Evidence suggesting that deletion of expression of N‐glycolylneuraminic acid (Neu5Gc) in the organ‐source pig is associated with increased antibody‐mediated rejection of kidney transplants in baboons

Iwase, Hayato; Jagdale, Abhijit; Yamamoto, Takayuki; Bikhet, Mohamed H; Nguyen, Huy Quoc; Ezzelarab, Mohamed; Ayares, David; Anderson, Douglas J.; Eckhoff, Devin E.; Foote, Jeremy B.; Fatima, Huma; Hj, Schuurman; Hara, Hidetaka; Cooper, David K. C.

doi:10.1111/xen.12700

Cited by 23 publications

(25 citation statements)

References 15 publications

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“…After pig-to-NHP organ transplantation, this has been demonstrated to result in a high incidence of early graft failure. 24 Although a TKO pig organ is preferred for clinical xenotransplantation, the transplantation of a GTKO pig organ may be associated with much better results in NHP recipients, and this is because galactose-α1,3-galactose (Gal) plays a much greater role as a target for the immune response in NHPs than in humans (Figure 6). 25 NHP serum antibody binding to pig cells in which only expression of Neu5Gc remains expressed (i.e., GTKO/β4GalNT2-KO [or doubleknockout, DKO] pigs) is significantly reduced, but organs from these DKO pigs do not exactly mimic the results that might be achieved after TKO pig organ transplantation in humans.…”

Section: The Problem Of the "Fourth" Xenoantigenmentioning

confidence: 99%

“…Our own experience with high-dose corticosteroid therapy has been uniformly unsuccessful, though additional therapy with an anti-TNF mAb (etanercept) appeared to delay graft failure for a month in one case. 24 It will therefore be important to ensure sufficient maintenance immunosuppressive therapy is administered. Histopathological evidence of predominantly T cell-mediated rejection has been rare.…”

Section: Anti-inflammatorymentioning

confidence: 99%

“…When these NHP serum antibodies bind to a pig cell, they have been found to be associated with a remarkably high level of complement‐mediated cytotoxicity (Figure 5). After pig‐to‐NHP organ transplantation, this has been demonstrated to result in a high incidence of early graft failure 24 …”

Section: Moving From the Laboratory To The Clinicmentioning

confidence: 99%

“…To my knowledge, successful reversal of biopsy‐proven severe antibody‐mediated rejection of a xenograft has never been reported. Our own experience with high‐dose corticosteroid therapy has been uniformly unsuccessful, though additional therapy with an anti‐TNF mAb (etanercept) appeared to delay graft failure for a month in one case 24 . It will therefore be important to ensure sufficient maintenance immunosuppressive therapy is administered.…”

Section: Moving From the Laboratory To The Clinicmentioning

confidence: 99%

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The 2021 IXA Keith Reemtsma Lecture: Moving xenotransplantation to the clinic

Cooper

2021

Xenotransplantation

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Keith Reemtsma was a pioneer in xenotransplantation, the Honorary Founding President of the International Xenotransplantation Association (in 1998), and a wonderful personality. It is a privilege to be invited to give this lecture in his memory.If he were alive today, he would be delighted to see the progress that has been made in pig organ transplantation into nonhuman primate recipients. This progress has largely resulted from two major advances: (i) the increasing availability of pigs with multiple genetic manipulations aimed at protecting the cells of the organ from the primate immune response and (ii) the introduction of novel immunosuppressive agents that block the CD40/CD154 costimulation pathway.There is strong evidence from numerous in vitro studies that the transplantation of a triple-knockout pig organ, particularly if expressing several human protective proteins, into a patient is likely to be significantly more successful than if that same organ is transplanted into a nonhuman primate recipient. With this fact in mind, and in view of the advances currently being made, the time has surely come when we need to consider moving from the laboratory to the clinic.However, there are still questions we need to definitively resolve: (i) What exact genetic modifications do we need in the organ-source pig? (ii) What exact immunosuppressive regimen will we choose? (iii) How will we monitor the immune response and diagnose and treat rejection? and (iv) How do we plan to prevent or treat potential infectious complications? Furthermore, when these matters have been resolved, which patients will be offered a pig organ in the first trial? We have suggested that patients who are very unlikely to survive until a suitable deceased human donor kidney becomes available are those who should be considered for the initial trials. Assessing public attitudes to xenotransplantation is also important before embarking on a clinical trial. I suggest that progress is much more likely to be made from a small clinical trial than if we persist in carrying out experiments in an animal model that no longer mimics the clinical situation.

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Section: The Problem Of the "Fourth" Xenoantigenmentioning

confidence: 99%

Section: Anti-inflammatorymentioning

confidence: 99%

Section: Moving From the Laboratory To The Clinicmentioning

confidence: 99%

Section: Moving From the Laboratory To The Clinicmentioning

confidence: 99%

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The 2021 IXA Keith Reemtsma Lecture: Moving xenotransplantation to the clinic

Cooper

2021

Xenotransplantation

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“…This is a lost opportunity because assessing the survival of TKO pig kidneys in nonhuman primates (NHPs) is beset with difficulties because all Old World NHPs have preformed antibodies against cells from these pigs, making in vivo studies almost certainly less successful than they would be in human recipients. 14,15 Hyperacute rejection of a GTKO pig organ has very rarely occurred in NHP models, but early rejection would be more likely to occur in a human recipient. 14 Whether any immunosuppressive or other therapy, for example, a complement inhibitor, was administered to the braindead recipient remains unreported at present.…”

Section: An Assessment Of the Experimentsmentioning

confidence: 99%

Genetically engineered pig kidney transplantation in a brain‐dead human subject

Cooper

2021

Xenotransplantation

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In September 2021, a kidney (with donor‐specific thymic tissue) from an α1, 3‐galactosyltransferase gene‐knockout (GTKO) pig was transplanted into the groin (with anastomoses to the femoral vessels) of a brain‐dead subject by a surgical team at New York University Langone Health (NYU). It was reported to function immediately, passing urine and excreting creatinine. The experiment was terminated after 54 h and, during this period, the kidney did not show macroscopic features of rejection. Does this experiment provide information not available to us previously and does it move the field forward to clinical trials? The information provided was very limited, but the following points are worthy of note. (i) Numerous in vivo studies in nonhuman primates have predicted that the pig kidney would function immediately. (ii) Numerous in vitro studies have predicted that a GTKO pig kidney would not be rejected within the first few days after transplantation into a human subject. (iii) GTKO kidneys are not optimal for clinical transplantation, and the transplantation of a triple‐knockout (TKO) pig kidney would have been more relevant. (iv) There was no purpose in transplanting a “thymokidney” without pre‐transplant conditioning therapy and follow‐up for several months. (v) Because the native kidneys were retained, it is difficult to determine whether the function of the graft was sufficient to support life. (vi) The experiment was announced to the media rather than published in a peer‐reviewed medical journal (although hopefully this will follow), suggesting that it was primarily carried out to gain attention to the great potential of xenotransplantation (and/or possibly to NYU). In this respect the experiment was successful. Because of the very limited period of time for which a brain‐dead subject can be maintained in a metabolically and hemodynamically stable state, the value of experiments in such subjects will remain very limited. It is hoped that any future similar experiments will be planned to be more relevant to the clinical situation. Nevertheless, the report has stimulated public attention towards xenotransplantation which, unless there is an adverse response to what some might consider to be a bizarre experiment, should be of significant benefit to future progress.

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