OPINION: Xenotransplantation and other means of organ replacement

154 | NOVEMBER 2001 | VOLUME 1 www.nature.com/reviews/immunol

P E R S P E C T I V E S

various alternatives to transplantation, suchas cellular therapies and organogenesis,might be applied in the future, it is impor-tant to consider how these technologiesmight develop in the next few years.

Cellular therapiesOne promising approach to replace or aug-ment the function of an organ is cellular trans-plantation, which involves the injection of cellsthat have the potential for replacing cells dam-aged or destroyed by disease. For example,recent studies have shown that skeletalmyoblasts (primitive muscle cells) or stemcells of various types can be transplanted intothe damaged heart, and on healing, the trans-planted cells assume the function of cardiacmyocytes and can augment cardiac functionreplacement2–4. As another example, isolatedhepatocytes or stem cells can be transplantedinto the liver to address genetic defects5,6. Oneadvantage of using stem cells is the possibilitythat the cells might be taken from the affectedpatient, therefore obviating immune responseto foreign cells. Reports indicating that suchcells can be derived from the bone marrow7,central nervous system8 or fat9 of individualsare encouraging. Cellular transplantation doeshave limitations, however. For example, itmight not be possible to improve the functionof structurally complex organs, such as thekidney or lung. In addition, cellular transplan-tation might prove ineffective in diffuse dis-eases, such as myocarditis, amyloidosis andportal hypertension.Another limitation is thatdifferentiated cells and stem cells from matureindividuals have a limited proliferative poten-tial and might therefore not be capable

seen as the best alternative to allotransplanta-tion, which can only address a small fractionof the need because there are severe shortagesof human hearts available for transplantation.However, there has been substantial progressin both the development of mechanicaldevices that can be used to supplement car-diac function and in the development of atotally artificial heart1. Furthermore, cellulartherapies might offer an alternative approachto augment cardiac function and avoid car-diac replacement2–4. So, the need for whole-organ cardiac transplants might conceivablydiminish over time. By contrast, in the case ofthe kidney and the lung, no fully implantabledevices exist, and there is little prospect forcellular therapy because the structure andfunction of these organs are too complex.Although renal failure can be treated by dial-ysis, pulmonary function cannot be replacedby any means other than transplantation. Inthe case of the liver, whole-organ xenotrans-plantation and implantable devices seemunfeasible because of the complex metabolicprocesses that occur; however, ALLOGENEIC andeven XENOGENEIC hepatocyte transplantationoffer promise. To properly assess how the

Exciting new technologies, such as cellulartransplantation, organogenesis andxenotransplantation, are thought to bepromising approaches for the treatment ofhuman disease. The feasibility of applyingthese technologies, however, might belimited by biological and immunologicalhurdles. Here, we consider whether, andhow, xenotransplantation and various othertechnologies might be applied in futureefforts to replace or supplement the functionof human organs and tissues.

Few fields of medicine have engenderedmore excitement and controversy than thosefocusing on the replacement of organs.Allotransplantation — the transplantation ofcells, tissues or organs between individuals ofthe same species — is now the preferredtreatment for organ failure, but its applica-tion is limited because human organs are inshort supply. Xenotransplantation — thetransplantation of cells, tissues or organsbetween individuals of different species —offers the possibility of overcoming theseorgan shortages, and is a potential avenue forthe application of new technologies, such asgenetic engineering, cloning and rationaldesign of therapeutics. However, xenotrans-plantation provokes controversy because suc-cessful application would require overcomingsevere immunological hurdles and becausethe transplanted organs might carry withthem organisms that could give rise to newinfections in human populations. Emergingtechnologies, such as artificial organs, stem-cell biology and organogenesis, might offer away around some of the biological and soci-etal hurdles, but these technologies mighthave limitations of their own. In this review,we shall consider some of the new opportuni-ties and limitations of xenotransplantationand other technologies.

Approaches to replacement of organsThe importance of xenotransplantation, andother approaches for the replacement oforgans, varies considerably between differentorgan systems. For example, in the case ofcardiac failure, xenotransplantation was once

Xenotransplantation and other meansof organ replacement

Marilia Cascalho and Jeffrey L. Platt

O P I N I O N

Box 1 | Zoonosis

One potential complication of transplantation is the conveying of infectious organisms fromthe transplant to the recipient; in xenotransplants, such an infection would be a zoonosis.The risk of the spread of pathogens should be less in xenotransplantation than inallotransplantation, because most pathogens of pigs do not infect humans, and because pigscan be raised to be free of known human pathogens. However, attention has been drawn to thepossibility that the xenotransplant might serve as the source of a ‘new’ infectious agentgenerated by spread of an endogenous pig virus, or mutation or recombination of pig viruses,and that such an agent might spread widely among humans. This concern has been widelydiscussed in the medical literature. To date, no ‘new’ organism, including the porcineendogenous retrovirus54, has been found to be transmitted to humans55,56. Although concernabout this subject will surely continue, that concern might be balanced by two furtherconsiderations. First, it is clear that whether or not xenotransplantation becomes available,epidemics caused by new infectious agents will occur, and some, like hepatitis C, might beassociated with organ failure. If larger numbers of individuals should experience organfailure, then xenotransplantation might be seen as a solution to the problem, rather than apotential cause. Second, if a new and dangerous zoonotic organism should emerge in thecourse of xenotransplantation, the carefully monitored recipients might alert society to therisk and enable the development of approaches to prevent introduction and spread of theorganism by other means.

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complex antigens)15. Third, immune regula-tion, which might partially control responsesto allografts, might, in our view, fail to do so inresponses to xenografts.

Xenotransplantation of cells and tissues.Grafts of isolated cells, such as hepatocytes,are nourished and maintained by themicroenvironment, growth factors and in-growth of capillaries of the recipient (FIG. 1).Transplants consisting of tissues, such as theskin, are maintained by both donor andrecipient growth factors, and have a mixedvascular supply, consisting of in-grown bloodvessels of recipient origin and blood vesselsformed by the spontaneous anastomosis ofdonor and recipient capillaries. Cell and tis-sue transplants, especially transplants of bonemarrow cells and pancreatic islets, might besubject to a condition known as ‘primarynon-function’. We believe that primary non-function of xenogeneic transplants is causedby one or more of three factors: first, theinability of growth factors of the recipient tosupport newly implanted cells and/or failureof graft factors to support angiogenesis by

of repairing large masses of defective tissue.For these purposes, an organ transplant wouldbe optimal.

OrganogenesisOne potential approach to replacing thefunction of structurally complex organs,such as the kidney or lung, is organogenesis,or the growing of organs de novo from prim-itive cells or tissues or stem cells8,10. If feasi-ble, organogenesis would avoid the mainlimitation of cellular transplants. Whetherorganogenesis can produce physiologicallycompetent organs is not yet clear. Fetalmouse metanephric kidney tissue can begrown from primitive mesenchyme in cul-ture11,12. However, the nephrons in theseorgans lack the blood vessels needed forfunction and can be grown to a size of only afew millimeters in vitro12. To overcome theseproblems, organogenesis might be carriedout in vivo. Hammerman recently reportedthat fetal kidneys transplanted in the renalcapsule or omentum of rats can undergovascularization and might even exhibit somefunction13. If the technical capability to alloworganogenesis in a human existed, thegrowth process would presumably require aperiod of months, if not years, and thereforea temporary measure, such as xenotrans-plantation, would be needed for vital organs.As an alternative, an animal could be used asa temporary host for the developing organ.

XenotransplantationUntil organogenesis becomes feasible, xeno-transplantation might be the best approachfor the replacement of the kidney and lung,and possibly for other organs, and for condi-tions not amenable to cellular therapies.Xenotransplantation might also contribute tothe development of organogenesis. As dis-cussed above, genetically modified xenotrans-plants might be used to deliver specific geneproducts for such purposes as reconstitutingdefective pathways or promoting tissuegrowth. We have recently discussed otherapplications of xenotransplantation14.However, several obstacles remain beforexenotransplantation can be widely used.These include the immune response of therecipient against the transplant and the physi-ological limitations of the transplant in theforeign host. In addition, there is a possibilitythat infectious agents might be transferredfrom the transplant to the recipient (BOX 1).Xenotransplantation has been attempted ona number of occasions during the past 100years, so more is known about the hurdles toxenotransplantation than the hurdles toother approaches to replace organ function.

In considering these obstacles, it is importantto distinguish between grafted cells and tis-sues on the one hand and grafted organs onthe other hand, as we believe the biologicalbarriers to xenotransplantation depend, to asignificant extent, on the way in which thegraft is connected to the recipient.

As mentioned above, the immuneresponse to a xenotransplant is a difficultobstacle to overcome. The elements of theimmune system involved in xenograft recog-nition have been recently reviewed by us14.The immune responses to xenotransplanta-tion are much more severe than the immuneresponses to allotransplantation for at leastthree reasons. First, all individuals have innateimmunity against xenogeneic cells, and thisinnate immune response, which in humansincludes xenoreactive antibodies (XA), com-plement and natural killer cells, recruits adap-tive immune responses against the graft14.Second, xenogeneic transplants carry a diverseset of foreign antigens against which cellularand humoral immune responses can be elicit-ed (in allotransplants, by contrast, the mainforeign antigens are major histocompatibility

NATURE REVIEWS | IMMUNOLOGY VOLUME 1 | NOVEMBER 2001 | 155

Primarynon-function

Cellularrejection

Hyperacuterejection

Acutevascularrejection

Cellularrejection

Chronicrejection

a

b

Cell xenotransplant,e.g. hepatocytes

Free tissue xenotransplant,e.g. skin

Organ xenotransplant,e.g. kidneys

Xenotransplant failure

Xenotransplant failure

Xenotransplantsuccessful

Xenotransplantsuccessful

Donorbloodvessel

Recipientbloodvessel

Recipientbloodvessel

Anastomosis

Recipientblood vessel

Donor bloodvessel

Figure 1 | Biological responses to xenotransplantation. Biological responses to transplantationdepend on the means by which a xenotransplant receives its vascular supply. a | Cell and tissuexenotransplants are vascularized, for the most part, by recipient blood vessels. These grafts are subject to failure of engraftment (primary non-function) or cellular rejection, but not to vascular rejection. b | Organxenografts are vascularized by donor blood vessels. The grafts are subject to a series of vascularresponses beginning with hyperacute rejection (minutes to hours), acute vascular rejection (days toweeks), cellular rejection and chronic rejection.




Xenotransplantation of vascularized organs.Whole-organ grafts are connected to therecipient by anastomosis of large blood ves-sels of the donor and recipient. Aside fromthis connection, the graft remains entirely ofdonor origin. Hence, organ xenografts arenot generally compromised by incompatibili-ty of the local environment in which they areplaced. Conversely, the blood vessels of organxenografts are directly exposed to compo-nents of the immune system of the recipient,and it is the interaction of the immune sys-tem with donor blood vessels that gives riseto distinct types of vascular disease whichhave to this point prevented the clinicaltransplantation of xenogeneic organs (FIG. 1).

Vascularized organs are first subject tohyperacute rejection, a devastating conditionthat destroys a xenograft within minutes to afew hours24. Hyperacute rejection of pigorgans transplanted into primates is trig-gered by the binding of xenoreactive naturalantibodies to Galα1-3Gal, a saccharideexpressed by pigs and other lower mammals25.

especially severe15,18,19 and might, in our view,be further amplified by the humoral immunereactions and by failure of immune regulationbetween species14,20. Some fundamentalaspects of the cellular immune response toxenotransplantation have been reviewed byus14 and others21. Although the cellularimmune response to xenotransplantation issevere, that response seems to be subject tocontrol by immunosuppressive agents thatare currently available6,22,23.

host vessels16; second, the action of naturalkiller cells or recently activated T cells onthe newly implanted graft; and third, theaction of complement on xenogeneic cellsand tissues introduced into the blood (forexample, pancreatic islets injected into theportal vein)17.

The main hurdle to xenotransplantationof cells and tissues is cellular rejection. Asmentioned, cell-mediated immune responsesto xenotransplantation are thought to be

Endothelium of blood vesselsin xenograft

Complement

Matrix

Vasoconstriction

Inflammation

Acutevascularrejection

Matrix exposed

Loss of NO

Apoptosis

IL-1αEndothelial cell activation

Tissuefactor

E-selectin

TXA2

XenoreactiveantibodiesMembrane-

attackcomplex

IL-1β

Thrombosis

Figure 2 | The pathogenesis of acute vascular rejection. Acute vascular rejection is induced by xenoreactive antibodies directed against the endothelial liningof blood vessels in the graft, and possibly by complement. Whereas the endothelium of normal blood vessels promotes blood flow and inhibits thrombosis andinflammation, the endothelium of xenografts promotes vasoconstriction, thrombosis and inflammation, giving rise to the picture of ischaemia and thrombosis thatis characteristic of acute vascular rejection of xenografts64,65. These pathophysiological changes in endothelium are due, at least in part, to coordinate elaborationof tissue factor, plasminogen-activator inhibitor type 1 (PAI-1), E-selectin and thromboxane A2 (TXA2), and other products of genes induced by the action ofxenoreactive antibodies, as well as small amounts of complement or platelets29,35,45,65,66. These coordinate changes induce thrombosis, inflammation andvasoconstriction and are, in turn, induced through two pathways. One pathway leads to the production of interleukin (IL)-1α, which acts as an autocrine factorinducing the production of various proteins, such as tissue factor and E-selectin, resulting in the release of thromboxane A2 and IL-1β. The other pathway involvesapoptosis, which leads to loss of endothelial cells, which exposes the matrix and decreases the availability of nitric oxide (NO).

Table 1 | Approaches to prevention of hyperacute rejection

Approach Method References

Depletion of xenoreactive antibodies Column absorption 67,68

Inhibition of complement Cobra venom factor, sCR1 69,70

Genetic engineering for the expression DAF, CD59, MCP 33,71,72 of complement-regulatory proteins

Genetic engineering to decrease Knock-out 40–42antigen expression α-1,3-galactosyltransferase

gene and possibly other genes in pigs

DAF, decay-accelerating factor; MCP, membrane co-factor protein; sCR1, soluble complementreceptor type 1.



Galα1-3Gal, which has been shown to bethe target of some of the antibodies thatcause acute vascular rejection44. However,although it might be possible to eliminatethis antigen from xenograft donors, it mightnot be possible to eliminate what we fearmight be a myriad of other xenogeneic anti-gens that could be targeted by xenoreactiveantibodies, and eliminating an antigen bygene targeting might uncover new epitopes.Another approach to preventing acute vas-cular rejection might involve inhibition ofexpression of genes associated with activa-tion of endothelium45. A fourth approachinvolves the induction of ‘accommodation’(BOX 2). First described in organs allograftedacross ABO blood-group barriers46,47,accommodation is an acquired resistance ofan organ to immune-mediated injury29. Asit might prove difficult or impossible to pre-vent humoral responses to xenotransplants,there is much interest in the possibility thataccommodation can be used to avert theconsequences of humoral rejection20,29,45.Accommodation has been used to preventacute vascular rejection in rodent and,arguably, in pig-to-primate xenografts44,48.

If acute vascular rejection of a xenograft isaverted, the graft might be subject to chronicrejection. Whether, and to what extent, organxenografts are susceptible to chronic rejectionis, as yet, unknown. If chronic rejection iscaused by an immune response to the graft, assome experimental evidence indicates49, thenit should be common and severe in xenotrans-plants. If chronic rejection is caused by quali-ties of the graft, such as preservation time,ISCHAEMIA and donor age, then it should not bemuch of a problem. In any case, because xeno-transplantation offers an unlimited supply oforgans, the impact of chronic rejection mightbe less serious as the chronically rejected organcan be replaced.

Binding of these antibodies activates comple-ment, which, in turn, causes graft destruction.The mechanisms underlying susceptibility tohyperacute rejection have been the subject ofcontroversy, as binding of antidonor antibod-ies occurs in a variety of conditions, includingsome xenografts in which hyperacute rejection is not observed26. We believe thathyperacute rejection is caused by the rapidinsertion of terminal complement complex-es in the cell membranes of the endotheliallining of blood vessels in the donor organ24,and anything that modifies the kinetics ofcomplex formation modifies susceptibilityto rejection (TABLE 1).

Among the factors that might influence therate of complement reactions is the availabilityand function of complement-regulatory pro-teins27,28. We had postulated that activation ofcomplement in xenografts is amplifiedbecause complement-regulatory proteins,such as decay-accelerating factor (CD55),CD59 and membrane cofactor protein, whichfunction more effectively against homologousthan against heterologous complement, fail toprotect the xenograft against complement-mediated injury29. However, on the basis ofstudies using isolated cells, some have ques-tioned whether complement-regulatory pro-teins, particularly CD59, do indeed functionin a species-specific fashion30. We believe thiscontroversy is addressed by xenotransplanta-tion. First, expression of CD55 (REF. 26), butnot CD59, prevents hyperacute rejection31,indicating that terminal complement com-ponents not controlled by CD59, that isC5b67, might be sufficient to induce changesin the endothelium underlying hyperacuterejection32. Second, pig organs expressinghuman complement-regulatory proteins atvery low levels are protected from hypera-cute rejection, so establishing the idea thatfailure of complement control is an impor-tant obstacle to xenotransplantation33. Theseobservations further establish that the safest,and perhaps the most clinically applicable,approach to preventing hyperacute rejectionis expression in the graft of complement-

regulatory proteins compatible with thecomplement system of the recipient.

If hyperacute rejection is prevented, anorgan xenograft becomes susceptible to acondition we have called ‘acute vascularrejection’34. Acute vascular rejection seemsto be caused by xenoreactive antibodies,which bind to the xenograft causing ‘activa-tion’ of endothelium in the graft34,35, andpossibly apoptosis36 (FIG. 2).

Acute vascular rejection is thought bymany in the field to be the main biologicalobstacle to xenotransplantation of organs;accordingly, much effort is now directed atdeveloping the means to prevent or treatthis disorder (TABLE 2). One way to preventacute vascular rejection might be to induceimmunological tolerance to the xenotrans-plant donor. Xenogeneic tolerance might beinduced by engraftment of donor bonemarrow or stem cells37,38, but the biologicalhurdles to engraftment of xenogeneic bonemarrow cells, which include the action ofantibodies and complement on the cells andthe incompatibility of host growth fac-tors16,39, might make induction of toleranceto organ xenografts difficult to achieve.Another way to prevent acute vascularrejection might be to eliminate the antigenstargeted by xenoreactive antibodies. Recentprogress in the cloning of pigs40–42, and ingene targeting43, makes it possible for thefirst time to consider knocking out pig antigens targeted by xenoreactive antibod-ies. Most of the efforts towards this end havefocused on knocking out α1,3-galactosyl-transferase, which catalyses the synthesis of


Table 2 | Approaches to prevention of acute vascular rejection

Method Result References

Pre-transplant infusion with Tolerance to Galα1,3Gal 37,73donor haematopoietic cells and other xenospecific antigens

Knock-out Decreased antigen expression 40–42α-1,3-galactosyltransferase andpossibly other genes in pigs

Suppression of pro-coagulant or Inhibition of endothelial cell 45pro-inflammatory genes activation

Transient depletion of Induction of accommodation 29,44,48xenoreactive antibodies

Glossary

ALLOGENEIC

Of, or relating to, the same species; for example, allo-geneic transplants are transplants between individualsof the same species.

ISCHAEMIA

A condition in which the flow of blood to a tissue ororgan is less than normal, and which results in injury tothat tissue or organ.

ISLETS OF LANGERHANS

The tissue of the pancreas that contains endocrine cells,including the β-cells that secrete insulin.

SUBSTANTIA NIGRA

A part of the brain affected by Parkinson’s disease.

XENOGENEIC

Of, or relating to, a foreign species.

“…accommodation mightbe vital to the success ofxenotransplantation… thereis much interest in how itcan be reliably induced…”




Xenotransplantation in the clinicHow close is xenotransplantation to clinicalapplication, and how might it be applied tothe treatment of human disease in the future?It is our view that xenotransplantation of iso-lated cells and tissues between species couldbe undertaken today. This view is based onaccumulating evidence that the rejection ofcell and tissue xenografts can be controlledwith conventional regimens of immunosup-pression6 and preliminary success in engraft-ment of porcine SUBSTANTIA NIGRA cells inhuman subjects23. Less obvious is how celland tissue xenotransplants might be applied.

would seem to preclude ready application ofhepatic xenotransplantation. However,Ramirez and colleagues53 recently reportedthat porcine liver xenografts can functionadequately in baboons, and pig hepatocyteshave been observed to sustain the life of ratswith cirrhosis (I. Fox et al., unpublishedobservations). Even if physiological hurdleswere found to be a barrier to xenotransplan-tation, genetic engineering could be appliedto the problem. For example, if an organ ortissue were missing a functional protein, thegene for that protein might be introduced bytransgenic techniques.

Physiological hurdles to xenotransplantation.Whether a xenogeneic organ or tissue wouldfunction adequately in a human patient is animportant consideration for the clinicalapplication of xenotransplantation. Studiesin which pig organs have been transplantedinto nonhuman primates indicate that thekidneys, hearts and lungs of pigs would func-tion sufficiently well in a human to sustainlife50–52. In fact, the main functional impair-ment of these xenogeneic organ grafts isfrom rejection. By contrast, presumedincompatibilities between the complex meta-bolic systems of the pig and human liver

Box 2 | Mechanisms of accommodation

Because accommodation might be vital to the success of xenotransplantation and might be exploited for treatment or prevention of vasculardisease, there is much interest in understanding how it can be reliably induced and what mechanisms underlie it. Accommodation ofxenotransplants has been induced by temporary depletion of xenoreactive antibodies followed by the return of those antibodies without causinghumoral rejection44. In this setting, accommodation might be brought about by a change in xenoreactive antibodies or a change in the antigens inthe graft57 (see figure). Another possibility is that the binding of xenoreactive antibodies or the action of inflammatory agonists, in subtoxicamounts induces changes in the graft, which make the graft inured to humoral injury. Resistance to injury might result from one or more of threechanges in the graft: first, desensitization or loss of receptors for inflammatory agonists; second, interruption of cell activation or effectorpathways — for example, by inhibitory κB (IκB) or BCL2; and third, production of proteins, such as CD59 or haem oxygenase-1 (HO-1), thatrepair or block the detrimental effects of the agonists that would otherwise induce tissue injury. Consistent with the latter possibility areexperiments showing that endothelial cells exposed to xenoreactive antibodies acquire resistance to complement-mediated injury owing toincreased expression of CD59 (REF. 58) and other inhibitors of injury59. Experiments in rodents have shown that accommodation is associated withexpression of Bcl-2 and HO-1 (REF. 60). Moreover, organ grafts deficient in HO-1 or in functional complement-regulatory proteins seem to besubject to severe vascular injury61. However, efforts to prevent vascular injury by expression of these genes might not be sufficient to induce a stateof accommodation, as grafts with increased expression of HO-1 and/or CD59 might still undergo acute vascular rejection (REFS 31,62; and Z.E.Holzknecht and J.L. Platt, unpublished observations). This indicates that accommodation is multifactorial and still incompletely understood.Although we discuss accommodation here in the context of acute vascular rejection, it is possible that accommodation will be found to mediateresistance to other forms of tissue injury63. IL-1α; interleukin-1α; IL-1R, IL-1 receptor.

Xenograftcell

Xenoreactiveantibodies

Complement

Matrix

Receptordesensitization

Negative regulation ofreceptor–effector pathway

Inhibition ofeffector function

Effector

Agonist (IL-1α)

Receptor(IL-1R)

The xenoreactive antibodies change

The antigens on the graft change

Xenograft cells develop resistance to injury

Tissue injury

Accommodation

Loss of IL-1R Expression of IκB or BCL2 Expression of CD59 or HO-1

BCL2 HO-1



16. Gritsch, H. A. et al. The importance of nonimmunefactors in reconstitution by discordant xenogeneichematopoietic cells. Transplantation 57, 906–917 (1994).

17. Bennet, W. et al. Expression of complement regulatoryproteins on islets of Langerhans: a comparisonbetween human islets and islets isolated from normaland hDAF transgenic pigs. Transplantation 72,312–319 (2001).

18. Murray, A. G., Khodadoust, M. M., Pober, J. S. &Bothwell, A. L. M. Porcine aortic endothelial cells activatehuman T cells: direct presentation of MHC antigens andcostimulation by ligands for human CD2 and CD28.Immunity 1, 57–63 (1994).

19. Yamada, K., Sachs, D. H. & DerSimonian, H. Humananti-porcine xenogeneic T cell response. Evidence forallelic specificity of mixed leukocyte reaction and for bothdirect and indirect pathways of recognition. J. Immunol.155, 5249–5256 (1995).

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31. Diamond, L. E. et al. Characterization of transgenic pigsexpressing functionally active human CD59 on cardiacendothelium. Transplantation 61, 1241–1249 (1996).

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One application might be in the treatment ofcirrhosis caused by hepatitis viruses. In suchcases, animal hepatocytes might be preferredover human hepatocytes to avoid reinfectionby human viruses. Another potential applica-tion is the transplantation of xenogeneic ISLETS

OF LANGERHANS for the treatment of diabetes.Xenogeneic islet transplants might be lesssubject to destruction by the autoimmuneresponse that underlies type 1 diabetes. In thefuture, cellular xenotransplants might, in con-junction with genetic engineering, be used todeliver genes or other cellular products thatare absent or deficient in expression.

The application of organ xenotransplanta-tion as a primary approach to replacement oforgans clearly depends on controlling theimmune response of the recipient so that the xenografted organ can endure. The chal-lenge is to reliably prevent or treat acute vascu-lar rejection. How can one know this challengehas been met? Nonhuman primate-modelsystems that have been used to explain funda-mental aspects of the immune response toxenotransplantation might not be optimalfor testing therapeutic strategies designed foroptimal effect in humans. For example, thehuman complement-regulatory proteinsexpressed in transgenic pigs might fail tofully control the complement system of thebaboon. So, evaluation of the feasibility ofxenotransplantation might be more effective-ly undertaken in human subjects who couldbe recipients of bridge or temporary trans-plants of pig organs. Such transplants mightbe used to keep a person alive until a deviceor an allograft can be inserted, or until anengineered organ can be fashioned from thepatient’s own cells.

The use of animals for treating organ fail-ure in humans might acquire a broader appli-cation than solely as a source of organs. Forexample, as in vitro tissue culture is unlikely toyield fully developed functional organs, per-haps pigs or other animals could be used assurrogate recipients to allow completion oforgan development. Human organs and tis-sues grown and maintained in animals mightthen be available for transplantation. Oneadvantage of this method would be the possi-bility of genetically modifying stem cells (for

example, to introduce antiviral genes) beforeimplantation in the animal host and transferinto the patient. A new application of xeno-transplantation might be in the cloning ofhuman cells, tissues or organs. This possibilityis raised by recent successes in the cloning ofanimals. For example, nuclei from a humanpatient might be transferred to enucleatedstem cells of an animal, and the cells mightthen be grown in vitro or in an animal togenerate differentiated human tissue that is autologous with the patient. Therefore,future applications of xenotransplantationmight call for ‘human’-to-animal transplants,and genetic modification of animals might beundertaken to sustain such transplants. Withthe use of animals as biological reactors,xenotransplantation might acquire broadermeaning and impact in the treatment ofhuman disease.

Marilia Cascalho and Jeffrey L. Platt are inTransplantation Biology and the Departments of

Surgery and Immunology, Medical SciencesBuilding 2–66, 200 1st Street SW, Mayo Clinic,

Rochester, Minnesota 55905, USA.

Jeffrey L. Platt is also in the Department ofPediatrics, Medical Sciences

Building 2–66, 200 1st Street SW, Mayo Clinic,Rochester, Minnesota 55905, USA.

Correspondence to J.L.P.e-mail: [email protected]

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“It is our view thatxenotransplantation ofisolated cells and tissuesbetween species could beundertaken today.”




AcknowledgmentsWork in the laboratories of the authors is supported by grantsfrom the National Institutes of Health and by the Von LiebigFoundation.

Online links

DATABASESThe following terms in this article are linked online to:LocusLink: http: //www.ncbi.nlm.nih.gov/LocusLink/BCL2 | CD55 | CD59 | E-selectin | HO-1 | IL-1α | IL-1β | IL-1R | PAI-1

FURTHER INFORMATIONJeffrey Platt’s lab:http://www.mayo.edu/research/people/3/34611_platt/Transplantation Society: http: //www.transplantation-soc.org/xeno.htmAccess to this interactive links box is free online.

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Vaccine safety–vaccine benefits:science and the public’s perception

Christopher B. Wilson and Edgar K. Marcuse

S C I E N C E A N D S O C I E T Y

The development of cowpox vaccination by Jenner led to the development ofimmunology as a scientific discipline. The subsequent eradication of smallpoxand the remarkable effects of othervaccines are among the most importantcontributions of biomedical science tohuman health. Today, the need for newvaccines has never been greater. However,in developed countries, the public’s fear ofvaccine-preventable diseases has waned,and awareness of potential adverse effectshas increased, which is threatening vaccineacceptance. To further the control ofdisease by vaccination, we must developsafe and effective new vaccines to combatinfectious diseases, and address thepublic’s concerns.

The discipline of immunology developedfrom observations in the fields of publichealth and clinical medicine. In the fifthcentury BC, Thucydides noted that individualswho recovered from plague did not developdisease again, and similar observations of‘immunity’ to plague were made in Europe inthe fourteenth century1,2. The observationthat mild smallpox infection protected againstdisease on subsequent exposure led to thepractice of variolation — the inoculation ofdried pus from smallpox pustules into theskin or nose. This was first practised in Indiaand China, and then introduced in 1721

in England by Lady Montague, and in NewEngland by Cotton Mather3. Jenner’s clinicaltrial of cowpox virus vaccination, and publi-cation of Variolae Vacciniae in 1798, gavebirth to the field of immunology, but neitheran understanding of the basis for its efficacynor universal acceptance of this practice weresoon to follow3,4. Instead, scientific and publicscepticism and alarm were common earlyresponses (FIG. 1).

The subsequent formulation of the germtheory of disease by Koch and Pasteur, andvon Berhing’s identification of neutralizingfactors for toxins, provided a foundation forthe mechanistic understanding of protectiveimmunity5. In the ensuing years, vaccines formore than 20 infectious diseases have beendeveloped, and in 1977, Jenner’s originalexperiment was brought to full fruitionwhen smallpox was eradicated worldwide6.Immunization is one of the most stunningand economically effective contributions ofbiomedical science to human health. So,immunologists can be proud of the funda-mental biomedical insights that have arisenfrom the field, and of the practical applicationof these insights in the prevention of disease.

Advances of the last century allow us tobetter understand the successes (and failures)of past vaccines, and enable a more rationaland diverse approach to new vaccine develop-ment. An example is the development ofpolysaccharide–protein conjugate vaccines


Documents

OPINION: Xenotransplantation and other means of organ replacement