Why Is the Immune Response to Xenotransplantation So Severe? The immune response to xenotransplantation is initiated

Department of Pediatrics by a number of components of inflammation and immu-Mayo Clinic nity(Table1).Theseinitiatingfactorsshould,inprincipal,Rochester, Minnesota 55905 trigger nearly every inflammatory pathway. It is intuitivethataxenograftshouldinduceasevereimmunereactionThe transplantation of cells, tissue, or organs between because of the great diversity of antigens introduced inthe host. However, diversity of antigens is not sufficientdisparate species, that is, “xenotransplantation,” hasto explain the fate of xenografts, as graft outcome onlybeen of increasing interest in the past decade. Thisweakly correlates with genetic disparity between donorintereststemsinlargepartfromthepossibilitythatxeno-and recipient. Indeed, parasites and commensual or-transplantation would address the severe shortage ofganisms carry far more antigens into the host. The pro-human organs and tissues for transplantation—a prob-found reaction to a xenograft may be the consequencelemthatseverelylimitstheapplicationoftransplantationof molecular differences between species that exist forfor the treatment of human disease. There are otherother reasons, such as from divergent evolution. If thatadvantagesofaxenotransplant.Axenotransplantmightwere to be the case, one might also expect the strengthbe carried out to avoid infection by a human virus. Forof the xenogeneic reaction to correlate with increasingexample, the liver and the bone marrow of baboonsdiversity between the species. However, nearly all spe-havebeentransplantedintohumansubjectsinattemptscies of animals and plants reject xenografts, and theto treat viral hepatitis and AIDS, respectively. A xeno-reaction is not necessarily a function of phylogenetictransplant can be planned, allowing the pretreatment of distance(Table2).Thissuggeststhealternativepossibil-the donor or the recipient for such purposes as preven- ity that the xenogeneic reaction may be adaptive.tionofinflammation,eliminationofinfectiousorganisms, Thepossibilitythatxenogeneicreactionsareadaptiveor induction of immunological tolerance. A xenotrans- may be drawn from an evolutionary perspective. Theplant may derive from animals genetically engineered in rejection of xenografts is manifested by the most primi-the germline to reduce the risk of rejection or to express tive species of multicellular organisms (Humphreys andgenes of therapeutic value for the recipient. Reinherz, 1994; Muller et al., 1999), suggesting that theForalloftheadvantagesofxenotransplantation,how- reaction may have arisen as an adaptation of multicellu-ever, there are also daunting hurdles to success. These larity. As one example, a sponge rejects an allograft orhurdles include the immune response of the recipient xenograft in approximately 3 days. Rejection of allo-against the transplant, the potential limitation and the grafts and xenografts by such primitive organisms isphysiologic function of the transplant in a foreign host, mediatedby phagocyticcells,coagulation proteins,andandthepossibilitythatnovelinfectiousorganismsmight possiblybycomplement-likeproteins,someofthesamebe transmitted from the transplant to the recipient. The components that mediate the rejection of xenografts inpotential applications of xenotransplantation and the higher animals (Table 1).hurdlesofconductingxenotransplantationinhumanpa- What advantage is brought about by the xenogeneictients have been the subject of recent reviews (Auchin- reaction? Several hypotheses can be advanced. Thecloss and Sachs, 1998; Platt, 1998). xenogeneic reaction could have evolved as a mecha-We shall summarize the current state of knowledge nism of speciation, maintaining diversity by protectingregarding the immunological hurdles to xenotransplan- the individual or progeny from damage caused by thetation. Understanding the nature of these responses presence of a foreign species or their products and/may facilitate the development of approaches to over- or by avoiding nonmutually advantageous colonization.coming the barrier to xenotransplantation. Understand- Both mechanisms may also, in turn, contribute to theing the natural and elicited immune responses to xeno- establishment of reproductive isolation, which is funda-transplantation may also yield new insights into the mental to speciation.function and control of immunity. Protection against engraftment of stem cells may wellXenotransplants are opposed by natural and elicited have been a strong adaptive drive for the xenogeneicimmune responses. We use the term “natural immunity” reaction. In fact, xenogeneic reactions to stem cells areto depict responses preexistent to xenotransplantation morevigorousthantoothercellulartransplantsbetweenas opposed to responses elicited by the xenograft. the same species. For example, inoculation of porcineSomeoftheresponsesthatoccurbeforexenotransplan- hematopoietic stem cells was recently shown to engen-tation, such as the production of xenoreactive natural deraprocoagulantresponseinbaboonsakintodissem-antibodies, are not present at birth but appear later and inated intravascular coagulation (Ierino et al., 1998).may, in fact, be adaptive responses to microorganisms. Mutations in the cytokines or receptors mediating in-teraction between stem cells and their environment maywell be of advantage in inhibiting colonization by cells