Genetic engineering of pigs for xenotransplantation to overcome immune rejection and physiological incompatibilities: The first clinical steps

Lei, Tiantian; Chen, Lin; Wang, Kejing; Du, Suya; Gonelle‐Gispert, Carmen; Wang, Yi; Bühler, Léo H.

doi:10.3389/fimmu.2022.1031185

Cited by 13 publications

(6 citation statements)

References 152 publications

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“…Removal of SLAs from donor pigs has been considered to avoid immune rejection of the xenograft. 60,61 However, SLA deletion can render the pig at risk for infectious complications. 62 Alternatively, site-specific SLA mutations are recommended to avoid the reactivity with anti-HLA antibodies.…”

Section: Discussionmentioning

confidence: 99%

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Genetic diversity, growth and heart function of Auckland Island pigs, a potential source for organ xenotransplantation

Lange,

Medugorac,

Ali

et al. 2024

Xenotransplantation

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One of the prerequisites for successful organ xenotransplantation is a reasonable size match between the porcine organ and the recipient's organ to be replaced. Therefore, the selection of a suitable genetic background of source pigs is important. In this study, we investigated body and organ growth, cardiac function, and genetic diversity of a colony of Auckland Island pigs established at the Center for Innovative Medical Models (CiMM), LMU Munich. Male and female Auckland Island pig kidney cells (selected to be free of porcine endogenous retrovirus C) were imported from New Zealand, and founder animals were established by somatic cell nuclear transfer (SCNT). Morphologically, Auckland Island pigs have smaller body stature compared to many domestic pig breeds, rendering their organ dimensions well‐suited for human transplantation. Furthermore, echocardiography assessments of Auckland Island pig hearts indicated normal structure and functioning across various age groups throughout the study. Single nucleotide polymorphism (SNP) analysis revealed higher runs of homozygosity (ROH) in Auckland Island pigs compared to other domestic pig breeds and demonstrated that the entire locus coding the swine leukocyte antigens (SLAs) was homozygous. Based on these findings, Auckland Island pigs represent a promising genetic background for organ xenotransplantation.

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Section: Discussionmentioning

confidence: 99%

“…Removal of SLAs from donor pigs has been considered to avoid immune rejection of the xenograft 60,61 . However, SLA deletion can render the pig at risk for infectious complications 62 .…”

Section: Discussionmentioning

confidence: 99%

Genetic diversity, growth and heart function of Auckland Island pigs, a potential source for organ xenotransplantation

Lange,

Medugorac,

Ali

et al. 2024

Xenotransplantation

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“…Xenotransplantion has been notorious for very high rates of failures when it was first suggested. The discovery of the Gal epitope and the finding of the concordant and discordant species was a serious advancement in the field (Lei et al, 2022; Sykes & Sachs, 2022). Recently, Griffith et al reported genetically modified porcine‐to‐human cardiac xenotransplantation.…”

Section: Discussionmentioning

confidence: 99%

Composite tissue xenopreservation: Preliminary results of staged VCA in rat to mouse model

et al. 2023

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BackgroundThe time between procurement and transplantation of composite tissues, especially regarding the limited donor pool, is a challenge effecting the outcomes of the transplantation. Current preservation techniques mainly include either cold preservation with a solution or machine perfusion using blood or certain oxygen‐carrying solutions. However, none enables preservation beyond 24 h. Increasing this time to several days will provide better usage of the donor pool, safer transplantation of VCA with significant muscle content, and gives time to stabilize a patient before long surgical procedures. Herein, we described a novel strategy of xenopreservation (preservation via xenotransplantation) to preserve composite tissues for 7 days, followed by staged transplantation.Materials and MethodsWe used two concordant species, female Sprague Dawley rats (n = 10) and female CF‐1 mice (n = 10) in this study. Four of pair of animals are used for anatomical study. The groin flap of the rat was used as a xenograft and xenotransplanted to the neck area of the carrier mouse. Cyclosporine (CsA) was administered used as immunosuppressant. After 7 days of preservation on the mouse neck, xenotransplanted groin flap (called xenopreserved flap) was re‐harvested, skin and vessels samples were collected for histopathological evaluation, and the xenopreserved flap was transplanted to the donor rat's opposite groin area. Anastomoses were performed between the flap's pedicle and the femoral vessels. Clinical observation regarding inflammation and tissue perfusion of the xenopreserved flap was monitored daily. Fifteen days after the second surgical procedure, the rats were euthanized, and skin and vessel samples were collected. Histologic evaluation, including inflammatory cell numbers, was performed. Wilcoxon test was used to compare the changes in inflammation severity and p < .05 was set for statistical significance.ResultsAll xenopreserved groin flaps except one survived. Mean lymphocyte count before the second operation (at the end of the xenopreservation procedure) was 20,22 ± 0.44 and reduced to 13,14 ± 0.47 at the end of 15 days, and the difference was statistically significant (p < .05).ConclusionThis proof‐of‐concept study with preliminary results showed that xenotransplantation might be a novel strategy for preservation of VCA for a certain period of time. However, additional translational studies are needed to modulate the tissue changes following xenopreservation.

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“…(An excellent review has been provided by others). 91 The innate immune cellular response can be inhibited by certain genetic modifications in the donor pig, for example, expression of human CD47 and/or HLA molecules (HLA-E and/or G) that suppress macrophage and NK cell activation, respectively. 92-96…”

Section: The Innate Cellular Immune Responsementioning

confidence: 99%

“…Innate immune cells, for example, macrophages, monocytes, and natural killer (NK) cells, also play significant roles 90 which to date have been insufficiently studied and are less well‐defined. (An excellent review has been provided by others) 91 . The innate immune cellular response can be inhibited by certain genetic modifications in the donor pig, for example, expression of human CD47 and/or HLA molecules (HLA‐E and/or G) that suppress macrophage and NK cell activation, respectively 92–96 …”

Section: The Mechanism Of Amr In Xenotransplantationmentioning

confidence: 99%

Antibody‐mediated rejection in xenotransplantation: Can it be prevented or reversed?

Habibabady,

McGrath,

Kinoshita

et al. 2023

Xenotransplantation

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Antibody‐mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46% vs. 7%) than in allotransplantation (3% vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti‐donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti‐inflammatory therapy. Depletion or neutralization of anti‐pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG‐degrading enzymes do not deplete IgM. Despite the expression of human complement‐regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti‐C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell‐targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti‐inflammatory agents, anti‐IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti‐inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ‐source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD‐L1, HLA E, and/or HLA‐G.

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Genetic engineering of pigs for xenotransplantation to overcome immune rejection and physiological incompatibilities: The first clinical steps

Cited by 13 publications

References 152 publications

Genetic diversity, growth and heart function of Auckland Island pigs, a potential source for organ xenotransplantation

Genetic diversity, growth and heart function of Auckland Island pigs, a potential source for organ xenotransplantation

Composite tissue xenopreservation: Preliminary results of staged VCA in rat to mouse model

Antibody‐mediated rejection in xenotransplantation: Can it be prevented or reversed?

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