NDT Advance Access originally published online on August 3, 2006
Nephrology Dialysis Transplantation 2006 21(10):2991-2992; doi:10.1093/ndt/gfl442
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Xenotransplantation—will tolerance be essential?
Email: cooperdk{at}upmc.eduSir,
I enjoyed reading the short review by Sprangers et al. [1] in your April 2006 issue. However, I wish to question one of their conclusions.
They state that successful application of xenotransplantation will still require induction of robust T- and B-cell xenotolerance.
I doubt if they have clear evidence for making this statement. In the articles they review, related to the transplantation of hearts and kidneys from 
1,3-galactosyltransferase gene-knockout (GT-KO) pigs into baboons [2,3], the heart transplants were protected from rejection by an immunosuppressive regimen. These grafts functioned for 
2–6 months, with no recipient baboon suffering any infectious or other immunosuppressive drug-related complication. This would suggest that the immunosuppressive therapy was not excessive, and would also suggest that with further genetic manipulation to the organ-source pig, prolonged graft survival of clinical relevance might be obtained with pharmacological immunosuppression alone.
In an effort to achieve graft tolerance, the kidney transplants were accompanied by donor thymus transplants [3]. Survival did not extend beyond 83 days, and all recipients died of complications of the ‘tolerance-inducing’ regimen. Although survival of kidney transplants in baboons that received only pharmacological immunosuppression (and did not also receive thymic grafts) was poor in this study [3], others have reported better survival. Kidney grafts have survived in monkeys for up to 90 days [4] and in baboons for up to 75 days [5] on pharmacological immunosuppression alone. Although the ultimate goal of xenotransplantation, as with allotransplantation, is the induction of tolerance, there is little evidence that the addition of the thymus graft contributed to prolonged survival, or that tolerance can be achieved.
In the heart transplant group [2] there was little T-cell infiltration into the grafts and no documented elicited T-cell-dependent antibody response, and the mixed lymphocyte reaction was completely suppressed throughout the course of the experiment until immunosuppressive therapy was discontinued. Although T-cells can certainly be found in the grafts after detailed search, the evidence is that T-cells did not play a major role in failure of the graft. Rather, it would appear that the innate immune system and discrepancies in the coagulation systems between primates and pigs may be far more important.
Work from several groups in rodent models would indicate that genetic manipulation of the donor, in the form of the introduction of ‘anticoagulant’ genes [6] or the deletion of ‘coagulant’ genes [7] that correct the coagulation dysregulation may be as important, if not more important, as what we normally consider as an immunological response. For example, Chen et al. [6] reported that, whereas control mouse hearts in immunosuppressed rats failed from acute humoral xenograft rejection after 6 days, hearts from transgenic mice expressing membrane-tethered fusion proteins of human tissue factor pathway inhibitor survived indefinitely (>100 days). No features of rejection were identified histologically despite antibody and complement deposition on the xenograft endothelium. This surprising result suggests that coagulation dysregulation may be playing a primary role in graft failure, and not the secondary role hitherto inferred based on kinetics and histology.
We are awaiting the birth of GT-KO pigs that are additionally transgenic for human tissue factor pathway inhibitor or other ‘anticoagulant’ gene. The evidence is that the availability of such pigs may play a much greater role in extending pig xenograft survival than further manipulation of the adaptive immune response.
Clearly, efforts to induce tolerance should continue in both allotransplantation and xenotransplantation, but this has proved an elusive goal. Furthermore, it does not preclude the fact that, as with allotransplantation during the past 50 years, clinically valuable and acceptable results may be achieved with chronic immunosuppressive therapy while we await breakthroughs that might induce tolerance.
Conflict of interest statement. None declared.
Thomas E. Starzl Transplantation
Institute University of Pittsburgh
Medical Center Pittsburgh
USA
References
- Sprangers B, Waer M, Billiau AD. (2006) Xenograft rejection – all that glitters is not Gal. Nephrol Dial Transplant 21:1486–1488.
[Free Full Text] - Kuwaki K, Tseng YL, Dor FJ, et al. (2005) Heart transplantation in baboons using 1,3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nat Med 11:29–31.[CrossRef][Web of Science][Medline]
- Yamada K, Yazawa K, Shimizu A, et al. (2005) Marked prolongation of porcine renal xenograft survival in baboons through the use of 1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Nat Med 11:32–34.[CrossRef][Web of Science][Medline]
- Baldan N, Rigotti P, Calabrese F, et al. (2004) Ureteral stenosis in HDAF pig-to-primate renal xenotransplantation: a phenomenon related to immunological events? Am J Transplant 4:475–481.[CrossRef][Web of Science][Medline]
- Zhong R, Luo Y, Yang H, et al. (2003) Improvement in human decay accelerating factor transgenic porcine kidney xenograft rejection with intravenous administration of gas914, a polymeric form of Gal. Transplantation 75:10–19.[Web of Science][Medline]
- Chen D, Weber M, McVey JH, et al. (2004) Complete inhibition of acute humoral rejection using regulated expression of membrane-tethered anticoagulants on xenograft endothelium. Am J Transplant 4:1958–1963.[CrossRef][Web of Science][Medline]
- Mendicino M, Liu M, Ghanekar A, et al. (2005) Targeted deletion of fgl-2/fibroleukin in the donor modulates immunologic response and acute vascular rejection in cardiac xenografts. Circulation 112:248–256.
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