{"id":3202,"date":"2021-12-13T19:00:00","date_gmt":"2021-12-13T11:00:00","guid":{"rendered":"https:\/\/transnovo.com\/news\/%e4%b8%96%e7%95%8c%e9%a6%96%e4%be%8b%e7%8c%aa%e8%82%be%e5%bc%82%e4%bd%93%e7%a7%bb%e6%a4%8d%e6%88%90%e5%8a%9f-%e5%bc%82%e7%a7%8d%e7%a7%bb%e6%a4%8d%e7%9a%84%e9%9a%9c%e7%a2%8d%e4%b8%8e%e6%b2%bb\/"},"modified":"2021-12-13T19:00:00","modified_gmt":"2021-12-13T11:00:00","slug":"%e4%b8%96%e7%95%8c%e9%a6%96%e4%be%8b%e7%8c%aa%e8%82%be%e5%bc%82%e4%bd%93%e7%a7%bb%e6%a4%8d%e6%88%90%e5%8a%9f-%e5%bc%82%e7%a7%8d%e7%a7%bb%e6%a4%8d%e7%9a%84%e9%9a%9c%e7%a2%8d%e4%b8%8e%e6%b2%bb","status":"publish","type":"post","link":"https:\/\/transnovo.com\/en\/news\/%e4%b8%96%e7%95%8c%e9%a6%96%e4%be%8b%e7%8c%aa%e8%82%be%e5%bc%82%e4%bd%93%e7%a7%bb%e6%a4%8d%e6%88%90%e5%8a%9f-%e5%bc%82%e7%a7%8d%e7%a7%bb%e6%a4%8d%e7%9a%84%e9%9a%9c%e7%a2%8d%e4%b8%8e%e6%b2%bb\/","title":{"rendered":"World's First Successful Porcine Kidney Allograft | Barriers to Allogeneic Transplantation and Advances in Treatment"},"content":{"rendered":"
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World's first human porcine kidney transplant successful<\/strong><\/p>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n

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On October 19, Montgomery's team, a professor of transplant surgery at NYU Langone Medical Center, announced that they successfullyAlpha-Gal knockout pig kidney transplanted to a brain dead person<\/strong>. After transplantation.The kidneys \"worked\" normally for 54 hours<\/strong>No hyperacute rejection occurred, and the patient's urine and creatinine levels dropped to normal. The operation was not a direct transplant of a kidney from a genetically modified pig into a human body, but was attached to a blood vessel in the upper thigh, outside the abdomen, of a brain-dead recipient. According to the World Health Organization, about 2 million people worldwide need organ transplants every year, but there is a serious shortage of organ donors, with the global average organ supply to demand ratio less than 1:20. More than 300,000 people in China have organ failure and need for transplantation every year, but only about 10,000 people can receive transplants every year due to the limitations of organ donor sources, economic conditions and medical conditions. The success of this surgery is a major milestone, bringing hope for future allogeneic organ transplants and hopefully solving the current donor shortage problem.<\/p>\n


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Barriers to xenotransplantation1-4<\/sup><\/strong><\/p>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n

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The main barriers that exist after xenotransplantation arePost-transplant rejection<\/strong><\/span>, ,Coagulation problems<\/strong>, ,Cross-species infection<\/strong>. Among the major rejection reactions are (1) hyperacute rejection (HAR), (2) acute body fluid xenograft rejection (AHXR), and (3) acute cellular rejection.<\/p>\n


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HAR for organ damage that occurs within 24h, usually within minutes and hours, withPre-existing anti-pig antibodies in primates<\/strong><\/span>withPorcine arterial endothelial cell surface antigen<\/strong><\/span>binding is related. The main antigens that cause hyper-HAR areAlpha-1,3-galactose antigen (a-Gal)<\/span>, which is encoded by the \u03b1-1,3-galactosyltransferase (GGTA1) gene. This oligosaccharide is present in all mammals except humans and non-human primates (e.g. gorillas, baboons). These primate species lost the expression of the \u03b1-1,3 galactose gene due to genetic mutations millions of years ago, which led to the production of antibodies against a-Gal in primates. Other antigens that cause HAR areN-Hydroxyacetylneuraminic acid (NeuGc) and Sd(a) antigens<\/strong><\/span>, which are encoded by the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) and \u03b2-1,4-N-acetylgalactosaminyltransferase (2b4GalNT2) genes, respectively.<\/p>\n


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AHXR is caused by a combination of humoral and immune cellular responses, combined with activated endothelium and inflammation, and typically occurs days or weeks after transplantation.The histopathological features of AHXR are similar to those of HAR and are also associated withActivation of arterial endothelial cells by antibody and complement deposition<\/strong>, , ,Innate immune cells<\/strong>(e.g., polymorphonuclear cells, macrophages, natural killer cells) infiltration is associated with destruction of the transplanted organ.<\/p>\n


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Acute cellular rejection is mediated by intrinsic and adaptive immunity, including NK cells, macrophages, and T cells. Among them, NK cells mediate xenograft rejection through direct NK cytotoxicity or antibody-dependent cytotoxicity. Macrophages mediate allograft rejection through modulation of adaptive immunity and direct cytotoxicity. macrophages can produce toxic effects through production of pro-inflammatory cytokines TNF-\u03b1, IL-1 and IL-6. signal regulatory protein (SIRP-a)-CD47 signaling pathway is an important negative pathway for macrophages. t cells are activated through direct and indirect pathways. t cell activation requires Two signals: the first signal is initiated by the binding of the T cell receptor to the antigen peptide-MHC complex on the antigen presenting cell (MHC), and the second signal is initiated by a co-stimulatory signal generated by the action of co-stimulatory molecules CD40-CD154, CD28-CD80\/86 between T cells and the MHC. (Figure 1)<\/p>\n


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Figure 1. A. NK cell-mediated rejection; B. Macrophage-mediated rejection; C. T cell-mediated rejection<\/span><\/strong><\/p>\n<\/section>\n

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Advances in the treatment of xenografts3-5<\/sup><\/strong><\/p>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n<\/section>\n

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The main therapeutic advances in xenotransplantation includeKnockout of xenograft-responsive antigen gene<\/strong><\/span>, ,Inhibition of cellular rejection<\/strong><\/span>, ,Introduction of human complement regulatory proteins (hCRPs)<\/strong><\/span>andHuman blood clotting regulatory protein (hTBM)<\/strong><\/span>.<\/p>\n


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The most common knockout was the knockout of GGTA1 gene (GTKO), in addition to GGTA1\/CMAH, GGTA1\/B4GalNT2 and GGTA1\/CMAH\/B4GalNT2 double or triple knockouts (Table 1).<\/p>\n


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Inhibition of cellular rejection can be achieved by blocking the co-stimulatory signaling pathways of SIRPa-CD47, CD40-CD154, and B7-CD28, such as anti-CD40 antibody and anti-CD154 antibody can block the CD40-CD154 signaling pathway, and human CTLA4-immunoglobulin (hCTLA4-Ig) can block the B7-CD28 signaling pathway, as well as by hCD47 , hCTLA4-Ig-transfected transgenic pigs (Table 1). There are also antibodies against inflammatory factors such as anti-IL-6 antibodies.<\/p>\n


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Table 1. xenograft transgenic pigs<\/strong><\/p>\n<\/section>\n

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In addition, introduction of human CRPs (hCRPs) (e.g. CD46, CD59 and CD55) into porcine cells inhibited complement-mediated graft injury, and it was demonstrated that introduction of hCRPs into porcine cells also prolonged xenograft survival. Introduction of hHBM into porcine cells inhibited thrombospondin activity and delayed clotting time.<\/p>\n


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Lifeport Mechanical Perfusion<\/strong><\/span>As an important preservation device for organ transplantation, it has a protective effect on porcine kidney, and studies have shown that Lifeport mechanical perfusion can protect porcine kidney tissue and reduce damage to porcine kidney tissue6<\/sup>It will play an important role in the future of xenotransplantation.<\/p>\n


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References<\/span><\/p>\n

1. Gao Bingshi, et al. Review of immune disorders in xenografts[J]. Modern medicine and health, 2017, 33(7):1032-1035.<\/span><\/p>\n

2. Zhang Q, Wang JF. Progress and prospects of allogeneic organ transplantation[J]. Experimental Animals and Comparative Medicine, 2018, 38(6):407-411.<\/span><\/p>\n

3. Lu T, et al. Xenotransplantation: Current Status in Preclinical Research.Front Immunol.2020 Jan 23;10:3060.<\/span><\/p>\n

4. Martin Wijkstrom, et al. Renal xenotransplantation: experimental progress and clinical prospects . Kidney Int . 2017;91(4):790-796.<\/span><\/p>\n

5. Hawthorne WJ, et al. Xenotransplantation literature update, November\/December 2020. xenotransplantation. 2021;28(2):e12674.<\/span><\/p>\n

6. Xie Dawei, et al. Effect of LifePort, a continuous hypothermic perfusion device, on the tissue structure of isolated porcine kidney[J]. Chinese Journal of Organ Transplantation, 2016(37):117-121.<\/span><\/p>\n


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Jianfeng Medicine, focus on transplant industry<\/p>\n<\/section>\n<\/section>\n<\/section>\n

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