunology, University Hospital, Queen’s MedicalCentre, Nottingham, NG7 2UH, UK

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