Genetic modification of pigs as organ donors for xenotransplantation

@article{Klymiuk2010GeneticMO,
  title={Genetic modification of pigs as organ donors for xenotransplantation},
  author={Nikolai Klymiuk and Bernhard Aigner and Gottfried Brem and Eckhard Wolf},
  journal={Molecular Reproduction and Development},
  year={2010},
  volume={77}
}
Transgenic pigs are promising donor organisms for xenotransplantation as they share many anatomical and physiological characteristics with humans. The most profound barrier to pig‐to‐primate xenotransplantation is the rejection of the grafted organ by a cascade of immune mechanisms commonly referred to as hyperacute rejection (HAR), acute humoral xenograft rejection (AHXR), immune cell‐mediated rejection, and chronic rejection. Various strategies for the genetic modification of pigs facilitate… 
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The delivery of immunoreceptor tyrosine‐based inhibitory motif (ITIM)‐dependent and related negative signals to control innate and adaptive T and B cells might overcome cell‐mediated xenogeneic immunity.
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Genome Engineering for Xenotransplantation
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In this review, the benefits and draw-backs of various genome engineering protocols, and examples of their application in xenotransplantation, are discussed.
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References

SHOWING 1-10 OF 87 REFERENCES
Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection.
TLDR
A strategy for developing a pig-to-primate xenogeneic transplantation model to test whether the expression of a human complement inhibitor in transgenic pigs could render Xenogeneic organs resistant to hyperacute rejection is demonstrated.
Transgenic pigs designed to express human CD59 and H‐transferase to avoid humoral xenograft rejection
TLDR
Transgenic pigs that coexpress hCD59 and HT in various cells and tissues are developed to address both natural antibody binding and complement activation and suggest that engineering donor pigs to express multiple molecules that address different humoral components of Xenograft rejection represents an important step toward enhancing xenograft survival and improving the prospect of clinical xenotransplantation.
Characterization of transgenic pigs expressing functionally active human CD59 on cardiac endothelium.
TLDR
Evidence is presented that shows that the low level of human CD59 protein expression in the porcine heart inhibits membrane attack complex assembly and reduces tissue damage when the heart is transplanted to a baboon, supporting the concept that the species specific function of CRPs contributes to the humoral barrier to xenotransplantation.
A HUMAN CD46 TRANSGENIC PIG MODEL SYSTEM FOR THE STUDY OF DISCORDANT XENOTRANSPLANTATION
TLDR
This is the first report to describe generation of transgenic pigs that express human CD46, and the first in vivo demonstration of the ability of humanCD46 expressed on pig organs to regulate complement activation and overcome hyperacute rejection upon transplantation of a vascularized organ into nonhuman primates.
The perspectives for porcine-to-human xenografts.
Expression of Biologically Active Human TRAIL in Transgenic Pigs
TLDR
Ubiquitous expression of human TRAIL was achieved in transgenic pigs without detrimental side effects and will be used for future xenotransplantation experiments to modulate primate anti-pig cellular immune responses.
Current cellular innate immune hurdles in pig-to-primate xenotransplantation
TLDR
Cellular human innate immune responses are increasingly recognized as barriers to successful pig-to-human xenotransplantation, and only a detailed knowledge of the molecular mechanisms involved will allow us to overcome this barrier.
TISSUE EXPRESSION OF HUMAN COMPLEMENT INHIBITOR, DECAY‐ACCELERATING FACTOR, IN TRANSGENIC PIGS A POTENTIAL APPROACH FOR PREVENTING XENOGRAFT REJECTION
Since complement-mediated hyperacute rejection of xenografts prevents the use of pigs as organ donors to man, the development of transgenic animals expressing species-specific complement inhibitors…
Characterization of a CD46 transgenic pig and protection of transgenic kidneys against hyperacute rejection in non‐immunosuppressed baboons
TLDR
The expression levels, tissue distribution and in vitro functional tests indicate highly efficient CD46 function, controlling both classical and alternative pathway complement activation, which suggests it might be the complement regulator of choice to protect xenografts.
Transgenic expression of CTLA4-Ig by fetal pig neurons for xenotransplantation
TLDR
Data show that neurons from transgenic pigs express hCTLA4-Ig in situ and support the use of this material in future pre-clinical trials in neuron xenotransplantation.
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