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Review
. 2017 Dec;22(6):522-528.
doi: 10.1097/MOT.0000000000000466.

Tolerance in xenotransplantation

Kazuhiko Yamada  1 , Megan Sykes, David H Sachs
Affiliations
Review

Tolerance in xenotransplantation

Kazuhiko Yamada et al. Curr Opin Organ Transplant. 2017 Dec.

Abstract

Purpose of review: This review describes recent progress in tolerance-inducing strategies across xenogeneic immunological barriers as well as the potential benefit of a tolerance strategy for islets and kidney xenotransplantation.

Recent findings: Using advanced gene editing technologies, xenotransplantation from multitransgenic alpha-1,3-galactosyltransferase knockout pigs has demonstrated marked prolongation of renal xenograft survival, ranging from days to greater than several months for life-supporting kidneys, and more than 2 years in a heterotopic nonlife-supporting cardiac xenograft model. Continuous administration of multiple immunosuppressive drugs has been required and attempts to taper immunosuppression have been unsuccessful. It appears likely that low levels of T cell dependent antibodies and activation of innate responses are responsible for xenograft loss. Mixed chimerism and thymic transplantation approaches have achieved xenogeneic tolerance in pig-to-mouse models and both have recently been extended to pig-to-baboon models. Encouraging results have been reported, including persistence of macrochimerism, prolonged pig skin graft survival, donor-specific unresponsiveness in vitro and detection of recent T cell emigrants in vivo.

Summary: Although tolerance induction in vivo has not yet been achieved in pig-to-baboon models, recent results are encouraging that this goal will be attainable through genetic engineering of porcine donors.

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Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic diagram of vascularized thymus plus kidney transplantation in pig-to-baboon models.
Figure 2
Figure 2
Schematic diagram of intra-bone bone marrow transplantation in pig-to-baboon models. * WBI: whole body irradiation. TI: thymic irradiation.
See this image and copyright information in PMC

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References

    1. Cowan PJ. The use of CRISPR/Cas associated technologies for cell transplant applications. Current opinion in organ transplantation. 2016;21(5):461–6. This article summarized recent developments in the use of the clustered, regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated 9 (Cas9) genome editing system for cell transplant applications, ranging from transplantation of corrected autologous patient stem cells, to the treatment of inherited diseases, as well as the tailoring of donor pigs for cell xenotransplantation. - PubMed
    1. Hai T, Teng F, Guo R, Li W, Zhou Q. One-step generation of knockout pigs by zygote injection of CRISPR/Cas system. Cell research. 2014;24(3):372–5. - PMC - PubMed
    1. Higginbotham L, Mathews D, Breeden CA, Song M, Farris AB, 3rd, Larsen CP, et al. Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model. Xenotransplantation. 2015;22(3):221–30. This article reported long-term survival (>133 and >126 days) of rhesus macaques that had low-titer levels of preformed natural antibodies that were treated with an anti-CD154-based regimen and then transplanted with galactose-α1,3-galactose knockout/CD55 transgenic pig kidneys. - PMC - PubMed
    1. Iwase H, Hara H, Ezzelarab M, Li T, Zhang Z, Gao B, et al. Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts. Xenotransplantation. 2017;24(2) The authors used porcine renal grafts from six-gene specific genetically modified swine that survied for >7 months in baboons. Although the number of experiments is very limited, the authors concluded that expression of human endothelial protein C receptor (±CD55) in the graft might be important to avoid coagulation dysregulation. - PMC - PubMed
    1. Hering BJ, Wijkstrom M, Graham ML, Hardstedt M, Aasheim TC, Jie T, et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nature medicine. 2006;12(3):301–3. - PubMed