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Genetically modified pigs as donors of cells, tissues, and organs for xenotransplantation

Wolf, Eckhard, Kemter, Elisabeth, Klymiuk, Nikolai, Reichart, Bruno·2019·Animal Frontiers
DOI 10.1093/af/vfz014PMC PMC6951927
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Figure 1. Protection of xenotransplanted porcine pancreatic islets against T-cell mediated rejection by local expression of LEA29Y. (A) Principle of co-stimulation blockade of T cells. Activation of T cells requires interaction between the T-cell receptor and a peptide-loaded MHC on an antigen-presenting cell (APC). In addition, a second signal such as the interaction between CD28 und CD80/CD86 is required. The interaction of CTLA4 and CD80/CD86 blocks T-cell activation. The latter can also be achieved by the soluble molecule CTLA4-Ig or its affinity-optimized version LEA29Y. (B) Immunohistochemical staining of LEA29Y in pancreas sections from INS-LEA29Y transgenic pigs. (C) Transplantation of neonatal islet-like cell clusters (NICCs) from wild-type (WT) or INS-LEA29Y transgenic pigs (LEA29Y) under the kidney capsule of immune deficient streptozotocin (STZ)-diabetic NSG mice results in an insulin-positive cell mass that is able to normalize their blood glucose level. If the mice are subsequently reconstituted with human peripheral blood mononuclear cells (hPBMCs), the WT islets are rejected while the LEA29Y transgenic islets are protected (Klymiuk et al., 2012). (D) Histology of the transplantation site. In recipients of WT NICCs, very few insulin-positive cells were found, but a massive T-cell infiltration (shown by CD45 staining) was evident. In contrast, LEA29Y expressing NICCs survived and formed large clusters of insulin-positive cells. T-cell infiltration was observed in the periphery, but not within the insulin-positive cell clusters.
Figure 1. Protection of xenotransplanted porcine pancreatic islets against T-cell mediated rejection by local expression of LEA29Y. (A) Principle of co-stimulation blockade of T cells. Activation of T cells requires interaction between the T-cell receptor and a peptide-loaded MHC on an antigen-presenting cell (APC). In addition, a second signal such as the interaction between CD28 und CD80/CD86 is required. The interaction of CTLA4 and CD80/CD86 blocks T-cell activation. The latter can also be achieved by the soluble molecule CTLA4-Ig or its affinity-optimized version LEA29Y. (B) Immunohistochemical staining of LEA29Y in pancreas sections from INS-LEA29Y transgenic pigs. (C) Transplantation of neonatal islet-like cell clusters (NICCs) from wild-type (WT) or INS-LEA29Y transgenic pigs (LEA29Y) under the kidney capsule of immune deficient streptozotocin (STZ)-diabetic NSG mice results in an insulin-positive cell mass that is able to normalize their blood glucose level. If the mice are subsequently reconstituted with human peripheral blood mononuclear cells (hPBMCs), the WT islets are rejected while the LEA29Y transgenic islets are protected (Klymiuk et al., 2012). (D) Histology of the transplantation site. In recipients of WT NICCs, very few insulin-positive cells were found, but a massive T-cell infiltration (shown by CD45 staining) was evident. In contrast, LEA29Y expressing NICCs survived and formed large clusters of insulin-positive cells. T-cell infiltration was observed in the periphery, but not within the insulin-positive cell clusters.CC BY · PubMed Central
Figure 2. Expression of human thrombomodulin (hTBM) in genetically (multi-)modified pigs. (A) Expression vector with the porcine THBD gene promoter. (B) Immunofluorescence staining of hTBM in transgenic porcine endothelial cells. (C) Expression of hTBM in vascular endothelial cells of myocardium from transgenic pigs. (D) Beads covered with hTBM expressing endothelial cells from genetically (multi-)modified pigs delay clotting of human blood (Wuensch et al., 2014).
Figure 2. Expression of human thrombomodulin (hTBM) in genetically (multi-)modified pigs. (A) Expression vector with the porcine THBD gene promoter. (B) Immunofluorescence staining of hTBM in transgenic porcine endothelial cells. (C) Expression of hTBM in vascular endothelial cells of myocardium from transgenic pigs. (D) Beads covered with hTBM expressing endothelial cells from genetically (multi-)modified pigs delay clotting of human blood (Wuensch et al., 2014).CC BY · PubMed Central
Figure 3. Factors enabling consistent success in life-supporting pig-to-baboon cardiac xenotransplantation. In addition to genetically multimodified porcine donor hearts (lacking αGal epitopes and expressing human CD46 as well as human thrombomodulin) and appropriate immunosuppression, two steps were key to success: 1) nonischemic preservation of the donor hearts by perfusion with oxygenated hyperoncotic blood-based solution; and 2) prevention of detrimental xeno-heart overgrowth by early weaning of cortisone, lowering of blood pressure and treatment with the mTOR inhibiting prodrug temsirolimus (Längin et al., 2018).
Figure 3. Factors enabling consistent success in life-supporting pig-to-baboon cardiac xenotransplantation. In addition to genetically multimodified porcine donor hearts (lacking αGal epitopes and expressing human CD46 as well as human thrombomodulin) and appropriate immunosuppression, two steps were key to success: 1) nonischemic preservation of the donor hearts by perfusion with oxygenated hyperoncotic blood-based solution; and 2) prevention of detrimental xeno-heart overgrowth by early weaning of cortisone, lowering of blood pressure and treatment with the mTOR inhibiting prodrug temsirolimus (Längin et al., 2018).CC BY · PubMed Central

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Metadata

Authors
Wolf, E., Kemter, E., Klymiuk, N., & Reichart, B.
Venue
Animal Frontiers
Publisher
Oxford University Press (OUP)
Published
2019-06-25
Volume
9
Issue
3
Pages
13-20
ISSN
  • 2160-6056
  • 2160-6064
DOI
10.1093/af/vfz014
PMC
PMC6951927
Cited by
61
References
1
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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Wolf, E., Kemter, E., Klymiuk, N., & Reichart, B. (2019). Genetically modified pigs as donors of cells, tissues, and organs for xenotransplantation. Animal Frontiers. https://doi.org/10.1093/af/vfz014