Xeno-transplantation PDF
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278 Current Topics in Microbiology and Immunology Editors R.W.Compans,Atlanta/Georgia M.D.Cooper,Birmingham/Alabama·Y.Ito,Singapore H.Koprowski,Philadelphia/Pennsylvania F.Melchers,Basel ·M.B.A.Oldstone,LaJolla/California S.Olsnes,Oslo·M.Potter,Bethesda/Maryland P.K.Vogt,LaJolla/California·H.Wagner,Munich Springer-Verlag Berlin Heidelberg GmbH D.R. Salomon · C. Wilson (Eds.) Xeno- transplantation With22Figuresand17Tables B D DanielR.Salomon,M.D. TheScrippsResearchInstitute DepartmentofMolecularandExperimentalMedicine MEM55,10550NorthTorreyPinesRoad,LaJolla,CA92037,USA e-mail:[email protected] CarolynWilson,M.D. U.S.FoodandDrugAdministration DivisionofCellularandGeneTherapies CenterforBiologicsEvaluationandResearch,FDA Building29B,Room2NN11 8800RockvillePike,HFM-530,Bethesda,MD20892,USA e-mail:[email protected] CoverIllustrationbyC.Wilson: Shownonthefrontcoverisafluorescentconfocalmicrograph(630x)ofHEK293cells productively infected with PERV-A (strain 14/220, provided by Clive Patience, Im- merge Therapeutics). Cells were immunostained as follows: 1) Green = Goat anti- simiansarcoma-associatedvirusgp70(whichcross-reactswithPERVgp70envelope) followed bya FITC donkey-anti-goat anti-serum (Jackson ImmunoResearch Labora- tories, Inc., West Grove, PA); 2) Red = Mouse monoclonal anti-human golgin-97 (Molecular Probes, Eugene, OR) followed by a Texas Red donkey-anti-mouse anti- serum (Jackson ImmunoResearch Laboratories, Inc., WestGrove, PA);and 3) Blue= Topro-3,afluorescentstainforthecellnucleus(MolecularProbes,Eugene,OR). ISSN0070-217X ISBN 978-3-642-62431-5 ISBN 978-3-642-55541-1 (eBook) DOI 10.1007/978-3-642-55541-1 LibraryofCongressCatalogCardNumber72-152360 Thisworkissubjecttocopyright.Allrightsarereserved,whetherthewholeorpartofthema- terialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,reci- tation,broadcasting,reproductiononmicrofilmorinanyotherway,andstorageindatabanks. Duplicationofthispublicationorpartsthereofispermittedonlyundertheprovisionsofthe German Copyright Law ofSeptember 9,1965, in itscurrent version,andpermission for use mustalwaysbeobtainedfromSpringer-Verlag.Violationsareliableforprosecutionunderthe GermanCopyrightLaw. http://www.springer.de (cid:2)Springer-VerlagBerlinHeidelberg2003 Originally published by Springer-Verlag Berlin Heidelberg New York in 2003 Softcover reprint of the hardcover 1st edition 2003 The use of general descriptive names, registered names, trademarks, etc. in this publication doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfrom therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. Typesetting:St(cid:3)rtzAG,W(cid:3)rzburg CoverDesign:Design&ProductionGmbH,Heidelberg ProductionEditor:Ang(cid:4)liqueGcouta,Berlin Printedonacid-freepaper SPIN:10835211 27/3020 543210 Forward Theadventoftransplantationsurgeryhasheraldedsignificantadvancesin medical therapy. The limiting factor is no longer the technical surgical procedure but the accompanying suppression of the recipient(cid:5)s immune responsethatisoftenrequiredandtheavailabilityorlackofavailabilityof donor tissues/cells for transplantation. One approach to this dilemma is the use of donor tissues from non-human species. The “Certain Promise and Uncertain Peril” of xenotransplantation as addressed by Robin Weiss in several of his earlier thoughtful papers sets the foundation for this de- bate. The issues of this debate are clearly addressed by eight knowledge- able workers in the area who participate in this interesting and important scientificandethicaldiscussionasco-ordinatedbytheguesteditorsofthis volume, Daniel Salomon from the Department of Molecular and Experi- mentalMedicineatTheScrippsResearchInstitute,andCarolyn Wilsonof the United States Food and Drug Administration. Both Drs. Salomon and Wilson have credentials in and have explored this ongoing debate at the scientificandadministrativelevelandareawareof thegermaneissuesen- compassing this field. As such this volume will provide a necessary back- ground for those interested in understanding the pros and cons of this medicaldilemma. MichaelB.A.Oldstone LaJolla,California Preface The purpose of the present book is to provide the reader with a series of discussions updating a numberof critical issues raised byclinicaltrials of animal cells, tissues and organs transplanted into humans — xenotrans- plantation.Obviously theprimary focusisonissuesofpotentialinfectious diseaseexposureraisedbyxenotransplantation.However,wherenecessary, wehaveincludedappropriatediscussionsoftheimmunologicalbarriersin xenotransplantation to help the reader understand the various immuno- suppressive strategies that will be required for successful clinical trials. A key point is that any consideration of infectious disease risks in this area must be seen in the context of fully and aggressively immunosuppressed patients. A few general ideas are appropriate to consider here so as to help pro- videthereaderwithaperspective. Infectious disease risks are part of living in our world. The movement of pathogens from animal reservoirs to human beings is a regular pheno- menon. Therefore, it is important to start byconsidering what kind of in- fectious disease risks are the specific issues for xenotransplantation. In other words, to phrase the questions in a proper perspective we need to ask: “What are the incremental risks of moving animal pathogens to hu- manswhicharecreatedbyxenotransplantation?” Many animal-to-human infections comprise the natural life cycle of certain pathogens (i.e., malaria or West Nile fever) that move regularly through animal and human hosts. Infection of human hosts with animal- bornepathogensduetocloselivingcontactsuchashappenswithhunting, animal husbandry, food preparation and food contamination are often re- ferred to as zoonoses or zoonotic infections (i.e., Ebola, Hanta virus and anynumberofparasiticinfectionsendemictoanimals).Theseformsofin- fectious disease have really little or nothing to do with our risk concerns for xenotransplantation. Basically, an animal herd designated as suitable forharvestingtissuesororganswillbederivedandmaintainedundercon- ditions in which known zoonotic agents will be eliminated from the herd. Indeed, considerable work has been doneworldwide in collaborationwith many experts in infectious disease and veterinary medicine to establish a set of guidelines for maintaining and screening animal herds suitable VIII Preface for xenotransplantation (for an example of what has been done in the UnitedStates,see“GuidelineonInfectiousDiseaseIssuesinXenotransplan- tation”http://www.fda.gov/cber/gdlns/xenophs1000.htm). In contrast, the infection of a human patient specifically by xenotrans- plantation is referred to as a xenogeneic infection or xenozoonosis. Xeno- geneicanimal-to-humaninfectionswilllargely involvepotentialpathogens containedinanimaltissuesthatwouldnotnormallyspreadtohumansbut couldbecarriedoverintheprocessoftransplantingtissuesororgans(i.e., porcine CMVor exogenous retroviruses in nonhuman primates). The do- noranimalswillnotbesickatthetimeoftransplantationandinmany in- stancesthepathogenwillnotproducediseaseinthedonoranimalbutonly intherecipienthumanpatient.Thecentralexamplefor xenotransplantati- on is the potential of transmitting endogenous retroviruses such as por- cine endogenous retrovirus (PERV) frompigs to humans. Endogenous re- troviruses have been incorporated into the donor animal(cid:5)s germ line and thereforecannotbeeliminated.Inmostcases,endogenousretrovirusesdo notproduceany pathology inthehostanimal.Nonetheless,porcineendo- genousretrovirusesretaintheability toinfectthecellsandtissuesofother speciesincludinghumans.Thisthenisagoodexampleoftheriskofxeno- transplantationthatistheissueathand. At the beginning of any clinical trial is a decision based on risk versus benefit. Simply put, if xenotransplantation has no chance of benefit then eventhe smallest risk is unacceptable. Unfortunately, there has been a se- riesofscientificsetbacksinxenotransplantationover thelast5years.Spe- cifically, the preclinical large animal experiments transplanting genetically engineeredpigheartsandkidneysintomonkeysandbaboonshavenotde- monstratedsurvivalofthexenograftsbeyondweekstoafewmonths.Also, a very well-designed trial of implanting pig fetal neural cells into patients with neurological disease was not successful. As a consequence, the cur- rentsituationforxenotransplantationsuggestslittlebenefitand,thus,infi- nite risk. Therefore, some critics have concludedthat there is no future to this procedure and further considerations of risk are unnecessary. We re- jectthisviewasshortsighted. Xenotransplantation, like manyendeavors atthe cutting edges of medi- cal science, has tremendous potential. The critical donor organ shortage for humantransplantationis suchthatthousandsof patientsdie eachyear waiting for a transplant, and millions of patients with diabetes that could benefit from a successful islet transplant will wait for their chance at the few thousand usable pancreata available each year. Therefore, it would be ridiculous to ignore the tremendous impetus to solve the problems and make xenotransplantation successful. History cautions us to take the lon- ger view where the temporary ups and downs of progress eventually lead to success. Thus, no one is likely to abandon the search for a cancer cure that has eluded us many decades longer than xenotransplantation despite Preface IX investment of substantially more resources. In other words, xenotrans- plantationresearchwillcontinue.In fact,aseries of12childrenwithjuve- nile onset diabetes mellitus underwent pig islet transplantation in Mexico last year and a report of successful pig liver cell transplantation has come out of China. In the United States, a number of small clinical xenotrans- plantation trials are underway using various pig cells, some in devices. Therefore, clinical trials in xenotransplantation are reality, not fantasy. Thatsomeofthesetrialsarebeingdoneinothercountrieswhereregulato- ry oversight and scientific resources are limited is even greater reason for concern. Risk also has several unique elements that are necessary to consider for xenotransplantation. The classic risk for a clinical trial is based on concerns for the individual patient. For example, a risk could be a side effectofanewdrugoranunexpected,adversereaction.Inxenotransplan- tation, the individual risk could be that the organ is rejected or never worksproperly.Fromaxenogeneicinfectiousdiseaseviewpoint,theindi- vidual risk could be that a xenotransplant transmits an animal pathogen and results in a human illness. In the case of an endogenous retrovirus this could bea form of cancer such as lymphoma or leukemia. Individual riskcanbedealtwithby proper informedconsent.Whilethisis animpe- rfectprocedure,it isonethathasbeenreviewedandcontinuously refined in clinical trials for many years. The interesting element of risk in xeno- transplantation is public risk — the potentialthat a xenogeneic pathogen willstart inthepatient andthen spreadto closecontacts, medicalprofes- sionals and the public. There is no instrument like an informed consent document to deal with public risk. Thus, while a patient dying of liver failure could make an informed decision to personally accept the risks of apigliver transplant,neitherthispatientnor thefamilycouldeveraccept any risk for transmission of a pathogen from the pig liver to the public. Atpresent,itisthenatureofthepublichealthriskinxenotransplantation thatisamajorissue. From our view, the only way to deal responsibly withthe public health riskof xenotransplantation is to engage in awide-ranging, science-based, public discussion of this risk. Thus, the present volume reviews what is known at this time about a number of potential xenogeneic risks and at- tempts wherever possible to point in the favored directions for future re- search. The hardest thing to define is an unknown risk. Thus it is one thing to be faced with the current AIDS pandemic and search originally to identify the new pathogen (i.e., HIV) and then develop strategies to control, treat and cure the disease. It is entirely another thing to be faced with a theoretical risk of a theoretical infection. Nonetheless, that is the current state of affairs in xenotransplantation. It does not change our re- sponsibility tothepublictodoeverythingpossibletoinsurethesafecon- duct of any clinical xenotransplant trial including those that are already X Preface underway. In this respect, we believe that more scientific knowledge is necessary to inform any debate of risk in xenotransplantation. With knowledge the risks can be placed in a propercontext and science-based evaluations of risk versus benefit can be made for xenotransplantation clinicaltrials. May2003 DanielR.SalomonandCarolynA.Wilson List of Contents GeneticModificationofXenografts J.L.Platt.................................................. 1 PublicHealthRisks–Patientvs.SocietyinanEmergingField L.E.Chapman .............................................. 23 Cross-SpeciesInfections R.A.Weiss ................................................. 47 Non-HumanPrimateHerpesviruses:Importancefor Xenotransplantation M.G.Michaels ............................................. 73 UnderstandingXenotransplantationRisksfromNon-HumanPrimate Retroviruses J.S.Allan ................................................. 101 ExogenousPorcineViruses P.S.Paul,P.Halbur,B.Janke,H.Joo,P.Nawagitgul,J.Singh, andS.Sorden ............................................. 125 SwineHepatitisEVirus:Cross-SpeciesInfectionandRiskin Xenotransplantation X.J.Meng ................................................. 185 MolecularCloningandFunctionalCharacterizationofInfectious PERVandDevelopmentofDiagnosticTests M.NiebertandR.R.T(cid:2)njes ................................. 217 Xenotransplantation–FederalRegulatoryConsiderations E.T.Bloom ................................................ 239 SubjectIndex .............................................. 253
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