Transgenic expression of human leukocyte antigen‐E attenuates Gal<scp>KO</scp>.h<scp>CD</scp>46 porcine lung xenograft injury

Laird, Christopher; Burdorf, Lars; French, Beth M.; Kubicki, Natalia; Cheng, Xiangfei; Braileanu, Gheorghe; Sun, Wenji; O’Neill, Natalie A.; Cimeno, Arielle; Parsell, Dawn; So, Edward; Bähr, Andrea; Klymiuk, Nikolai; Phelps, Carol J.; Ayares, David; Azimzadeh, Agnes M.; Pierson, Richard N.

doi:10.1111/xen.12294

Cited by 46 publications

(38 citation statements)

References 28 publications

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“…However, neither sTNF-αR-Fc nor HO-1 suppressed anti-pig humoral reaction as attested by antipig IgG and IgM levels 1 month post-implantation [40]. Expression of human leukocyte antigen-E (HLA-E) on porcine endothelial cells decreased natural killer cell-mediated cytotoxicity in vitro and prolonged survival time of pig lungs perfused with human blood ex vivo [41]. Perhaps, the most challenging immunological hurdle to overcome in xenotransplantation is the adaptive immune system's cell-mediated response.…”

Section: Modification Of Donor Pigs To Mitigate the Immunementioning

confidence: 99%

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Mourad

Gianello

2017

Curr Transpl Rep

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Purpose of Review Cell xenotransplantation has the potential to provide a safe, ethically acceptable, unlimited source for cell replacement therapies. This review focuses on genetic modification strategies aimed to overcome remaining hurdles standing in the way of clinical porcine islet transplantation and to develop neural cell xenotransplantation. Recent Findings In addition to previously described genetic modifications aimed to mitigate hyperacute rejection, instant blood-mediated inflammatory reaction, and cell-mediated rejection, new data showing the possibility of increasing porcine islet insulin secretion by transgenesis is an interesting addition to the array of genetically modified pigs available for xenotransplantation. Moreover, combining multiple modifications is possible today thanks to new, improved genomic editing tools. Summary Genetic modification of large animals, pigs in particular, has come a long way during the last decade. These modifications can help minimize immunological and physiological incompatibilities between porcine and human cells, thus allowing for better tolerance and function of xenocells.

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Section: Modification Of Donor Pigs To Mitigate the Immunementioning

confidence: 99%

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Mourad

Gianello

2017

Curr Transpl Rep

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“…Finally, pCD45 vs SSC plot was generated and pig cells populations defined on the base of their cytometric properties, referred to as population A, B, and C, respectively (right plot), from which different pig markers were further analyzed as shown in Table 2 xenoperfusions and the numbers of circulating pig NK cells did not differ between wt and tg perfusions (table 2 and adhesion assays. 13,23,28 In addition, we have previously reported that transmigration of human NK cells through pig endothelium depends on hCD49d-pCD106 interactions 45 and on hCD99 interactions with so far unknown ligands expressed by pEC. 46 In light of reduced endothelial cell activation during HLA-E/hCD46 tg compared to wt pig limb xenoperfusion, 35 LCA, leukocyte common antigen.…”

Section: Discussionmentioning

confidence: 98%

“…Preferential recruitment of human NK cells, to rat hearts perfused with human peripheral blood lymphocytes, was reported in a seminal paper by Inverardi et al 25 This finding was corroborated in the Munich heart model showing reduced tissue infiltration by NK cells in HLA-E transgenic pig hearts perfused with human blood, as recently reported in abstract form. [28][29][30][31] During the past years, our collaborative group has established a novel model of ex vivo xenoperfusion with human blood using porcine forelimbs of genetically modified pigs. 32 In the current work, a combined strategy to reduce humoral and cellular innate xenoresponses by overexpression of HLA-E and hCD46, respectively, was used to study interactions between human NK cells and the porcine vascular system.…”

Section: Introductionmentioning

confidence: 99%

Release of pig leukocytes and reduced human NK cell recruitment during ex vivo perfusion of HLA‐E/human CD46 double‐transgenic pig limbs with human blood

Yung

Bongoni

Pradier

et al. 2017

Xenotransplantation

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Ex vivo perfusion of pig forelimbs using whole human blood represents a powerful tool to study humoral and early cell-mediated rejection mechanisms of vascularized pig-to-human xenotransplantation, although there are several limitations of the model. Here, we show that (i) transgenic expression of HLA-E/hCD46 in pig limbs provides partial protection from human NK cell-mediated xeno responses and (ii) the emergence of a pig cell population during xenoperfusions with implications for the immunogenicity of xenografts.

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“…Burdorf et al showed that platelet sequestration and activation during GTKO.hCD46 pig lung perfusion by human blood was primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor [22]. Laird et al showed that transgenic expression of human leukocyte antigen (HLA)-E attenuates GTKO.hCD46 pig lung xenograft injury [23]. A recent review from the same group concluded that genetic modification of pigs coupled with drugs targeting complement activation, coagulation, and inflammation have significantly increased duration of pig lung function in ex vivo human blood perfusion models, and life-supporting lung xenograft survival in vivo [24].…”

Section: Introductionmentioning

confidence: 99%

Xenotransplantation

Ekser

Li²,

Cooper³

2017

Current Opinion in Organ Transplantation

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Purpose of review To review the progress in the field of xenotransplantation with special attention to most recent encouraging findings which will eventually bring xenotransplantation to the clinic in the near future. Recent findings Starting from early 2000, with the introduction of Gal-knockout pigs, prolonged survival especially in heart and kidney xenotransplantation was recorded. However, remaining antibody barriers to nonGal antigens continue to be the hurdle to overcome. The production of genetically-engineered pigs was difficult requiring prolonged time. However, advances in gene editing, such as zinc finger nucleases, transcription activator-like effector nucleases, and most recently CRISPR technology made the production of genetically-engineered pigs easier and available to more researchers. Today, the survival of pig-to-nonhuman primate heterotopic heart, kidney, and islet xenotransplantation reached >900 days, >400 days, and >600 day, respectively. The availability of multiple-gene pigs (5 or 6 genetic modifications) and/or newer costimulation blockade agents significantly contributed to this success. Now, the field is getting ready for clinical trials with an international consensus. Summary Clinical trials in cellular or solid organ xenotransplantation are getting closer with convincing preclinical data from many centers. The next decade will show us new achievements and additional barriers in clinical xenotransplantation.

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Transgenic expression of human leukocyte antigen‐E attenuates GalKO.hCD46 porcine lung xenograft injury

Abstract: We conclude human NK cell activation contributes significantly to GalTKO.hCD46 pig endothelial injury and lung inflammation and show that expression of HLA-E is associated with physiologically meaningful protection of GalTKO.hCD46 cells and organs exposed to human blood.

Cited by 46 publications

References 28 publications

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Gene Editing, Gene Therapy, and Cell Xenotransplantation: Cell Transplantation Across Species

Release of pig leukocytes and reduced human NK cell recruitment during ex vivo perfusion of HLA‐E/human CD46 double‐transgenic pig limbs with human blood

Xenotransplantation

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