Release of pig leukocytes and reduced human <scp>NK</scp> cell recruitment during ex vivo perfusion of <scp>HLA</scp>‐E/human <scp>CD</scp>46 double‐transgenic pig limbs with human blood

Yung, Gisella Puga; Bongoni, Anjan K.; Pradier, Amandine; Madelon, Natacha; Papaserafeim, Maria; Sfriso, Riccardo; Ayares, David; Wolf, Eckhard; Klymiuk, Nikolai; Bähr, Andrea; Constantinescu, Mihai A.; Voegelin, Esther; Kiermeir, David; Jenni, Hansjörg; Rieben, Robert

doi:10.1111/xen.12357

Cited by 17 publications

(9 citation statements)

References 68 publications

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“…This mechanism might be aggravated by incompatibilities between the porcine and primate coagulation and complement systems. In our study, donor genetic modifications were identical in both groups; all donor animals were hemizygous transgenic for hCD46 and hTBM, which have been shown to reduce any type of rejection reaction as well as thrombotic microangiopathy 33,34 . As we did not observe any case of early graft failure in the CP group, it is unlikely that complement or coagulation incompatibilities may cause PCXD in absence of ischemia‐reperfusion injury.…”

Section: Discussionmentioning

confidence: 67%

Cold non‐ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig‐to‐baboon xenotransplantation

Längin

Reichart²,

Steen

et al. 2020

Xenotransplantation

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Background Successful preclinical transplantations of porcine hearts into baboon recipients are required before commencing clinical trials. Despite years of research, over half of the orthotopic cardiac xenografts were lost during the first 48 hours after transplantation, primarily caused by perioperative cardiac xenograft dysfunction (PCXD). To decrease the rate of PCXD, we adopted a preservation technique of cold non‐ischemic perfusion for our ongoing pig‐to‐baboon cardiac xenotransplantation project. Methods Fourteen orthotopic cardiac xenotransplantation experiments were carried out with genetically modified juvenile pigs (GGTA1‐ KO/hCD46/hTBM) as donors and captive‐bred baboons as recipients. Organ preservation was compared according to the two techniques applied: cold static ischemic cardioplegia (IC; n = 5) and cold non‐ischemic continuous perfusion (CP; n = 9) with an oxygenated albumin‐containing hyperoncotic cardioplegic solution containing nutrients, erythrocytes and hormones. Prior to surgery, we measured serum levels of preformed anti‐non‐Gal‐antibodies. During surgery, hemodynamic parameters were monitored with transpulmonary thermodilution. Central venous blood gas analyses were taken at regular intervals to estimate oxygen extraction, as well as lactate production. After surgery, we measured troponine T and serum parameters of the recipient’s kidney, liver and coagulation functions. Results In porcine grafts preserved with IC, we found significantly depressed systolic cardiac function after transplantation which did not recover despite increasing inotropic support. Postoperative oxygen extraction and lactate production were significantly increased. Troponin T, creatinine, aspartate aminotransferase levels were pathologically high, whereas prothrombin ratios were abnormally low. In three of five IC experiments, PCXD developed within 24 hours. By contrast, all nine hearts preserved with CP retained fully preserved systolic function, none showed any signs of PCXD. Oxygen extraction was within normal ranges; serum lactate as well as parameters of organ functions were only mildly elevated. Preformed anti‐non‐Gal‐antibodies were similar in recipients receiving grafts from either IC or CP preservation. Conclusions While standard ischemic cardioplegia solutions have been used with great success in human allotransplantation over many years, our data indicate that they are insufficient for preservation of porcine hearts transplanted into baboons: Ischemic storage caused severe impairment of cardiac function and decreased tissue oxygen supply, leading to multi‐organ failure in more than half of the xenotransplantation experiments. In contrast, cold non‐ischemic heart preservation with continuous perfusion reliably prevented early graft failure. Consistent survival in the perioperative phase is a prerequisite for preclinical long‐term results after cardiac xenotransplantation.

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Section: Discussionmentioning

confidence: 67%

Cold non‐ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig‐to‐baboon xenotransplantation

Längin

Reichart²,

Steen

et al. 2020

Xenotransplantation

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“…Seebach) reported in vitro studies of HLA‐E/hCD46 expression in the same ex vivo pig limb xenoperfusion model. NK cytotoxicity against hCD46 single transgenic porcine endothelial cells was not different when compared to wt cells . Similar to the results presented here, NK cell infiltration in the HLA‐E/hCD46 gm tissue was less than in wt controls at the end of limb perfusion.…”

Section: Discussionmentioning

confidence: 99%

Multiple genetically modified GTKO/hCD46/HLA‐E/hβ2−mg porcine hearts are protected from complement activation and natural killer cell infiltration during ex vivo perfusion with human blood

Abicht

Sfriso

Reichart³

et al. 2018

Xenotransplantation

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“…The fetal maternal interface is an immune protected site due to a complex expression of a concert of immunoregulatory proteins including HLA‐E. Yung et al, have cloned and expressed HLA‐E in pigs along with a complement regulatory protein. To study the intact vascular system the authors perfused an isolated forelimb with human blood.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Xenotransplantation literature update, January/February 2018

Hawthorne

Burlak

2018

Xenotransplantation

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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

Cited by 17 publications

References 68 publications

Cold non‐ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig‐to‐baboon xenotransplantation

Cold non‐ischemic heart preservation with continuous perfusion prevents early graft failure in orthotopic pig‐to‐baboon xenotransplantation

Multiple genetically modified GTKO/hCD46/HLA‐E/hβ2−mg porcine hearts are protected from complement activation and natural killer cell infiltration during ex vivo perfusion with human blood

Xenotransplantation literature update, January/February 2018

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