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Pontifical Academy for Life
Prospects for xenotransplantation
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  • FIRST PART Scientific Aspects
    • Current Situation
      • Rejection: Immunology of Organ Xenografting
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Current Situation

Rejection: Immunology of Organ Xenografting

2. There are four immunological barriers that must be overcome for achieving successful organ xenotransplantation from pig to primate (human and non-human). First, hyperacute rejection, which is caused by xenoreactive natural antibodies and complement of the recipient acting against endothelial cells of the source animal organ. Second, acute vascular rejection caused by the combined effect of elicited xenoreactive antibodies and activated host natural killer cells and monocytes. In combination these stimuli (the anti-graft antibodies and the activated host cells) result in activation of the endothelial cells of the source organ. Endothelial cell activation leads to general inflammation with resultant thrombosis (platelet aggregation and activation of the coagulation cascade) resulting in organ rejection. Third, the xenograft counterpart of classical T cell mediated rejection of allografts (transplantation between individuals of the same species) will almost certainly occur. Finally, xenografts may also be subject to chronic rejection in a manner analogous to allografts.

Hyperacute Rejection. Recipient xenoreactive natural antibodies and complement are the two major factors that result in hyperacute rejection of an immediately-vascularized organ. Pre-existing xenoreactive natural antibodies bind with vascular endothelial cells of the pig organ.(13) These antibodies are directed primarily towards a sugar moiety, the Gal-a (1,3)-Gal-ß (1,4)-GlcNac antigens of the pig, also known as "a-gal".(14) The bound antibodies fix and activate complement, with the combination of antibodies and activated complement leading to endothelial activation which result in thrombosis, rapid graft ischemia and rejection. Elimination of xenoreactive natural antibodies provides one method to overcome hyperacute rejection.(15) Hyperacute rejection has also been overcome by methods that inhibit complement.(16)

Among the different approaches for achieving inhibition of complement, the one that has proven most effective is based on in vitro experiments in which a human protein that inhibits human complement activation is introduced into the membrane of pig endothelial cells. The molecule first tested was human Decay Accelerating Factor, or hDAF. The presence of hDAF in the pig endothelial cells prevented lysis of those cells and would thus, presumably, prevent the activation of the cells.(17) These findings suggested that the production of transgenic pigs expressing hDAF might provide an approach for overcoming hyperacute rejection of pig organs transplanted into primates.

Certain research groups have produced such transgenic pigs and have demonstrated that organs from these pigs usually do not undergo hyperacute rejection.(18) Based on these results with transgenic hDAF-expressing pigs, it appears that hyperacute rejection can be overcome, which is the first major triumph of gene therapy in the field of organ transplantation.

Another possible solution to hyperacute rejection is to eliminate, or greatly reduce the expression of "a-gal" from pigs by knocking out the 1,3 galactosyl transferase gene, which is needed for the expression of "a-gal".(19) This has not yet been accomplished in pigs, although present-day cloning technology could make this possible.

Acute Vascular Rejection. Acute Vascular Rejection is precipitated by elicited xenoreactive antibodies and by the possible infiltration of host inflammatory cells, monocytes and natural killer cells, that invade the xenograft.(20) Endothelial cells are activated resulting in thrombosis, compromised blood flow and rejection.(21) Acute vascular rejection now represents the principle immunological barrier to successful xenotransplantation. Studies of acute vascular rejection in animals has shown that the use of immunosuppression leads to organ survival for a far greater length of time than is seen in untreated cases.(22) An alternative approach for overcoming acute vascular rejection is further genetic engineering animals/organs.(23) A number of genes that may suppress the inflammatory response that appears to cause acute vascular rejection are now being studied.

T Cell Response. If acute vascular rejection can be overcome, it is expected that there will be a xenograft counterpart of the allogeneic T cell rejection response.(24) There are disagreements whether the xenogenic T cell response will be more difficult to overcome than the allogeneic one, which today is easily controlled. In addition to the use of immunosuppression, there is the possibility that in pig-to-primate transplants we might achieve tolerance (non-reactivity of the immune system of the recipient to pig antigens without immunosuppression).(25) Such tolerance is the hope of transplantation in general and may be aided in the xenogenic arena by further genetic engineering of the source animal.

Chronic Xenograft Rejection. There is evidence that - as with allotransplants, - even when a transplant survives all the above rejection phases, there is the possibility that it will be rejected months or years later.(26) This is referred to as "chronic" rejection. The main pathology of chronic graft failure involves smooth muscle cell proliferation and obliteration of the lumens of blood vessels.



13) Cf. Platt J.L., Fischel R.J., Matas A.J., et al., Immunopathology of hyperacute xenograft rejection in a swine-to-primate model, Transplantation 1991, 52: 214-220; Dalmasso A.P., Vercellotti G.M., Fischel R.J., et al., Mechanisms of complement activation in the hyperacute rejection of porcine organs transplanted into primate recipients, Am J Pathol 1992, 140: 1157-66.



14) Cf. Good A.H., Cooper D.K.C., Malcom A.J. et al., Identification of carbohydrate structures which bind human antiporcine antibodies:  implications for discordant xenografting in man, Transplant Proc 1992, 24: 559-60; Sandrin M.S., Vaughan H.A., Dabkowski P.L., et al., Anti-pig IgM antibodies in human serum react predominantly with Gal(a1-3) Gal epitopes, PNAS 1993, 90: 11391-5.



15) Cf. Leventhal J.R., John R., Fryer J.P., et al., Removal of baboon and human antiporcine IgG and IgM natural antibodies by immunoadsorption:  Results of in vitro and in vivo studies, Transplantation 1995, 59: 294-300; Cooper D.K.C., Lexer G., Rose A.G., et al., Effects of cyclosporine and antibody adsorption on pig cardiac xenograft survival in the baboon, J. Heart. Transplant. 1988, 7: 238-46; Latinne D., Soares M., Havaux X., et al., Depletion of IgM xenoreactive natural antibodies by injection of anti-mu monoclonal antibodies, Immunol Rev 1994, 141: 95-125; Rydberg L., Hallberg E., Bjorck S., et al., Studies on the removal of anti-pig xenoantibodies in the human by plasmapheresis/immunoadsorption, Xenotransplantation 1995, 2: 253-63.



16) Cf. Gewurz H., Clark D.S., Finstad J., et al., Role of the complement system in graft rejections in experimental animals and man, Ann. NY Acad. Sci., 1966, 129: 673-713; Pruitt S.K., Kirk D.A., Bollinger R.R., et al., The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts, Transplantation 1994, 57: 363-70; Kobayashi T., Neethling F.A., Koren E., et al., In vitro and in vivo investigation of anticomplement agents FUT-175 and K76COOH, in the prevention of hyperacute rejection following discordant xenotransplantation in a nonhuman primate model, Trans Proc 1996, 28: 604; Kroshus T.J., Rollins S.A., Dalmasso A.P., et al., Complement inhibition with an anti-C5 monoclonal antibody prevents acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation, Transplantation 1995, 60: 1194-202.



17) Cf. Bach F.H., Turman M.A., Vercellotti G.M., et al., Accomodation: a working paradigm for progressing toward clinical discordant xenografting, Transplant Proc. 1991; 23: 205-7; Dalmasso A.P., Vercellotti G.M., Platt J.L., Bach F.H., Inhibition of complement mediated endothelial cell cytotoxicity by decay accelerating factor. Potential for prevention of xenograft hyperacute rejection, Transplantation 1991; 52: 530-3.



18) Cf. Diamond L.E., Quinn C.M., Martin M.J., et al., A human CD46 transgenic pig model system for the study of discordant xenotransplantation, Transplantation 2001; 7: 132; Cozzi E., White D.J.G., The generation of transgenic pigs as potential organ donors for humans, Nature Medicine 1995, 1: 964-6; Fodor W.L., Williams B.L., Matis L.A., et al., Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogenic hyperacute organ rejection, Proc Natl Acad Sci 1994, 91: 11153-7; McCurry K.R., Kooyman D.L., Alvarado C.G., et al., Human complement regulatory proteins protect swine-to-primate cardiac xenografts from tumoral injury, Nature Med 1995, 1: 423-7; Cowan P.J., Aminian A., Barlow H. et al., Renal xenografts from triple-transgenic pigs are not hyperacutely rejected but cause coagulopathy in non-immunosuppressed baboons, Transplantation 2000, 69: 2504-15; Lavitrano M., Forni M., Varzi V., et al., Sperm-mediated gene transfer:  production of pigs transgenic for a human regulator of complement activation, Transplant Proc 1997;29: 3508-9.



19) Cf. Sandrin M.S., Fodor W.L., Mouhtouris E., et al., Enzymatic remodeling of the carbohydrate surface of a xenogenic cell substantially reduces human antibody binding and complement-mediated cytolysis, Nature Medicine 1995, 1: 1261-7.



20) Cf. Soares M.P., Lin Y., Sato K., et al., Pathogenesis of and potential therapies for delayed xenograft rejection,  Opin  Organ  Transplant  1999 4: 80-8.



21) Cf. Hancock W.W., Delayed xenograft rejection, World J. Surg. 1997, 21: 917-23; Platt J.L., Lin S.S. and McGregor C.G.A., Acute vascular rejection, Xenotransplantation 1998, 5: 169-175.



22) Cf. Cozzi E., Bhatti F., Schmoeckel M. et al., Long-term survival of nonhuman primates receiving life-supporting transgenic porcine kidney xenografts, Transplantation 2000, 70: 15-21; Vial C.M., Ostlie D.J., Bhatti F.N. et al., Life supporting function for over one month of a transgenic porcine heart in a baboon, J. Heart. Lung Transplant 2000, 19: 224-9.



23) Cf. Bach F.H., Xenotransplantation: problems and prospects, Annu.Rev.Med.1998, 49: 301-10.



24) Cf. Yamada A., Auchincloss H. Jr., Cell-mediated xenograft rejection, Current Opinion in Organ Transplantation 1999, 4: 90-94.



25) Cf. Auchincloss H. Jr., Sachs D.H., Xenogeneic transplantation, Annu.Rev.Immunol. 1998, 16: 433-70.



26) Cf. Bach F.H., Ferran C., Soares M., et al., Modification of vascular responses in xenotransplantation:  inflammation and apoptosis, Nat. Med 1997. 3: 944-8.





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