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Meier RPH, Pierson RN, Fishman JA, Buhler LH, Bottino R, Ladowski JM, Ekser B, Wolf E, Brenner P, Ierino F, Mohiuddin M, Cooper DKC, Hawthorne WJ. International Xenotransplantation Association (IXA) Position Paper on Kidney Xenotransplantation. Transplantation 2025:00007890-990000000-01051. [PMID: 40197435 DOI: 10.1097/tp.0000000000005372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
Porcine kidney xenotransplantation for end-stage renal disease (ESRD) has reached the stage of clinical testing following major advances in donor pig genetic modifications and effective immunosuppressive strategies through decades of rigorous translational research. Reports of pig kidney xenograft survival beyond 1 year post-transplant in nonhuman primate (NHP) models justify optimism for its potential as an alternative to allotransplantation. In the United States, experimental transplantations of genetically engineered (GE) porcine kidneys into brain-dead subjects and a small number of ESRD patients have shown no evidence of hyperacute rejection and adequate pig kidney function for up to several months. Here we discuss pre-clinical/clinical results, infectious disease, ethical, and regulatory considerations, and propose evidence-based recommendations. For initial clinical trials in kidney xenotransplantation, we make the following recommendations: (i) transplantation with organs from a triple knockout (TKO) donor pig, preferably with added human transgenes, (ii) an immunosuppressive regimen with induction therapy to deplete T (and possibly B) cells, and maintenance therapy based on a cluster of differentiation (CD)40/CD154 co-stimulation pathway blockade, (iii) the patient should be fully acceptable as a candidate for allotransplantation but should be unlikely ever to receive an allograft. Patients aged 60-69 years (extendable to 40-75 years, if one of the criteria mentioned below is present), of blood group B or O, and with diabetes are most at risk in this regard. Other patients who could be considered are (i) those who have lost two or more previous kidney allografts from recurrent disease in the graft, (ii) those with broad human leukocyte antigen (HLA)-reactivity but no evidence of anti-pig antibodies, including swine leukocyte antigen (SLA), and (iii) those with failing vascular access. Clinical pilot studies in carefully and highly selected patients with no alternative therapy will provide the foundation upon which to base subsequent formal expanded clinical trials.
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Affiliation(s)
- Raphael P H Meier
- Department of Surgery, University of Maryland School of, Medicine, Baltimore, MD
| | - Richard N Pierson
- Division of Cardiac Surgery and Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA
| | - Jay A Fishman
- Transplantation Infectious Disease Program and Massachusetts General Hospital Transplant Center, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Leo H Buhler
- Cantonal Hospital Fribourg, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Rita Bottino
- Allegheny Health Network, Carnegie Mellon University, Pittsburgh, PA
| | - Joseph M Ladowski
- Department of Surgery, Duke University School of Medicine, Durham, NC
| | - Burcin Ekser
- Division of Abdominal Transplant Surgery, Stritch School of Medicine, Loyola University Chicago, Maywood, IL
| | | | - Paolo Brenner
- Department of Cardiac Surgery, University Hospital, LMU Munich, Munich, Germany
| | - Francesco Ierino
- Department of Nephrology and Transplantation, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - Muhammad Mohiuddin
- Cardiac Xenotransplantation Program, University of Maryland School of Medicine, Baltimore, MD
| | - David K C Cooper
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA
| | - Wayne J Hawthorne
- The Department of Surgery, University of Sydney, Westmead Hospital, Westmead, NSW, Australia
- The Centre for Transplant & Renal Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia
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2
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Meier RPH, Pierson RN, Fishman JA, Buhler LH, Bottino R, Ladowski JM, Ekser B, Wolf E, Brenner P, Ierino F, Mohiuddin M, Cooper DKC, Hawthorne WJ. International Xenotransplantation Association (IXA) Position Paper on Kidney Xenotransplantation. Xenotransplantation 2025; 32:e70003. [PMID: 40198240 DOI: 10.1111/xen.70003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 10/12/2024] [Indexed: 04/10/2025]
Abstract
Porcine kidney xenotransplantation for end-stage renal disease (ESRD) has reached the stage of clinical testing following major advances in donor pig genetic modifications and effective immunosuppressive strategies through decades of rigorous translational research. Reports of pig kidney xenograft survival beyond 1 year posttranplant in nonhuman primate (NHP) models justify optimism for its potential as an alternative to allotransplantation. In the United States, experimental transplantations of genetically engineered (GE) porcine kidneys into brain-dead subjects and a small number of ESRD patients have shown no evidence of hyperacute rejection and adequate pig kidney function for up to several months. Here we discuss pre-clinical/clinical results, infectious disease, ethical, and regulatory considerations, and propose evidence-based recommendations. For initial clinical trials in kidney xenotransplantation, we make the following recommendations: (i) transplantation with organs from a triple knockout (TKO) donor pig, preferably with added human transgenes, (ii) an immunosuppressive regimen with induction therapy to deplete T (and possibly B) cells, and maintenance therapy based on a cluster of differentiation (CD)40/CD154 co-stimulation pathway blockade, (iii) the patient should be fully acceptable as a candidate for allotransplantation but should be unlikely ever to receive an allograft. Patients aged 60-69 years (extendable to 40-75 years, if one of the criteria mentioned below is present), of blood group B or O, and with diabetes are most at risk in this regard. Other patients who could be considered are (i) those who have lost two or more previous kidney allografts from recurrent disease in the graft, (ii) those with broad human leukocyte antigen (HLA)-reactivity but no evidence of anti-pig antibodies, including swine leukocyte antigen (SLA), and (iii) those with failing vascular access. Clinical pilot studies in carefully and highly selected patients with no alternative therapy will provide the foundation upon which to base subsequent formal expanded clinical trials.
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Affiliation(s)
- Raphael P H Meier
- Department of Surgery, University of Maryland School of, Medicine, Baltimore, Maryland, USA
| | - Richard N Pierson
- Division of Cardiac Surgery and Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Jay A Fishman
- Transplantation Infectious Disease Program and Massachusetts General Hospital Transplant Center, Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Leo H Buhler
- Cantonal Hospital Fribourg, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Rita Bottino
- Allegheny Health Network, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA
| | - Joseph M Ladowski
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Burcin Ekser
- Division of Abdominal Transplant Surgery, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
| | | | - Paolo Brenner
- Department of Cardiac Surgery, University Hospital, LMU Munich, Munich, Germany
| | - Francesco Ierino
- Department of Nephrology and Transplantation, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - Muhammad Mohiuddin
- Cardiac Xenotransplantation Program, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - David K C Cooper
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Wayne J Hawthorne
- The Department of Surgery, University of Sydney, Westmead Hospital, Westmead, NSW, Australia
- The Centre for Transplant & Renal Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia
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3
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Shirini K, Meier RPH. Systematic Review and Comparative Outcomes Analysis of NHP Liver Allotransplants and Xenotransplants. Xenotransplantation 2025; 32:e70017. [PMID: 39960351 PMCID: PMC11832012 DOI: 10.1111/xen.70017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/22/2025] [Indexed: 02/20/2025]
Abstract
Patients with fulminant liver failure ineligible for transplantation have a high mortality rate. With recent progress in genetic modifications and clinical achievements, using pig livers as a bridge-to-transplant has regained popularity. Preclinical testing has been done in small cohorts of nonhuman primates (NHP), and maximum survival is limited to 1-month. We conducted a systematic review and comparative outcomes analysis of NHP-liver xenotransplantation and gathered 203 pig-to-NHP and NHP-to-NHP transplants reported in 23 studies. Overall, NHP survival after pig-liver xenotransplantation was limited (1, 3, 4 weeks: 18.0%, 5.6%, 1.1%), compared to NHPs after allotransplantation (1, 3, 4 weeks: 60.6%, 47.4%, 45.4%). A focus on pigs with genetic modifications evidenced some short-term survival benefits (1, 3, 4 weeks: 29.1%, 9.1%, 1.8%). The use of the auxiliary transplant technique was also associated with better short-term results (1, 3, 4 weeks: 40.9%, 9.1%, 4.5%). Causes of graft and animal loss were mostly rejection and liver failure in allotransplants, while bleeding, liver, and respiratory failure predominated in xenotransplants. Notably, the 1-month survival rate for NHP-allotransplants was significantly lower than the national > 98% rate for human liver transplants. This data confirms the short-term improvements brought by genetic modifications and auxiliary implantation in the NHP model, which remains imperfect.
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Affiliation(s)
- Kasra Shirini
- Division of Transplant SurgeryDepartment of SurgeryUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Raphael P. H. Meier
- Division of Transplant SurgeryDepartment of SurgeryUniversity of Maryland School of MedicineBaltimoreMarylandUSA
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Adams AB, Blumberg EA, Gill JS, Katz E, Kawai T, Schold JD, Sykes M, Tector A, Sachs DH. Enhancing Kidney Transplantation and the Role of Xenografts: Report of a Scientific Workshop Sponsored by the National Kidney Foundation. Am J Kidney Dis 2024; 84:94-101. [PMID: 38452918 PMCID: PMC11558888 DOI: 10.1053/j.ajkd.2023.12.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 12/10/2023] [Accepted: 12/30/2023] [Indexed: 03/09/2024]
Abstract
Chronic kidney disease affects an estimated 37 million people in the United States; of these,>800,000 have end-stage renal disease requiring chronic dialysis or a kidney transplant to survive. Despite efforts to increase the donor kidney supply, approximately 100,000 people are registered on the kidney transplant wait-list with no measurable decrease over the past 2 decades. The outcomes of kidney transplantation are significantly better than for chronic dialysis: kidney transplant recipients have lower rates of mortality and cardiovascular events and better quality of life, but wait-list time matters. Time on dialysis waiting for a deceased-donor kidney is a strong independent risk factor for outcomes after a kidney transplant. Deceased-donor recipients with wait-list times on dialysis of<6 months have graft survival rates equivalent to living-donor recipients with waitlist times on dialysis of>2 years. In 2021,>12,000 people had been on the kidney transplant waitlist for ≥5 years. As the gap between the demand for and availability of donor kidneys for allotransplantation continues to widen, alternative strategies are needed to provide a stable, sufficient, and timely supply. A strategy that is gaining momentum toward clinical application is pig-to-human kidney xenotransplantation. This report summarizes the proceedings of a meeting convened on April 11-12, 2022, by the National Kidney Foundation to review and assess the state of pig-to-human kidney xenotransplantation as a potential cure for end-stage renal disease.
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Affiliation(s)
- Andrew B Adams
- Department of Surgery, School of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Emily A Blumberg
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - John S Gill
- Division of Nephrology, University of British Columbia, British Columbia, Vancouver, Canada
| | | | - Tatsuo Kawai
- Massachusetts General Hospital, Harvard University, Boston, Massachusetts; Center for Transplantation Sciences, Harvard University, Boston, Massachusetts
| | - Jesse D Schold
- Department of Surgery and Epidemiology, Anschutz Medical Campus, University of Colorado, Aurora, Colorado
| | - Megan Sykes
- Department of Medicine, Columbia Center for Translational Immunology, and Department of Medicine, Department of Microbiology and Immunology, and Department of Surgery; Columbia University, New York, New York
| | - Alfred Tector
- DeWitt Daughtry Family Department of Surgery, School of Medicine, University of Miami, Miami, Florida
| | - David H Sachs
- Massachusetts General Hospital, Harvard University, Boston, Massachusetts; Medical School, Harvard University, Boston, Massachusetts; Columbia University Medical Center, New York, New York.
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Ojha AK, Rajasekaran R, Hansda AK, Choudhury P, Biswas A, Sharma S, Chaudhuri PP, Dogra N, Goswami R, Chaudhury K, Dhara S. Biochemical and immunomodulatory insights of extracellular matrix from decellularized human whole cervix: recellularization and in vivoECM remodeling interplay. Biofabrication 2024; 16:035014. [PMID: 38663394 DOI: 10.1088/1758-5090/ad4393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 04/25/2024] [Indexed: 05/08/2024]
Abstract
Extracellular matrix (ECM) rich whole organ bio-scaffolds, preserving structural integrity and essential growth factors, has potential towards regeneration and reconstruction. Women with cervical anomalies or trauma can benefit from clinical cervicovaginal repair using constructs rich in site specific ECM. In this study, complete human cervix decellularization was achieved using a modified perfusion-based stir bench top decellularization method. This was followed by physico-chemical processes including perfusion of ionic agents, enzymatic treatment and washing using detergent solutions for a duration of 10-12 d. Histopathological analysis, as well as DNA quantification confirmed the efficacy of the decellularization process. Tissue ultrastructure integrity was preserved and the same was validated via scanning electron microscopy and transmission electron microscopy studies. Biochemical analysis and structural characterizations like Fourier transform infrared, Raman spectroscopy of decellularized tissues demonstrated preservation of important proteins, crucial growth factors, collagen, and glycosaminoglycans.In vitrostudies, using THP-1 and human umbilical vein endothelial cell (HUVEC) cells, demonstrated macrophage polarization from M1 to M2 and vascular functional genes enhancement, respectively, when treated with decellularized human cervical matrix (DHCp). Crosslinked DHC scaffolds were recellularized with site specific human cervical epithelial cells and HUVEC, showing non-cytotoxic cell viability and enhanced proliferation. Furthermore, DHC scaffolds showed immunomodulatory effectsin vivoon small rodent model via upregulation of M2 macrophage genes as compared to decellularized rat cervix matrix scaffolds (DRC). DHC scaffolds underwent neo-vascularization followed by ECM remodeling with enhanced tissue integration.
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Affiliation(s)
- Atul Kumar Ojha
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Ragavi Rajasekaran
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Arman Kunwar Hansda
- School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Priyanka Choudhury
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Asmita Biswas
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Sunita Sharma
- Institute of Reproductive Medicine, Salt Lake, Kolkata, India
| | - Prithwis Pal Chaudhuri
- Department of Obstetrics and Gynecology, Zenith Super specialty hospital, Kolkata, India
| | - Nantu Dogra
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Ritobrata Goswami
- School of Bioscience, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Koel Chaudhury
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Santanu Dhara
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
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Ghazi M, Saleh A, Abdallah M, El Masri D, El Masri J, El Ayoubi LM, Hawi J, Jurjus A. Barriers toward xenotransplantation in Arab World. Xenotransplantation 2024; 31:e12852. [PMID: 38526015 DOI: 10.1111/xen.12852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 02/19/2024] [Accepted: 02/22/2024] [Indexed: 03/26/2024]
Abstract
Organ transplant is a crucial therapeutic strategy offering a life-saving and transformative medical intervention. It provides an opportunity to improve their quality of life and increase their lifespan. The shortage of organs remains a critical global challenge, leading to a prolonged waiting times for organ receivers, which contributes to an increase in morbidity and mortality rates. Hence, xenotransplantation offered a promising solution to the global shortage of organs through the use of animal organs, leading to an increase in donor availability, reducing waiting times, minimizing organ trafficking, improving genetic engineering advancements, and driving scientific innovation. Even though xenotransplantation has many benefits in the clinical setting, it has many barriers that are hindering its achievements and constraining its occurrence. Some barriers to xenotransplant are general, such as the immunological barrier, while others are specific to certain regions due to local causes. The Arab region exhibits disparities in clinical settings compared to the global context, marked by the huge economic crisis and a shortage of trained healthcare professionals. Considering the huge resources and advancements needed in the field of xenotransplantation, this review aims to explore the specific barriers toward xenotransplantation in the Arab countries, highlighting the challenges to overcome these barriers.
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Affiliation(s)
- Maya Ghazi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Aalaa Saleh
- Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Malak Abdallah
- Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | - Diala El Masri
- Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
- Faculty of Medicine, University of Balamand, Koura, Lebanon
| | - Jad El Masri
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
- Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon
| | | | - Jihad Hawi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Abdo Jurjus
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Hafa L, Breideband L, Ramirez Posada L, Torras N, Martinez E, Stelzer EHK, Pampaloni F. Light Sheet-Based Laser Patterning Bioprinting Produces Long-Term Viable Full-Thickness Skin Constructs. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2306258. [PMID: 37822216 DOI: 10.1002/adma.202306258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 10/04/2023] [Indexed: 10/13/2023]
Abstract
Tissue engineering holds great promise for biomedical research and healthcare, offering alternatives to animal models and enabling tissue regeneration and organ transplantation. 3D bioprinting stands out for its design flexibility and reproducibility. Here, an integrated fluorescent light sheet bioprinting and imaging system is presented that combines high printing speed (0.66 mm3 /s) and resolution (9 µm) with light sheet-based imaging. This approach employs direct laser patterning and a static light sheet for confined voxel crosslinking in photocrosslinkable materials. The developed bioprinter enables real-time monitoring of hydrogel crosslinking using fluorescent recovery after photobleaching (FRAP) and brightfield imaging as well as in situ light sheet imaging of cells. Human fibroblasts encapsulated in a thiol-ene click chemistry-based hydrogel exhibited high viability (83% ± 4.34%) and functionality. Furthermore, full-thickness skin constructs displayed characteristics of both epidermal and dermal layers and remained viable for 41 days. The integrated approach demonstrates the capabilities of light sheet bioprinting, offering high speed, resolution, and real-time characterization. Future enhancements involving solid-state laser scanning devices such as acousto-optic deflectors and modulators will further enhance resolution and speed, opening new opportunities in light-based bioprinting and advancing tissue engineering.
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Affiliation(s)
- Levin Hafa
- Institute of Cell Biology and Neurosciences (IZN), Buchman Institute for Molecular Life Sciences (BMLS), Goethe-Universität Frankfurt am Main, Max-von-Laue-Straße 15, 60438, Frankfurt am Main, Germany
| | - Louise Breideband
- Institute of Cell Biology and Neurosciences (IZN), Buchman Institute for Molecular Life Sciences (BMLS), Goethe-Universität Frankfurt am Main, Max-von-Laue-Straße 15, 60438, Frankfurt am Main, Germany
| | - Lucas Ramirez Posada
- Institute of Cell Biology and Neurosciences (IZN), Buchman Institute for Molecular Life Sciences (BMLS), Goethe-Universität Frankfurt am Main, Max-von-Laue-Straße 15, 60438, Frankfurt am Main, Germany
| | - Núria Torras
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, 08028, Spain
| | - Elena Martinez
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Barcelona, 08028, Spain
| | - Ernst H K Stelzer
- Institute of Cell Biology and Neurosciences (IZN), Buchman Institute for Molecular Life Sciences (BMLS), Goethe-Universität Frankfurt am Main, Max-von-Laue-Straße 15, 60438, Frankfurt am Main, Germany
| | - Francesco Pampaloni
- Institute of Cell Biology and Neurosciences (IZN), Buchman Institute for Molecular Life Sciences (BMLS), Goethe-Universität Frankfurt am Main, Max-von-Laue-Straße 15, 60438, Frankfurt am Main, Germany
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DeLaura I, Zikos J, Anwar IJ, Yoon J, Ladowski J, Jackson A, Van Rompay K, Magnani D, Knechtle SJ, Kwun J. The impact of IdeS (imlifidase) on allo-specific, xeno-reactive, and protective antibodies in a sensitized rhesus macaque model. Xenotransplantation 2024; 31:e12833. [PMID: 37864433 PMCID: PMC10999173 DOI: 10.1111/xen.12833] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/17/2023] [Accepted: 10/13/2023] [Indexed: 10/22/2023]
Abstract
BACKGROUND Highly sensitized patients face many barriers to kidney transplantation, including higher rates of antibody-mediated rejection after HLA-incompatible transplant. IdeS, an endopeptidase that cleaves IgG nonspecifically, has been trialed as desensitization prior to kidney transplant, and successfully cleaves donor-specific antibody (DSA), albeit with rebound. METHODS IdeS was generated and tested (2 mg/kg, IV) in two naïve and four allosensitized nonhuman primates (NHP). Peripheral blood samples were collected at regular intervals following IdeS administration. Total IgG, total IgM, and anti-CMV antibodies were quantified with ELISA, and donor-specific antibody (DSA) and anti-pig antibodies were evaluated using flow cytometric crossmatch. B cell populations were assessed using flow cytometry. RESULTS IdeS successfully cleaved rhesus IgG in vitro. In allosensitized NHP, robust reduction of total, DSA, anti-pig, and anti-CMV IgG was observed within one day following IdeS administration. Rapid rebound of all IgG antibody populations was observed, with antibody levels returning to baseline around day 14 post-infusion. Total IgM level was not affected by IdeS. Interestingly, a comparable reduction in antibody populations was observed after the second dose of IdeS. However, we have not observed any significant modulation of B cell subpopulations after IdeS. CONCLUSIONS This study evaluated efficacy of IdeS in the allosensitized NHP in IgG with various specificities, mirroring antibody kinetics in human patients. The efficacy of IdeS on preexisting anti-pig antibodies may be useful in clinical xenotransplantation. However, given the limitation of IdeS on its durability as a monotherapy, optimization of IdeS with other agents targeting the humoral response is further needed.
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Affiliation(s)
- Isabel DeLaura
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710
| | - Joanna Zikos
- MassBiologics of University of Massachusetts Medical School, Boston, MA, 02126, USA
| | - Imran J. Anwar
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710
| | - Janghoon Yoon
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710
| | - Joseph Ladowski
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710
| | - Annette Jackson
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710
| | - Koen Van Rompay
- California National Primate Research Center, University of California, Davis, CA 95616, USA
| | - Diogo Magnani
- MassBiologics of University of Massachusetts Medical School, Boston, MA, 02126, USA
| | - Stuart J. Knechtle
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710
| | - Jean Kwun
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710
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9
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Zhou Y, Zhou S, Wang Q, Zhang B. Mitigating Cross-Species Viral Infections in Xenotransplantation: Progress, Strategies, and Clinical Outlook. Cell Transplant 2024; 33:9636897241226849. [PMID: 38258759 PMCID: PMC10807386 DOI: 10.1177/09636897241226849] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 01/02/2024] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
Xenotransplantation holds great promise as a solution to address the critical shortage of organs, but it raises concerns regarding the potential transmission of porcine viruses to recipients, leading to infections and even zoonotic diseases. Data used in this review were mainly from literature of Pubmed database. Keywords included xenotransplantation, infection, virus, and epidemiology. The original articles and critical reviews selected were relevant to this review's theme. We review the major viral infections of concern in xenotransplantation, their risk of transmission, diagnosis, treatment, and ways to prevent infection. Then, we pivot to a comprehensive overview of the current status of xenotransplantation. In addition, we offer our own insights and recommendations for propelling xenotransplantation forward, transitioning from preclinical experiments to the critical phase of clinical trials. Viral infections pose considerable safety concerns within xenotransplantation, particularly with the possibility of emerging or currently unidentified viruses. Clinical trials serve as a crucial platform to progress the safety standards of xenotransplantation. However, further studies and dedicated efforts are required to effectively translate findings into practical applications that can improve safety measures in this field.
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Affiliation(s)
- Yenong Zhou
- Department of Cardiovascular Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Shuyu Zhou
- Inner Mongolia Autonomous Region Hospital of Traditional Chinese Medicine, Hohhot, China
| | - Qian Wang
- Nutriology Department, Qingdao Special Servicemen Recuperation Center of PLA Navy, Qingdao, China
| | - Bing Zhang
- Department of Cardiovascular Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
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10
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Goerlich CE, Kamberi SS, Ladowski J, Citro A, Connolly M, Fischer K, Salvaris EJ, Singh AK, Wang Y, Stern J, Meier RPH. The Young Investigator Committee of the International Xenotransplantation Association-Perspective of advancements in the field in 2023. Xenotransplantation 2024; 31:e12845. [PMID: 38407937 DOI: 10.1111/xen.12845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 01/23/2024] [Indexed: 02/27/2024]
Abstract
The 2023 IXA conference, hosted in San Diego, CA, brimmed with excitement against the backdrop of recent innovations in both the pre-clinical and clinical realms with several first-in-human applications of xenotransplantation. The theme, "Pigs are flying," alluded to the adage that xenotransplantation would only become a clinical reality "when pigs fly," suggesting a day that might never come. The event witnessed significant attendance, with 600 participants-the highest in the history of an IXA-IPITA joint congress. Among the attendees were members of the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and corporate sponsors deeply engaged in the field. We summarize the latest topics from the congress, ranging from the pros/cons of decedent models of xenotransplantation and genetic engineering of porcine heart valves, solid organs, and cells for clinical translation and their regulatory and ethical landscape.
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Affiliation(s)
- Corbin E Goerlich
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
| | - Shani S Kamberi
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Joseph Ladowski
- Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA
| | - Antonio Citro
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Margaret Connolly
- Department of Surgery, Division of Cardiac Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Konrad Fischer
- School of Life Sciences, Technical University of Munich, Munich, Germany
| | - Evelyn J Salvaris
- Immunology Research Centre, St. Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia
| | - Avneesh K Singh
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital & Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Jeffrey Stern
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Raphael P H Meier
- Department of Surgery, The University of Maryland School of Medicine, Baltimore, Maryland, USA
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11
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Schmalkuche K, Schwinzer R, Wenzel N, Valdivia E, Petersen B, Blasczyk R, Figueiredo C. Downregulation of Swine Leukocyte Antigen Expression Decreases the Strength of Xenogeneic Immune Responses towards Renal Proximal Tubular Epithelial Cells. Int J Mol Sci 2023; 24:12711. [PMID: 37628892 PMCID: PMC10454945 DOI: 10.3390/ijms241612711] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/03/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Xenotransplantation reemerged as a promising alternative to conventional transplantation enlarging the available organ pool. However, success of xenotransplantation depends on the design and selection of specific genetic modifications and on the development of robust assays allowing for a precise assessment of tissue-specific immune responses. Nevertheless, cell-based assays are often compromised by low proliferative capacity of primary cells. Proximal tubular epithelial cells (PTECs) play a crucial role in kidney function. Here, we generated immortalized PTECs (imPTECs) by overexpression of simian virus 40 T large antigen. ImPTECs not only showed typical morphology and phenotype, but, in contrast to primary PTECs, they maintained steady cell cycling rates and functionality. Furthermore, swine leukocyte antigen (SLA) class I and class II transcript levels were reduced by up to 85% after transduction with lentiviral vectors encoding for short hairpin RNAs targeting β2-microglobulin and the class II transactivator. This contributed to reducing xenogeneic T-cell cytotoxicity (p < 0.01) and decreasing secretion of pro-inflammatory cytokines such as IL-6 and IFN-γ. This study showed the feasibility of generating highly proliferative PTECs and the development of tissue-specific immunomonitoring assays. Silencing SLA expression on PTECs was demonstrated to be an effective strategy to prevent xenogeneic cellular immune responses and may strongly support graft survival after xenotransplantation.
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Affiliation(s)
- Katharina Schmalkuche
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Reinhard Schwinzer
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Transplantation Laboratory, Clinic for General, Visceral and Transplantation-Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Nadine Wenzel
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Emilio Valdivia
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Björn Petersen
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Institute of Farm Animal Genetics, Höltystr. 10, 31535 Neustadt am Rübenberge, Germany
| | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Constanca Figueiredo
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
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12
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Habibabady Z, McGrath G, Kinoshita K, Maenaka A, Ikechukwu I, Elias GF, Zaletel T, Rosales I, Hara H, Pierson RN, Cooper DKC. Antibody-mediated rejection in xenotransplantation: Can it be prevented or reversed? Xenotransplantation 2023; 30:e12816. [PMID: 37548030 PMCID: PMC11101061 DOI: 10.1111/xen.12816] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 07/19/2023] [Accepted: 07/26/2023] [Indexed: 08/08/2023]
Abstract
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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Affiliation(s)
- Zahra Habibabady
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Gannon McGrath
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Kohei Kinoshita
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Akihiro Maenaka
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Ileka Ikechukwu
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Gabriela F. Elias
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Tjasa Zaletel
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Ivy Rosales
- Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Hidetaka Hara
- Yunnan Xenotransplantation Engineering Research Center, Yunnan Agricultural University, Kunming, Yunnan, China
| | - Richard N. Pierson
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - David K. C. Cooper
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
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13
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Mubarak M. Transitioning of renal transplant pathology from allograft to xenograft and tissue engineering pathology: Are we prepared? World J Transplant 2023; 13:86-95. [PMID: 36968134 PMCID: PMC10037233 DOI: 10.5500/wjt.v13.i3.86] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/21/2022] [Accepted: 01/11/2023] [Indexed: 03/16/2023] Open
Abstract
Currently, the most feasible and widely practiced option for patients with end-stage organ failure is the transplantation of part of or whole organs, either from deceased or living donors. However, organ shortage has posed and is still posing a big challenge in this field. Newer options being explored are xenografts and engineered/bioengineered tissues/organs. Already small steps have been taken in this direction and sooner or later, these will become a norm in this field. However, these developments will pose different challenges for the diagnosis and management of problems as compared with traditional allografts. The approach to pathologic diagnosis of dysfunction in these settings will likely be significantly different. Thus, there is a need to increase awareness and prepare transplant diagnosticians to meet this future challenge in the field of xenotransplantation/ regenerative medicine. This review will focus on the current status of transplant pathology and how it will be changed in the future with the emerging scenario of routine xenotransplantation.
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Affiliation(s)
- Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
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14
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Groth T, Stegmayr BG, Ash SR, Kuchinka J, Wieringa FP, Fissell WH, Roy S. Wearable and implantable artificial kidney devices for end-stage kidney disease treatment-Current status and review. Artif Organs 2022; 47:649-666. [PMID: 36129158 DOI: 10.1111/aor.14396] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 08/17/2022] [Accepted: 08/24/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Chronic kidney disease (CKD) is a major cause of early death worldwide. By 2030, 14.5 million people will have end-stage kidney disease (ESKD, or CKD stage 5), yet only 5.4 million will receive kidney replacement therapy (KRT) due to economic, social, and political factors. Even for those who are offered KRT by various means of dialysis, the life expectancy remains far too low. OBSERVATION Researchers from different fields of artificial organs collaborate to overcome the challenges of creating products such as Wearable and/or Implantable Artificial Kidneys capable of providing long-term effective physiologic kidney functions such as removal of uremic toxins, electrolyte homeostasis, and fluid regulation. A focus should be to develop easily accessible, safe, and inexpensive KRT options that enable a good quality of life and will also be available for patients in less-developed regions of the world. CONCLUSIONS Hence, it is required to discuss some of the limits and burdens of transplantation and different techniques of dialysis, including those performed at home. Furthermore, hurdles must be considered and overcome to develop wearable and implantable artificial kidney devices that can help to improve the quality of life and life expectancy of patients with CKD.
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Affiliation(s)
- Thomas Groth
- Department Biomedical Materials, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.,International Federation for Artificial Organs, Painesville, Ohio, USA
| | - Bernd G Stegmayr
- Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden
| | | | - Janna Kuchinka
- Department Biomedical Materials, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Fokko P Wieringa
- IMEC, Eindhoven, The Netherlands.,Department of Nephrology, University Medical Centre, Utrecht, The Netherlands.,European Kidney Health Alliance, WG3 "Breakthrough Innovation", Brussels, Belgium
| | | | - Shuvo Roy
- University of California, California, San Francisco, USA
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15
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Sun S, Lu D, Zhong H, Li C, Yang N, Huang B, Ni S, Li X. Donors for nerve transplantation in craniofacial soft tissue injuries. Front Bioeng Biotechnol 2022; 10:978980. [PMID: 36159691 PMCID: PMC9490317 DOI: 10.3389/fbioe.2022.978980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/16/2022] [Indexed: 11/13/2022] Open
Abstract
Neural tissue is an important soft tissue; for instance, craniofacial nerves govern several aspects of human behavior, including the expression of speech, emotion transmission, sensation, and motor function. Therefore, nerve repair to promote functional recovery after craniofacial soft tissue injuries is indispensable. However, the repair and regeneration of craniofacial nerves are challenging due to their intricate anatomical and physiological characteristics. Currently, nerve transplantation is an irreplaceable treatment for segmental nerve defects. With the development of emerging technologies, transplantation donors have become more diverse. The present article reviews the traditional and emerging alternative materials aimed at advancing cutting-edge research on craniofacial nerve repair and facilitating the transition from the laboratory to the clinic. It also provides a reference for donor selection for nerve repair after clinical craniofacial soft tissue injuries. We found that autografts are still widely accepted as the first options for segmental nerve defects. However, allogeneic composite functional units have a strong advantage for nerve transplantation for nerve defects accompanied by several tissue damages or loss. As an alternative to autografts, decellularized tissue has attracted increasing attention because of its low immunogenicity. Nerve conduits have been developed from traditional autologous tissue to composite conduits based on various synthetic materials, with developments in tissue engineering technology. Nerve conduits have great potential to replace traditional donors because their structures are more consistent with the physiological microenvironment and show self-regulation performance with improvements in 3D technology. New materials, such as hydrogels and nanomaterials, have attracted increasing attention in the biomedical field. Their biocompatibility and stimuli-responsiveness have been gradually explored by researchers in the regeneration and regulation of neural networks.
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Affiliation(s)
- Sishuai Sun
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Di Lu
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Hanlin Zhong
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Chao Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Ning Yang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Bin Huang
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
| | - Shilei Ni
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
- *Correspondence: Shilei Ni, ; Xingang Li,
| | - Xingang Li
- Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
- Jinan Microecological Biomedicine Shandong Laboratory and Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
- *Correspondence: Shilei Ni, ; Xingang Li,
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16
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Huang J. Expert consensus on clinical trials of human xenotransplantation in China. HEALTH CARE SCIENCE 2022; 1:7-10. [PMID: 38939355 PMCID: PMC11080631 DOI: 10.1002/hcs2.6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/10/2022] [Accepted: 06/15/2022] [Indexed: 06/29/2024]
Abstract
The history of xenotransplantation started in the 19th century. After a few decades of investigation, significant breakthroughs and preclinical milestones have been achieved worldwide. With the recent transplantation of genetically modified porcine kidneys and heart into humans, these ground-breaking achievements have attracted great attention worldwide, in the hope that xenotransplantation might alleviate or even solve the problem of organ shortage. On January 20, 2022, the China Organ Transplantation Development Foundation convened a symposium on "The History, Current Situation and Future of Human Xenotransplantation Clinical Trials," where ways to promote the ethical and sustainable development of xenotransplantation in China were discussed among the participating experts. A formal consensus was reached as the product of the symposium, outlining the expert opinions on scientific, regulatory, and ethical issues of clinical trials of xenotransplantation in China.
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Affiliation(s)
- Jiefu Huang
- China Organ Transplantation Development FoundationBeijingChina
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17
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Carrier AN, Verma A, Mohiuddin M, Pascual M, Muller YD, Longchamp A, Bhati C, Buhler LH, Maluf DG, Meier RPH. Xenotransplantation: A New Era. Front Immunol 2022; 13:900594. [PMID: 35757701 PMCID: PMC9218200 DOI: 10.3389/fimmu.2022.900594] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Organ allotransplantation has now reached an impassable ceiling inherent to the limited supply of human donor organs. In the United States, there are currently over 100,000 individuals on the national transplant waiting list awaiting a kidney, heart, and/or liver transplant. This is in contrast with only a fraction of them receiving a living or deceased donor allograft. Given the morbidity, mortality, costs, or absence of supportive treatments, xenotransplant has the potential to address the critical shortage in organ grafts. Last decade research efforts focused on creation of donor organs from pigs with various genes edited out using CRISPR technologies and utilizing non-human primates for trial. Three groups in the United States have recently moved forward with trials in human subjects and obtained initial successful results with pig-to-human heart and kidney xenotransplantation. This review serves as a brief discussion of the recent progress in xenotransplantation research, particularly as it concerns utilization of porcine heart, renal, and liver xenografts in clinical practice.
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Affiliation(s)
- Amber N Carrier
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Anjali Verma
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Muhammad Mohiuddin
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Manuel Pascual
- Department of Vascular Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
| | - Yannick D Muller
- Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
| | - Alban Longchamp
- Department of Vascular Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
| | - Chandra Bhati
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Leo H Buhler
- Faculty of Science and Medicine, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Daniel G Maluf
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Raphael P H Meier
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
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18
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Lee H, Park EM, Ko N, Choi K, Oh KB, Kang HJ. Effect of Factor H on Complement Alternative Pathway Activation in Human Serum Remains on Porcine Cells Lacking N-Glycolylneuraminic Acid. Front Immunol 2022; 13:859261. [PMID: 35444661 PMCID: PMC9014258 DOI: 10.3389/fimmu.2022.859261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Background Triple knockout (TKO) donor pigs lacking alpha-1,3-galactose (Gal), N-glycolylneuraminic acid (Neu5Gc), and Sd(a) expressions were developed to improve the clinical success of xenotransplantation. Neu5Gc, a sialic acid expressed on cell surfaces, recruits factor H to protect cells from attack by the complement system. Lack of Neu5Gc expression may cause unwanted complement activation, abrogating the potential benefit of gene-modified donor pigs. To investigate whether TKO porcine cells display increased susceptibility to complement activation in human serum, pathway-specific complement activation, apoptosis, and human platelet aggregation by porcine cells were compared between alpha-1,3-galactosyltransferase gene-knockout (GTKO) and TKO porcine cells. Methods Primary porcine peripheral blood mononuclear cells (pPBMCs) and endothelial cells (pECs) from GTKO and TKO pigs were used. Cells were incubated in human serum diluted in gelatin veronal buffer (GVB++) or Mg++-EGTA GVB, and C3 deposition and apoptotic changes in these cells were measured by flow cytometry. C3 deposition levels were also measured after incubating these cells in 10% human serum supplemented with human factor H. Platelet aggregation in human platelet-rich plasma containing GTKO or TKO pECs was analyzed. Results The C3 deposition level in GTKO pPBMCs or pECs in GVB++ was significantly higher than that of TKO pPBMCs or pECs, respectively, but C3 deposition levels in Mg++-EGTA-GVB were comparable between them. The addition of factor H into the porcine cell suspension in 10% serum in Mg++ -EGTA-GVB inhibited C3 deposition in a dose-dependent manner, and the extent of inhibition by factor H was similar between GTKO and TKO porcine cells. The percentage of late apoptotic cells in porcine cell suspension in GVB++ increased with the addition of human serum, of which the net increase was significantly less in TKO pPBMCs than in GTKO pPBMCs. Finally, the lag time of platelet aggregation in recalcified human plasma was significantly prolonged in the presence of TKO pECs compared to that in the presence of GTKO pECs. Conclusion TKO genetic modification protects porcine cells from serum-induced complement activation and apoptotic changes, and delays recalcification-induced human platelet aggregation. It does not hamper factor H recruitment on cell surfaces, allowing the suppression of alternative complement pathway activation.
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Affiliation(s)
- Haneulnari Lee
- Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, South Korea
| | - Eun Mi Park
- Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, South Korea
| | - Nayoung Ko
- Department of Transgenic Animal Research, Optipharm Inc., Cheongju, South Korea
| | - Kimyung Choi
- Department of Transgenic Animal Research, Optipharm Inc., Cheongju, South Korea
| | - Keon Bong Oh
- Animal Biotechnology Division, National Institute of Animal Science, Rural Development Administration (RDA), Wanju, South Korea
| | - Hee Jung Kang
- Department of Laboratory Medicine, Hallym University College of Medicine, Anyang, South Korea
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19
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Feng H, Li T, Du J, Xia Q, Wang L, Chen S, Zhu L, Pan D, Wang Y, Chen G. Both Natural and Induced Anti-Sda Antibodies Play Important Roles in GTKO Pig-to-Rhesus Monkey Xenotransplantation. Front Immunol 2022; 13:849711. [PMID: 35422817 PMCID: PMC9004458 DOI: 10.3389/fimmu.2022.849711] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/07/2022] [Indexed: 01/30/2023] Open
Abstract
Sda, produced by the B4GALNT2 enzyme, has been recognized as an important xenoantigen for pig-to-nonhuman primate xenotransplantation. However, little is known about Sda expression in pigs and its immunogenicity in xenotransplantation. In this study, peripheral blood mononuclear cells (PBMCs) were isolated from wildtype, GTKO (with high, moderate, and low Sda expression), GTKO/β4GalNT2KO, GTKO/CMAHKO, or GTKO/CMAHKO/β4GalNT2KO pigs. Anti-pig IgM/IgG binding and complement-dependent cytotoxicity (CDC) to pig PBMCs was measured by flow cytometry using pooled rhesus monkey sera (n=20) or human sera (n=20). As compared to wild-type pigs (n=12), GTKO pigs (n=17) had a significantly higher mean level of Sda expression on PBMCs and showed a greater individual difference in expression. Both the overall binding of monkey serum IgM/IgG antibody to GTKO pig PBMCs and CDC against these PBMCs decreased significantly with a progressive reduction in Sda expression, showing a clear dose-effect relationship. Both the monkey serum antibody binding and CDC decreased significantly after the additional deletion of Sda, whereas the binding of human serum antibody and CDC against the GTKO pig PBMCs were markedly reduced after the deletion of Neu5Gc in the pigs. In addition, anti-Sda antibody accounted for > 50% of the induced anti-non-Gal antibody at the time of rejection in two rhesus monkeys that received GTKO/hCD55 pig kidney xenotransplantation, and the anti-Sda antibody showed significant cytotoxic activity against GTKO pig cells. We conclude that both natural and induced anti-Sda antibodies play important roles in GTKO pig-to-rhesus monkey xenotransplantation, thus providing further evidence for GTKO/β4GalNT2KO pigs as the preferred organ source for rhesus monkeys as a preclinical model of xenotransplantation.
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Affiliation(s)
- Hao Feng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Tao Li
- Department of Organ Transplantation, The Transplantation Institute of Hainan Medical University, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Jiaxiang Du
- Genetic Engineering Department, Chengdu Clonorgan Biotechnology Co., Ltd, Chengdu, China
| | - Qiangbing Xia
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Lu Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Song Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Lan Zhu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Dengke Pan
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Yi Wang
- Department of Organ Transplantation, The Transplantation Institute of Hainan Medical University, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Gang Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
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20
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Feng H, Li T, Du J, Xia Q, Wang L, Chen S, Zhu L, Pan D, Wang Y, Chen G. Both Natural and Induced Anti-Sda Antibodies Play Important Roles in GTKO Pig-to-Rhesus Monkey Xenotransplantation. Front Immunol 2022. [DOI: 10.3389/fimmu.2022.849711
expr 981672748 + 872648996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Sda, produced by the B4GALNT2 enzyme, has been recognized as an important xenoantigen for pig-to-nonhuman primate xenotransplantation. However, little is known about Sda expression in pigs and its immunogenicity in xenotransplantation. In this study, peripheral blood mononuclear cells (PBMCs) were isolated from wildtype, GTKO (with high, moderate, and low Sda expression), GTKO/β4GalNT2KO, GTKO/CMAHKO, or GTKO/CMAHKO/β4GalNT2KO pigs. Anti-pig IgM/IgG binding and complement-dependent cytotoxicity (CDC) to pig PBMCs was measured by flow cytometry using pooled rhesus monkey sera (n=20) or human sera (n=20). As compared to wild-type pigs (n=12), GTKO pigs (n=17) had a significantly higher mean level of Sda expression on PBMCs and showed a greater individual difference in expression. Both the overall binding of monkey serum IgM/IgG antibody to GTKO pig PBMCs and CDC against these PBMCs decreased significantly with a progressive reduction in Sda expression, showing a clear dose-effect relationship. Both the monkey serum antibody binding and CDC decreased significantly after the additional deletion of Sda, whereas the binding of human serum antibody and CDC against the GTKO pig PBMCs were markedly reduced after the deletion of Neu5Gc in the pigs. In addition, anti-Sda antibody accounted for > 50% of the induced anti-non-Gal antibody at the time of rejection in two rhesus monkeys that received GTKO/hCD55 pig kidney xenotransplantation, and the anti-Sda antibody showed significant cytotoxic activity against GTKO pig cells. We conclude that both natural and induced anti-Sda antibodies play important roles in GTKO pig-to-rhesus monkey xenotransplantation, thus providing further evidence for GTKO/β4GalNT2KO pigs as the preferred organ source for rhesus monkeys as a preclinical model of xenotransplantation.
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21
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Meier RPH. Invited commentary. Xenotransplantation 2022; 29:e12736. [PMID: 35166408 DOI: 10.1111/xen.12736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Raphael P H Meier
- Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA
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22
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Yerly P, Rotman S, Regamey J, Aubert V, Aur S, Kirsch M, Hullin R, Pascual M. Complement blockade with eculizumab to treat acute symptomatic humoral rejection after heart transplantation. Xenotransplantation 2022; 29:e12726. [PMID: 35001433 PMCID: PMC9285545 DOI: 10.1111/xen.12726] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/23/2021] [Accepted: 12/17/2021] [Indexed: 12/12/2022]
Abstract
Antibody‐mediated rejection (AMR) is a major barrier preventing successful discordant organ xenotransplantation, but it also occurs in allotransplantation due to anti‐HLA antibodies. Symptomatic acute AMR is rare after heart allograft but carries a high risk of mortality, especially >1 year after transplant. As complement activation may play a major role in mediating tissue injury in acute AMR, drugs blocking the terminal complement cascade like eculizumab may be useful, particularly since “standards of care” like plasmapheresis are not based on strong evidence. Eculizumab was successfully used to treat early acute kidney AMR, a typical condition of “active AMR,” but showed mitigated results in late AMR, where “chronic active” lesions are more prevalent. Here, we report the case of a heart recipient who presented with acute heart failure due to late acute AMR with eight de novo donor‐specific anti‐HLA antibodies (DSA), and who fully recovered allograft function and completely cleared DSA following plasmapheresis‐free upfront eculizumab administration in addition to thymoglobulin, intravenous immunoglobulins (IVIG), and rituximab. Several clinical (acute onset, abrupt and severe loss of graft function), biological (sudden high‐level production of DSA), and pathological features (microvascular injury, C4d deposits) of this cardiac recipient are shared with early kidney AMR and may indicate a strong role of complement in the pathogenesis of acute graft injury that may respond to drugs like eculizumab. Terminal complement blockade should be further explored to treat acute AMR in recipients of heart allografts and possibly also in recipients of discordant xenografts in the future.
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Affiliation(s)
- Patrick Yerly
- Service of Cardiology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
| | - Samuel Rotman
- Service of Clinical Pathology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
| | - Julien Regamey
- Service of Cardiology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
| | - Vincent Aubert
- Service of Immunology and Allergology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
| | - Stefania Aur
- Service of Cardiology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
| | - Matthias Kirsch
- Service of Cardiac Surgery, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
| | - Roger Hullin
- Service of Cardiology, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
| | - Manuel Pascual
- Center for Organ Transplantation, Lausanne University Hospital (CHUV) and Lausanne University, Lausanne, Switzerland
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23
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Feng H, Li T, Du J, Xia Q, Wang L, Chen S, Zhu L, Pan D, Wang Y, Chen G. Both Natural and Induced Anti-Sda Antibodies Play Important Roles in GTKO Pig-to-Rhesus Monkey Xenotransplantation. Front Immunol 2022. [PMID: 35422817 PMCID: PMC9004458 DOI: 10.3389/fimmu.2022.849711&set/a 866800723+810249609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Sda, produced by the B4GALNT2 enzyme, has been recognized as an important xenoantigen for pig-to-nonhuman primate xenotransplantation. However, little is known about Sda expression in pigs and its immunogenicity in xenotransplantation. In this study, peripheral blood mononuclear cells (PBMCs) were isolated from wildtype, GTKO (with high, moderate, and low Sda expression), GTKO/β4GalNT2KO, GTKO/CMAHKO, or GTKO/CMAHKO/β4GalNT2KO pigs. Anti-pig IgM/IgG binding and complement-dependent cytotoxicity (CDC) to pig PBMCs was measured by flow cytometry using pooled rhesus monkey sera (n=20) or human sera (n=20). As compared to wild-type pigs (n=12), GTKO pigs (n=17) had a significantly higher mean level of Sda expression on PBMCs and showed a greater individual difference in expression. Both the overall binding of monkey serum IgM/IgG antibody to GTKO pig PBMCs and CDC against these PBMCs decreased significantly with a progressive reduction in Sda expression, showing a clear dose-effect relationship. Both the monkey serum antibody binding and CDC decreased significantly after the additional deletion of Sda, whereas the binding of human serum antibody and CDC against the GTKO pig PBMCs were markedly reduced after the deletion of Neu5Gc in the pigs. In addition, anti-Sda antibody accounted for > 50% of the induced anti-non-Gal antibody at the time of rejection in two rhesus monkeys that received GTKO/hCD55 pig kidney xenotransplantation, and the anti-Sda antibody showed significant cytotoxic activity against GTKO pig cells. We conclude that both natural and induced anti-Sda antibodies play important roles in GTKO pig-to-rhesus monkey xenotransplantation, thus providing further evidence for GTKO/β4GalNT2KO pigs as the preferred organ source for rhesus monkeys as a preclinical model of xenotransplantation.
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Affiliation(s)
- Hao Feng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Tao Li
- Department of Organ Transplantation, The Transplantation Institute of Hainan Medical University, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Jiaxiang Du
- Genetic Engineering Department, Chengdu Clonorgan Biotechnology Co., Ltd, Chengdu, China
| | - Qiangbing Xia
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Lu Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Song Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Lan Zhu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Dengke Pan
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Yi Wang
- Department of Organ Transplantation, The Transplantation Institute of Hainan Medical University, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Gang Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
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24
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Cozzi E, Schneeberger S, Bellini MI, Berglund E, Böhmig G, Fowler K, Hoogduijn M, Jochmans I, Marckmann G, Marson L, Neuberger J, Oberbauer R, Pierson RN, Reichart B, Scobie L, White C, Naesens M. Organ transplants of the future: planning for innovations including xenotransplantation. Transpl Int 2021; 34:2006-2018. [PMID: 34459040 DOI: 10.1111/tri.14031] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/10/2021] [Accepted: 08/24/2021] [Indexed: 12/15/2022]
Abstract
The future clinical application of animal-to-human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to cell, tissue and solid organ xenotransplants have been obtained from many animal models utilizing genetic engineering and protocols of pathogen-free husbandry. Findings have reached a tipping point, and xenotransplantation of solid organs is approaching clinical evaluation, the process of which now requires close deliberation. Such discussions include considering when there is sufficient evidence from preclinical animal studies to start first-in-human xenotransplantation trials. The present article is based on evidence and opinions formulated by members of the European Society for Organ Transplantation who are involved in the Transplantation Learning Journey project. The article includes a brief overview of preclinical concepts and biology of solid organ xenotransplantation, discusses the selection of candidates for first-in-human studies and considers requirements for study design and conduct. In addition, the paper emphasizes the need for a regulatory framework for xenotransplantation of solid organs and the essential requirement for input from public and patient stakeholders.
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Affiliation(s)
- Emanuele Cozzi
- Department of Cardiac, Thoracic and Vascular Sciences and Public Health, Transplant Immunology Unit, Padua University Hospital, Padua, Italy
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Maria Irene Bellini
- Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy
- Department of Emergency Medicine and Surgery, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
| | - Erik Berglund
- Department of Clinical Science, Intervention and Technology (CLINTEC), Division of Transplantation Surgery, Karolinska Institute and ITB-MED, Stockholm, Sweden
| | - Georg Böhmig
- Division of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria
| | - Kevin Fowler
- The Voice of the Patient, Inc., Chicago, IL, USA
| | - Martin Hoogduijn
- Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Ina Jochmans
- Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Georg Marckmann
- Institute of Ethics, History and Theory of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Lorna Marson
- The Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Edinburgh, UK
| | | | | | - Richard N Pierson
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Bruno Reichart
- Walter Brendel Center for Experimental Medicine, LMU Munich, Munich, Germany
| | - Linda Scobie
- Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, UK
| | | | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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