Volume 13 Issue 6
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Jiang Hongtao, Li Tao, He Songzhe, et al. Problems and challenges of genetically modified pig to non-human primate kidney xenotransplantation[J]. ORGAN TRANSPLANTATION, 2022, 13(6): 810-817. doi: 10.3969/j.issn.1674-7445.2022.06.018
Citation: Jiang Hongtao, Li Tao, He Songzhe, et al. Problems and challenges of genetically modified pig to non-human primate kidney xenotransplantation[J]. ORGAN TRANSPLANTATION, 2022, 13(6): 810-817. doi: 10.3969/j.issn.1674-7445.2022.06.018

Problems and challenges of genetically modified pig to non-human primate kidney xenotransplantation

doi: 10.3969/j.issn.1674-7445.2022.06.018
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  • Corresponding author: Wang Yi, Email: wayne0108@126.com
  • Received Date: 2022-06-07
    Available Online: 2022-11-14
  • Publish Date: 2022-11-15
  • Xenotransplantation is one of the potential approaches to mitigate the shortage of donor kidneys. With the progress of gene modification techniques and the development of immunosuppressant, significant progress has been made in the preclinical research of genetically modified pig to non-human primate (NHP) xenotransplantation. The longest survival time of recipients exceeds 500 d. However, the number of recipients surviving for over 1 year is extremely low, and most recipients die within postoperative 1-2 months. Therefore, several problems remain to be clarified and resolved. In this article, rejection, refractory coagulation dysfunction, persistent inflammation, the selection of immunosuppressant, the selection of clinical recipients and the risk of cross-infection in genetically modified pig to NHP xenotransplantation were reviewed, and current problems and potential solutions of genetically modified pig to NHP xenotransplantation were summarized, aiming to provide reference for promoting xenotransplantation in clinical settings.

     

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  • [1]
    陆新章, 张梅, 娄颜坤, 等. 利用基因编辑技术进行猪异种器官移植及人类疾病模型研究的进展[J]. 上海农业学报, 2021, 37(1): 136-144. DOI: 10.15955/j.issn1000-3924.2021.01.23.

    LU XZ, ZHANG M, LOU YK, et al. Genome editing technologies for xenotransplantation and disease model in pigs[J]. Acta Agric Shanghai, 2021, 37(1): 136-144. DOI: 10.15955/j.issn1000-3924.2021.01.23.
    [2]
    COOPER DKC, HARA H, IWASE H, et al. Pig kidney xenotransplantation: progress toward clinical trials[J]. Clin Transplant, 2021, 35(1): e14139. DOI: 10.1111/ctr.14139.
    [3]
    ADAMS AB, KIM SC, MARTENS GR, et al. Xenoantigen deletion and chemical immunosuppression can prolong renal xenograft survival[J]. Ann Surg, 2018, 268(4): 564-573. DOI: 10.1097/SLA.0000000000002977.
    [4]
    KIM SC, MATHEWS DV, BREEDEN CP, et al. Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion[J]. Am J Transplant, 2019, 19(8): 2174-2185. DOI: 10.1111/ajt.15329.
    [5]
    CLEVELAND DC, JAGDALE A, CARLO WF, et al. The genetically engineered heart as a bridge to allotransplantation in infants just around the corner?[J]. Ann Thorac Surg, 2022, 114(2): 536-544. DOI: 10.1016/j.athoracsur.2021.05.025.
    [6]
    LÄNGIN M, MAYR T, REICHART B, et al. Consistent success in life-supporting porcine cardiac xenotransplantation[J]. Nature, 2018, 564(7736): 430-433. DOI: 10.1038/s41586-018-0765-z.
    [7]
    FIRL DJ, MARKMANN JF. Measuring success in pig to non-human-primate renal xenotransplantation: systematic review and comparative outcomes analysis of 1051 life-sustaining NHP renal allo- and xeno-transplants[J]. Am J Transplant, 2022, 22(6): 1527-1536. DOI: 10.1111/ajt.16994.
    [8]
    CARVALHO OLIVEIRA M, VALDIVIA E, VERBOOM M, et al. Generating low immunogenic pig pancreatic islet cell clusters for xenotransplantation[J]. J Cell Mol Med, 2020, 24(9): 5070-5081. DOI: 10.1111/jcmm.15136.
    [9]
    VOURC'H M, DAVID G, GABORIT B, et al. Pseudomonas aeruginosa infection impairs NKG2D-dependent NK cell cytotoxicity through regulatory T-cell activation[J]. Infect Immun, 2020, 88(12): e00363-20. DOI: 10.1128/IAI.00363-20.
    [10]
    TAKEUCHI K, ARIYOSHI Y, SHIMIZU A, et al. Expression of human CD47 in pig glomeruli prevents proteinuria and prolongs graft survival following pig-to-baboon xenotransplantation[J]. Xenotransplantation, 2021, 28(6): e12708. DOI: 10.1111/xen.12708.
    [11]
    ZHOU Q, LI T, WANG K, et al. Current status of xenotransplantation research and the strategies for preventing xenograft rejection[J]. Front Immunol, 2022, 13: 928173. DOI: 10.3389/fimmu.2022.928173.
    [12]
    YUE Y, XU W, KAN Y, et al. Extensive germline genome engineering in pigs[J]. Nat Biomed Eng, 2021, 5(2): 134-143. DOI: 10.1038/s41551-020-00613-9.
    [13]
    GAO Y, SHAN W, GU T, et al. Daratumumab prevents experimental xenogeneic graft-versus-host disease by skewing proportions of T cell functional subsets and inhibiting T cell activation and migration[J]. Front Immunol, 2021, 12: 785774. DOI: 10.3389/fimmu.2021.785774.
    [14]
    BOCKERMANN R, JÄRNUM S, RUNSTRÖM A, et al. Imlifidase-generated single-cleaved IgG: implications for transplantation[J]. Transplantation, 2022, 106(7): 1485-1496. DOI: 10.1097/TP.0000000000004031.
    [15]
    IWASE H, EKSER B, HARA H, et al. Regulation of human platelet aggregation by genetically modified pig endothelial cells and thrombin inhibition[J]. Xenotransplantation, 2014, 21(1): 72-83. DOI: 10.1111/xen.12073.
    [16]
    CAO PP, WANG BF, NORTON JE, et al. Studies on activation and regulation of the coagulation cascade in chronic rhinosinusitis with nasal polyps[J]. J Allergy Clin Immunol, 2022, 150(2): 467-476. DOI: 10.1016/j.jaci.2022.02.018.
    [17]
    ADAMS AB, LOVASIK BP, FABER DA, et al. Anti-C5 antibody tesidolumab reduces early antibody-mediated rejection and prolongs survival in renal xenotransplantation[J]. Ann Surg, 2021, 274(3): 473-480. DOI: 10.1097/SLA.0000000000004996.
    [18]
    IWASE H, HARA H, EZZELARAB M, et al. Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts[J]. Xenotransplantation, 2017, 24(2): 10.1111/xen. 12293. DOI: 10.1111/xen.12293.
    [19]
    LI J, HARA H, WANG Y, et al. Evidence for the important role of inflammation in xenotransplantation[J]. J Inflamm (Lond), 2019, 16: 10. DOI: 10.1186/s12950-019-0213-3.
    [20]
    IWASE H, LIU H, LI T, et al Therapeutic regulation of systemic inflammation in xenograft recipients[J]. Xenotransplantation, 2017, 24(2): 10.1111/xen. 12296. DOI: 10.1111/xen.12296.
    [21]
    JAFFAR J, MCMILLAN L, WILSON N, et al. Coagulation factor-XⅡ induces interleukin-6 by primary lung fibroblasts: a role in idiopathic pulmonary fibrosis?[J]. Am J Physiol Lung Cell Mol Physiol, 2022, 322(2): L258-L272. DOI: 10.1152/ajplung.00165.2021.
    [22]
    EZZELARAB MB, COOPER DKC. Systemic inflammation in xenograft recipients (SIXR): a new paradigm in pig-to-primate xenotransplantation?[J]. Int J Surg, 2015, 23(Pt B): 301-305. DOI: 10.1016/j.ijsu.2015.07.643.
    [23]
    BEAVERS DP, KRITCHEVSKY SB, GILL TM, et al. Elevated IL-6 and CRP levels are associated with incident self-reported major mobility disability: a pooled analysis of older adults with slow gait speed[J]. J Gerontol A Biol Sci Med Sci, 2021, 76(12): 2293-2299. DOI: 10.1093/gerona/glab093.
    [24]
    ZHANG G, IWASE H, LI Q, et al. The role of interleukin-6 (IL-6) in the systemic inflammatory response in xenograft recipients and in pig kidney xenograft failure[J]. Front Immunol, 2021, 12: 788949. DOI: 10.3389/fimmu.2021.788949.
    [25]
    LI T, JIANG H, LIU H, et al. Extracellular histones and xenotransplantation[J]. Xenotransplantation, 2020, 7(5): e12618. DOI: 10.1111/xen.12618.
    [26]
    TANG T, CHENG X, TRUONG B, et al. Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint[J]. Pharmacol Ther, 2021, 219: 107709. DOI: 10.1016/j.pharmthera.2020.107709.
    [27]
    ANGELI F, VERDECCHIA P, SAVONITTO S, et al. Soluble CD40 ligand and outcome in patients with coronary artery disease undergoing percutaneous coronary intervention[J]. Clin Chem Lab Med, 2021, 60(1): 118-126. DOI: 10.1515/cclm-2021-0817.
    [28]
    BIKHET M, IWASE H, YAMAMOTO T, et al. What therapeutic regimen will be optimal for initial clinical trials of pig organ transplantation?[J]. Transplantation, 2021, 105(6): 1143-1155. DOI: 10.1097/TP.0000000000003622.
    [29]
    MICHAELS AJ, STOPPATO M, FLORES WJ, et al. Anti-CD40 antibody 2C10 binds to a conformational epitope at the CD40-CD154 interface that is conserved among primate species[J]. Am J Transplant, 2020, 20(1): 298-305. DOI: 10.1111/ajt.15574.
    [30]
    VINCENTI F, KLINTMALM G, YANG H, et al. A randomized, phase 1b study of the pharmacokinetics, pharmacodynamics, safety, and tolerability of bleselumab, a fully human, anti-CD40 monoclonal antibody, in kidney transplantation[J]. Am J Transplant, 2020, 20(1): 172-180. DOI: 10.1111/ajt.15560.
    [31]
    ESPIÉ P, HE Y, KOO P, et al. First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody[J]. Am J Transplant, 2020, 20(2): 463-473. DOI: 10.1111/ajt.15661.
    [32]
    KIM SC, WAKWE W, HIGGINBOTHAM LB, et al. Fc-silent anti-CD154 domain antibody effectively prevents nonhuman primate renal allograft rejection[J]. Am J Transplant, 2017, 17(5): 1182-1192. DOI: 10.1111/ajt.14197.
    [33]
    PORRETT PM, ORANDI BJ, KUMAR V, et al. First clinical-grade porcine kidney xenotransplant using a human decedent model[J]. Am J Transplant, 2022, 22(4): 1037-1053. DOI: 10.1111/ajt.16930.
    [34]
    ZHANG Z, HARA H, LONG C, et al. Immune responses of HLA highly sensitized and nonsensitized patients to genetically engineered pig cells[J]. Transplantation, 2018, 102(5): e195-e204. DOI: 10.1097/TP.0000000000002060.
    [35]
    LI T, FENG H, DU J, et al. Serum antibody binding and cytotoxicity to pig cells in Chinese subjects: relevance to clinical renal xenotransplantation[J]. Front Immunol, 2022, 13: 844632. DOI: 10.3389/fimmu.2022.844632.
    [36]
    LADOWSKI JM, HARA H, COOPER DKC. The role of SLAs in xenotransplantation[J]. Transplantation, 2021, 105(2): 300-307. DOI: 10.1097/TP.0000000000003303.
    [37]
    LI Q, HARA H, ZHANG Z, et al. Is sensitization to pig antigens detrimental to subsequent allotransplantation?[J]. Xenotransplantation, 2018, 25(3): e12393. DOI: 10.1111/xen.12393.
    [38]
    HARTLINE CB, CONNER RL, JAMES SH, et al. Xenotransplantation panel for the detection of infectious agents in pigs[J]. Xenotransplantation, 2018, 25(4): e12427. DOI: 10.1111/xen.12427.
    [39]
    FISHMAN JA. Infectious disease risks in xenotransplantation[J]. Am J Transplant, 2018, 18(8): 1857-1864. DOI: 10.1111/ajt.14725.
    [40]
    DENNER J. The porcine cytomegalovirus (PCMV) will not stop xenotransplantation[J]. Xenotransplantation, 2022, 29(3): e12763. DOI: 10.1111/xen.12763.
    [41]
    MA Y, JIA J, FAN R, et al. Screening and identification of the first non-CRISPR/Cas9-treated Chinese miniature pig with defective porcine endogenous retrovirus pol genes[J]. Front Immunol, 2022, 12: 797608. DOI: 10.3389/fimmu.2021.797608.
    [42]
    BOSE S, VOLPATTI LR, THIONO D, et al. A retrievable implant for the long-term encapsulation and survival of therapeutic xenogeneic cells[J]. Nat Biomed Eng, 2020, 4(8): 814-826. DOI: 10.1038/s41551-020-0538-5.
    [43]
    HINRICHS A, KESSLER B, KUROME M, et al. Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver[J]. Mol Metab, 2018, 11: 113-128. DOI: 10.1016/j.molmet.2018.03.006.
    [44]
    IWASE H, BALL S, ADAMS K, et al. Growth hormone receptor knockout: relevance to xenotransplantation[J]. Xenotransplantation, 2021, 28(2): e12652. DOI: 10.1111/xen.12652.
    [45]
    ASHTON-CHESS J, ROUSSEL JC, BERNARD P, et al. The effect of immunoglobulin immunadsorptions on delayed xenograft rejection of human CD55 transgenic pig kidneys in baboons[J]. Xenotransplantation, 2003, 10(6): 552-561. DOI: 10.1034/j.1399-3089.2003.00052.x.
    [46]
    BALDAN N, RIGOTTI P, CALABRESE F, et al. Ureteral stenosis in HDAF pig-to-primate renal xenotransplantation: a phenomenon related to immunological events?[J]. Am J Transplant, 2004, 4(4): 475-481. DOI: 10.1111/j.1600-6143.2004.00407.x.
    [47]
    ASHTON-CHESS J, MEURETTE G, KARAM G, et al. The study of mitoxantrone as a potential immunosuppressor in transgenic pig renal xenotransplantation in baboons: comparison with cyclophosphamide[J]. Xenotransplantation, 2004, 11(2): 112-122. DOI: 10.1111/j.1399-3089.2004.00040.x.
    [48]
    COZZI E, SIMIONI P, BOLDRIN M, et al. Effects of long-term administration of high-dose recombinant human antithrombin in immunosuppressed primate recipients of porcine xenografts[J]. Transplantation, 2005, 80(10): 1501-1510. DOI: 10.1097/01.tp.0000178377.55615.8b.
    [49]
    MOSCOSO I, HERMIDA-PRIETO M, MAÑEZ R, et al. Lack of cross-species transmission of porcine endogenous retrovirus in pig-to-baboon xenotransplantation with sustained depletion of anti-alphagal antibodies[J]. Transplantation, 2005, 79(7): 777-782. DOI: 10.1097/01.tp.0000152662.55720.83.
    [50]
    CHEN G, QIAN H, STARZL T, et al. Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys[J]. Nat Med, 2005, 11(12): 1295-1298. DOI: 10.1038/nm1330.
    [51]
    YAMADA K, YAZAWA K, SHIMIZU A, et al. Marked prolongation of porcine renal xenograft survival in baboons through the use of alpha1, 3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue[J]. Nat Med, 2005, 11(1): 32-34. DOI: 10.1038/nm1172.
    [52]
    CHEN G, SUN H, YANG H, et al. The role of anti-non-Gal antibodies in the development of acute humoral xenograft rejection of hDAF transgenic porcine kidneys in baboons receiving anti-Gal antibody neutralization therapy[J]. Transplantation, 2006, 81(2): 273-283. DOI: 10.1097/01.tp.0000188138.53502.de.
    [53]
    EZZELARAB M, GARCIA B, AZIMZADEH A, et al. The innate immune response and activation of coagulation in alpha1, 3-galactosyltransferase gene-knockout xenograft recipients[J]. Transplantation, 2009, 87(6): 805-812. DOI: 10.1097/TP.0b013e318199c34f.
    [54]
    LE BAS-BERNARDET S, TILLOU X, POIRIER N, et al. Xenotransplantation of galactosyl-transferase knockout, CD55, CD59, CD39, and fucosyl-transferase transgenic pig kidneys into baboons[J]. Transplant Proc, 2011, 43(9): 3426-3430. DOI: 10.1016/j.transproceed.2011.09.024.
    [55]
    NISHIMURA H, SCALEA J, WANG Z, et al. First experience with the use of a recombinant CD3 immunotoxin as induction therapy in pig-to-primate xenotransplantation: the effect of T-cell depletion on outcome[J]. Transplantation, 2011, 92(6): 641-647. DOI: 10.1097/TP.0b013e31822b92a5.
    [56]
    SPIEZIA L, BOLDRIN M, RADU C, et al. Thromboelastographic evaluation of coagulative profiles in pig-to-monkey kidney xenotransplantation[J]. Xenotransplantation, 2013, 20(2): 89-99. DOI: 10.1111/xen.12024.
    [57]
    SEKIJIMA M, WAKI S, SAHARA H, et al. Results of life-supporting galactosyltransferase knockout kidneys in cynomolgus monkeys using two different sources of galactosyltransferase knockout swine[J]. Transplantation, 2014, 98(4): 419-426. DOI: 10.1097/TP.0000000000000314.
    [58]
    AZIMZADEH AM, KELISHADI SS, EZZELARAB MB, et al. Early graft failure of GalTKO pig organs in baboons is reduced by expression of a human complement pathway-regulatory protein[J]. Xenotransplantation, 2015, 22(4): 310-316. DOI: 10.1111/xen.12176.
    [59]
    HIGGINBOTHAM L, MATHEWS D, BREEDEN CA, et al. Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model[J]. Xenotransplantation, 2015, 22(3): 221-230. DOI: 10.1111/xen.12166.
    [60]
    IWASE H, LIU H, WIJKSTROM M, et al. Pig kidney graft survival in a baboon for 136 days: longest life-supporting organ graft survival to date[J]. Xenotransplantation, 2015, 22(4): 302-309. DOI: 10.1111/xen.12174.
    [61]
    RIVARD CJ, TANABE T, LANASPA MA, et al. Upregulation of CD80 on glomerular podocytes plays an important role in development of proteinuria following pig-to-baboon xeno-renal transplantation - an experimental study[J]. Transpl Int, 2018, 31(10): 1164-1177. DOI: 10.1111/tri.13273.
    [62]
    YAMAMOTO T, HARA H, FOOTE J, et al. Life-supporting kidney xenotransplantation from genetically engineered pigs in baboons: a comparison of two immunosuppressive regimens[J]. Transplantation, 2019, 103(10): 2090-2104. DOI: 10.1097/TP.0000000000002796.
    [63]
    MA D, HIROSE T, LASSITER G, et al. Kidney transplantation from triple-knockout pigs expressing multiple human proteins in cynomolgus macaques[J]. Am J Transplant, 2022, 22(1): 46-57. DOI: 10.1111/ajt.16780.
    [64]
    IWASE H, JAGDALE A, YAMAMOTO T, et al. Evidence suggesting that deletion of expression of N-glycolylneuraminic acid (Neu5Gc) in the organ-source pig is associated with increased antibody-mediated rejection of kidney transplants in baboons[J]. Xenotransplantation, 2021, 28(4): e12700. DOI: 10.1111/xen.12700.
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