LIVER ALLOTRANSPLANTATION AFTER EXTRACORPOREAL HEPATIC SUPPORT WITH TRANSGENIC (hCD55/hCD59) PORCINE LIVERS

Levy, Marlon F.; Crippin, Jeffrey S.; Sutton, Steve G.; Netto, George J.; McCormack, Jeffrey M.; Curiel, Tyler J.; Goldstein, Robert M.; Newman, Joseph T.; Gonwa, Thomas A.; Banchereau, Jacques; Diamond, Lisa E.; Byrne, Guerard W.; Logan, John S.; Klintmalm, Göran B.

doi:10.1097/00007890-200001270-00013

Cited by 145 publications

(23 citation statements)

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“…Also, the antibodies used for Western blotting should be antihuman rather than (in the majority) anti-rat or rabbit, as it has been used in works of Friis (1999, 2000) or in our article on this subject Hence, the article by Myers et al (2001) opens some interesting questions and contributes to the general knowledge of the pig (minipig) liver microsomal P450 enzymes. Because the (mini)pig is a purported source of cells, tissues, and organs in human therapy (see Levy et al, 2000 or Dixit and Gitnick, 1996 for a review) and, possibly, a species of choice for studies of hepatic metabolism of drugs in humans , these studies are needed. …”

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confidence: 99%

Pig and Minipig Cytochromes P450

Anzenbacher¹,

Anzenbacherová²,

Zuber³

et al. 2002

Drug Metab Dispos

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In the June issue (29:908-915) of Drug Metabolism and Disposition, an interesting article on hepatic cytochromes P450 in pig was published by . The authors looked for swine cytochromes P450 (P450 1 ) analogous to human or rat liver microsomal P450 enzymes using Western blotting. In the next step, an induction of P450 enzymes had been followed after induction by a mixture of popular inducers, such as ␤-naphthoflavone, phenobarbital, and dexamethasone, to confirm the expected induction of CYP1A, 2A, B, and C, and 3A activities. From differences in specific activities expressed for characteristic substrates of various P450 enzymes present in microsomes or S9 fraction, the authors concluded that there are many similarities, but also some differences, between pig and human cytochrome P450 enzymes. The conclusion reached by the authors is correct; however, we feel that it is necessary to comment on several points raised in the article in question.First, the fact that several pig P450 enzymes have been cloned and characterized (i.e., not only those mentioned by authors as steroid-metabolizing ones) is overlooked. CYP3A29 has been identified in porcine small intestine, and two more cDNA clones belonging to the CYP2C subfamily were also characterized from the same source . Because it is well known that the P450 enzymes of the gastrointestinal tract are identical, the pig CYP3A29 of the small intestine and this of the liver are the same gene products. An interesting conclusion on the presence of CYP2D enzymes in pig liver microsomes was obtained recently; a CYP2D enzyme, performing N-hydroxylations and N-reductions, was isolated and characterized . This enzyme has been shown to catalyze Ndemethylation of dextromethorphan, a prototypical reaction of human CYP2D6. Moreover, pig liver microsomal vitamin D 3 hydroxylating CYP2D25 has been isolated and thoroughly characterized . This enzyme, showing 77% sequence identity with human CYP2D6, is able to share some substrate specificities with the human enzyme. Hence, the statement of the authors ) that ". . . the available information on DNA sequences of swine P450 enzymes is confined to those enzymes responsible for steroid metabolism in the ovary, brain, and adrenal gland" does not give the full picture of the actual progress in this field.The second comment deals with the investigation of induction of various pig hepatic P450 enzymes by different inducers. First of all, the methodical approach chosen by the authors was not able to give detailed information on the induction of particular P450 activity because the inductors were given to two identical animals in a sequence of 3 days. The animals were induced with the phenobarbital on day 1, then with ␤-naphthoflavone on days 2 and 3, and finally with dexamethasone again on day 3. This approach, however, excluded the possibility to discern the effect of phenobarbital from that of the dexamethasone. In fact, there are numerous detailed studies on the influence of various inducers to liver microsomal P450 activities in the pig or ...

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mentioning

confidence: 99%

Pig and Minipig Cytochromes P450

Anzenbacher¹,

Anzenbacherová²,

Zuber³

et al. 2002

Drug Metab Dispos

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“…Immunoapheresis has been demonstrated to delay HXR and thus to improve perfusion (6). Just recently, Levy et al reported two patients with liver failure that were bridged to transplantation by ECLP with transgeneic organs (15). In all these cases, however, it still remains speculative whether long-term ECLP is beneficial or even harmful for the patient.…”

Section: Discussionmentioning

confidence: 99%

Impact of Ig-Therasorb® Immunoapheresis on Stability of Xenogeneic Ex Vivo Porcine Liver Perfusion – Value of Aminotransferases and Flow Rates for the Assessment of Metabolic Graft Viability

Kornberg¹,

Dietz²,

Mau³

et al. 2000

Clinical Chemistry and Laboratory Medicine

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Due to growing shortage of donor organs, the concept of extracorporeal pig liver perfusion in the treatment of acute liver failure has been rediscovered. Immunomodulation, such as immunoapheresis or inhibition of complement, results in long-term perfusion without exact knowledge of the remaining metabolic graft viability. This study was aimed at the comparison of conventional parameters of graft stability such as perfusion rates and release of aminotransferases with parameters of metabolic graft function. Ig-Therasorb ® immunoapheresis (IA) of the xenogeneic perfusate was performed to protect the discordant pig livers from hyperacute rejection, mediated by preformed naturally occurring human xenogeneic antibodies. The application of IA created stable autologous graft reperfusion after a short time of xenoperfusion, but it was not able to prevent the livers from severe synthetic and functional damage. In the future, improvement of xenogeneic graft function, rather than pure prolongation of perfusion, must be the principal aim.

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“…Two of these patients are alive today for more than 28 years later, and are in excellent health [59][60][61]. Other investigators have used similar apparatus using the livers from transgenic pigs to keep these patients alive until a human liver becomes available for transplantation [62].…”

Section: The Use Of Animal Organs and Xenotransplantationsmentioning

confidence: 99%

Ethical Issues in Organ Transplantation

Abouna¹

2003

Med Princ Pract

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Clinical organ transplantation has been recognized as one of the most gripping medical advances of the century as it provides a way of giving the gift of life to patients with terminal failure of vital organs, which requires the participation of other fellow human beings and of society by donating organs from deceased or living individuals. The increasing incidence of vital organ failure and the inadequate supply of organs, especially from cadavers, has created a wide gap between organ supply and organ demand, which has resulted in very long waiting times to receive an organ as well as an increasing number of deaths while waiting. These events have raised many ethical, moral and societal issues regarding supply, the methods of organ allocation, the use of living donors as volunteers including minors. It has also led to the practice of organ sale by entrepreneurs for financial gains in some parts the world through exploitation of the poor, for the benefit of the wealthy. The current advances in immunology and tissue engineering and the use of animal organs, xenotransplantation, while offering very promising solutions to many of these problems, also raise additional ethical and medical issues which must be considered by the medical profession as well as society. This review deals with the ethical and moral issues generated by the current advances in organ transplantation, the problem of organ supply versus organ demand and the appropriate allocation of available organs. It deals with the risks and benefits of organ donation from living donors, the appropriate and acceptable methods to increase organ donation from the deceased through the adoption of the principle of ‘presumed consent’, the right methods of providing acceptable appreciation and compensation for the family of the deceased as well as volunteer and altruistic donors, and the duties and responsibilities of the medical profession and society to help fellow humans. The review also deals with the appropriate and ethically acceptable ways of utilizing the recent advances of stem cell transplantation from adult versus fetal donors, tissue engineering and the use of organs from animals or xenotransplantation. Data provided in support of the concept that clinical organ and tissue transplantation can be more beneficial and life saving if everyone involved in the process, including physicians and medical institutions, respect and consider the best interests of the patients, as well as honor the ethical, moral and religious values of society and are not tempted to seek personal fame or financial rewards.

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LIVER ALLOTRANSPLANTATION AFTER EXTRACORPOREAL HEPATIC SUPPORT WITH TRANSGENIC (hCD55/hCD59) PORCINE LIVERS

Abstract: The CD55/CD59 transgenic porcine liver appears capable of safely "bridging" a patient to liver transplantation. Human PoERV infection from these livers has yet to be demonstrated.

Cited by 145 publications

References 19 publications

Pig and Minipig Cytochromes P450

Pig and Minipig Cytochromes P450

Impact of Ig-Therasorb® Immunoapheresis on Stability of Xenogeneic Ex Vivo Porcine Liver Perfusion – Value of Aminotransferases and Flow Rates for the Assessment of Metabolic Graft Viability

Ethical Issues in Organ Transplantation

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