Pigs expressing the human inhibitory ligand <scp>PD</scp>‐L1 (<scp>CD</scp> 274) provide a new source of xenogeneic cells and tissues with low immunogenic properties

Buermann, Anna; Petkov, Stoyan; Petersen, Björn; Hein, Rabea; Lucas‐Hahn, Andrea; Baars, Wiebke; Brinkmann, Antje; Niemann, Heiner; Schwinzer, Reinhard

doi:10.1111/xen.12387

Cited by 45 publications

(31 citation statements)

References 70 publications

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“…Although there are many other genetic manipulations that could be considered, some of which are aimed to protect against the human adaptive immune response, for example, swine leukocyte antigen (SLA) class I‐knockout, SLA class II knockdown, transgenic expression of cytotoxic T lymphocyte‐associated protein 4‐immunoglobulin (CTLA4‐Ig) or programmed cell death‐ligand 1 (PD‐L1), our opinion is that, although they are likely to be beneficial, they are not as important at this early stage in the development of xenotransplantation as manipulations that protect against the innate immune response. Although they will be advantageous in the near future, at present there are immunosuppressive agents (admittedly not all yet approved by national regulatory authorities) that can effectively prevent the adaptive response, for example, anti‐CD40 monoclonal antibodies (mAbs) .…”

Section: Introductionmentioning

confidence: 99%

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Cooper

Hara

Iwase

et al. 2019

Xenotransplantation

132

131

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Xenotransplantation research has made considerable progress in recent years, largely through the increasing availability of pigs with multiple genetic modifications. We suggest that a pig with nine genetic modifications (ie, currently available) will provide organs (initially kidneys and hearts) that would function for a clinically valuable period of time, for example, >12 months, after transplantation into patients with end‐stage organ failure. The national regulatory authorities, however, will likely require evidence, based on in vitro and/or in vivo experimental data, to justify the inclusion of each individual genetic modification in the pig. We provide data both from our own experience and that of others on the advantages of pigs in which (a) all three known carbohydrate xenoantigens have been deleted (triple‐knockout pigs), (b) two human complement‐regulatory proteins (CD46, CD55) and two human coagulation‐regulatory proteins (thrombomodulin, endothelial cell protein C receptor) are expressed, (c) the anti‐apoptotic and “anti‐inflammatory” molecule, human hemeoxygenase‐1 is expressed, and (d) human CD47 is expressed to suppress elements of the macrophage and T‐cell responses. Although many alternative genetic modifications could be made to an organ‐source pig, we suggest that the genetic manipulations we identify above will all contribute to the success of the initial clinical pig kidney or heart transplants, and that the beneficial contribution of each individual manipulation is supported by considerable experimental evidence.

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Section: Introductionmentioning

confidence: 99%

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Cooper

Hara

Iwase

et al. 2019

Xenotransplantation

132

131

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“…Nevertheless, further genetic modifications are needed to increase long‐term graft survival and reduce immunosuppressive treatments. Especially, concepts to decrease cellular immune responses are now coming into focus as they are thought to reduce immune suppressive regimes to clinical applicable levels …”

Section: Discussionmentioning

confidence: 99%

“…Porcine peripheral blood mononuclear cells (PBMC) from piglet 7070 F3 were isolated and cultivated as previously described . For maintaining cells in culture for up to 13 days, 2 µg/mL concanavalin A (Sigma‐Aldrich) and 100 ng/mL rhIL‐2 (ImmunoTools) were added to the culture.…”

Section: Methodsmentioning

confidence: 99%

Possible detrimental effects of beta‐2‐microglobulin knockout in pigs

Sake

Frenzel

Lucas‐Hahn

et al. 2019

Xenotransplantation

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Background Despite major improvements in pig‐to‐primate xenotransplantation, long‐term survival of xenografts is still challenging. The major histocompatibility complex (MHC) class I, which is crucial in cellular immune response, is an important xenoantigen. Abrogating MHC class I expression on xenografts might be beneficial for extending graft survival beyond current limits. Methods In this study, we employed the CRISPR/Cas9 system to target exon 2 of the porcine beta‐2‐microglobulin (B2M) gene to abrogate SLA class I expression on porcine cells. B2M‐KO cells served as donor cells for somatic cell nuclear transfer, and cloned embryos were transferred to three recipient sows. The offspring were genotyped for mutations at the B2M locus, and blood samples were analyzed via flow cytometry for the absence of SLA class I molecules. Results Pregnancies were successfully established and led to the birth of seven viable piglets. Genomic sequencing proved that all piglets carried biallelic modifications at the B2M locus leading to a frameshift, a premature stop codon, and ultimately a functional knockout. However, survival times of these animals did not exceed 4 weeks due to unexpected disease processes. Conclusion Here, we demonstrate the feasibility of generating SLA class I knockout pigs by targeting the porcine beta‐2‐microglobulin gene using the CRISPR/Cas9 system. Additionally, our findings indicate for the first time that this genetic modification might have a negative impact on the viability of the animals. These issues need to be solved to unveil the real value for xenotransplantation in the future.

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“…It has been shown that human PD-L1 expression protects pig fibroblasts from human CTL and NK cell cytotoxicity. This protection is increasable by tumor necrosis factor-α (TNF-α)-induced PD-L1 upregulation (Buermann et al, 2018).…”

Section: Pd-l1 Expression On Donor Cells Renders Them Somewhat Lowmentioning

confidence: 99%

“…It has been shown that human PD‐L1 expression protects pig fibroblasts from human CTL and NK cell cytotoxicity. This protection is increasable by tumor necrosis factor‐α (TNF‐α)‐induced PD‐L1 upregulation (Buermann et al, ). Similar results were obtained by Plege‐Fleck et al () in the case of a pig to rat xenotransplantation.…”

Section: Introductionmentioning

confidence: 99%

An update on potentials and promises of T cell co‐signaling molecules in transplantation

Mardomi

Mohammadi

Khosroshahi

et al. 2019

Journal Cellular Physiology

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Pigs expressing the human inhibitory ligand PD‐L1 (CD 274) provide a new source of xenogeneic cells and tissues with low immunogenic properties

Abstract: These data indicate a low immunogenic, immune-protected status of cells from hPD-L1 transgenic pigs. The integration of the hPD-L1 concept into existing multi-transgenic pigs is promising to achieve long-term survival of porcine xenografts in non-human primate recipients.

Cited by 45 publications

References 70 publications

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Justification of specific genetic modifications in pigs for clinical organ xenotransplantation

Possible detrimental effects of beta‐2‐microglobulin knockout in pigs

An update on potentials and promises of T cell co‐signaling molecules in transplantation

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