Xenotransplantation最新文献

{"title":"Bridging Therapies-Ex Vivo Liver Xenoperfusion and the Role of Machine Perfusion: An Update.","authors":"Zoltan Czigany, Kasra Shirini, Aghnia J Putri, Alban E Longchamp, Subarna Bhusal, Shani Kamberi, Raphael P H Meier","doi":"10.1111/xen.70011","DOIUrl":"10.1111/xen.70011","url":null,"abstract":"<p><p>Advancements in xenotransplantation intersecting with modern machine perfusion technology offer promising solutions to patients with liver failure providing a valuable bridge to transplantation and extending graft viability beyond current limitations. Patients facing acute or acute chronic liver failure, post-hepatectomy liver failure, or fulminant hepatic failure often require urgent liver transplants which are severely limited by organ shortage, emphasizing the importance of effective bridging approaches. Machine perfusion is now increasingly used to test and use genetically engineered porcine livers in translational studies, addressing the limitations and costs of non-human primate models. Current reports about artificial and bioartificial liver support combined with xenografts showcase the potential in ex vivo xenogeneic perfusion. Breakthroughs, such as the perfusion of genetically modified porcine liver with FDA-approved machine perfusion systems connected to human blood circulation, underscore the interest and potential feasibility of a \"liver dialysis\" bridge to allotransplantation or recovery. This review provides an overview of the past and current research in the field of ex vivo pig liver xenoperfusion.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70011"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Complement-Dependent Cytotoxicity Assays for Gene-Edited Pig-to-Human Xenotransplantation.","authors":"Hao Feng, Man Zhang, Qiangbing Xia, Jiaxiang Du, Tao Li, Song Chen, Yi Wang, Dengke Pan, Lan Zhu, Gang Chen","doi":"10.1111/xen.70012","DOIUrl":"10.1111/xen.70012","url":null,"abstract":"<p><strong>Background: </strong>Gene-edited pigs for xenotransplantation usually contain one or more transgenes encoding human complement regulatory proteins (CRPs). Because of species differences, human CRP(s) expressed in gene-edited pigs may have difficulty inhibiting the activation of exogenous rabbit complement added to a complement-dependent cytotoxicity (CDC) assay. The use of human complement instead of rabbit complement in CDC experiments may more accurately reflect the actual regulatory activity of human CRP(s).</p><p><strong>Methods: </strong>Peripheral blood mononuclear cells (PBMCs) were obtained from one GTKO pig and two GTKO/hCD55 pigs with a high or low level of hCD55 expression. After incubation of heat-inactivated normal human sera (HINHS) with porcine PBMCs, CDC levels were measured after the addition of commercial rabbit complement or human complement. In addition, a modified one-step CDC method was established using pooled normal human sera (NHS) without the addition of exogenous complement.</p><p><strong>Results: </strong>There was no significant difference in the binding of IgM/IgG to PBMCs from the three pigs. Both rabbit and human complement mediated a significant cytotoxic effect on GTKO pig PBMCs (98.97% vs. 82.73%). Even the high expression of hCD55 only had a very limited inhibitory effect on rabbit complement-mediated cytotoxicity (81.70% vs. 98.97%). However, regardless of whether the expression level was high or low, hCD55 had a very remarkable inhibitory effect on human complement-mediated cytotoxicity (2.94% and 23.83% vs. 82.73%; p < 0.01). Similar results were obtained using the modified one-step CDC method. In addition, the inhibitory effect of hCD55 on C3c and C5b-9 deposition on pig PBMCs was positively correlated with the expression level of hCD55.</p><p><strong>Conclusion: </strong>The use of human complement instead of rabbit complement in CDC assays can better reflect the actual cytotoxic effect of human xenoantibodies against pig PBMCs expressing human CRP(s), and thus may have potential application to gene-edited pig-to-human xenotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70012"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An IgM Cleaving Enzyme for Clearance of Anti-Pig Xenoreactive Antibodies in a Nonhuman Primate Model.","authors":"Alessandro Martinino, Timothy J Smith, Zachary C Elmore, Janghoon Yoon, Joseph Ladowski, Davide Schiliro, Joshua A Hull, Allie Schwalb, Meghan Hu, Ryan Spangler, Kyo Won Lee, Min Jung Kim, Kyha Williams, Annette Jackson, Stuart J Knechtle, Aravind Asokan, Jean Kwun","doi":"10.1111/xen.70015","DOIUrl":"10.1111/xen.70015","url":null,"abstract":"<p><strong>Background: </strong>The removal of preformed antibodies with cleaving enzyme like IdeS (Imlifidase) has demonstrated therapeutic potential in organ transplantation for sensitized recipients. However, preformed xenoreactive antibodies (XAbs) against porcine glycans are predominantly IgM and considered detrimental in pig-to-human xenotransplantation.</p><p><strong>Methods: </strong>Recombinant IceM, an endopeptidase cleaving IgM, was generated in Escherichia coli. Four maximally MHC-mismatched rhesus macaques underwent two serial skin transplantations to model allosensitized patients awaiting xenotransplantation. IceM was administered IV in allosensitized animals at 28 and 56 days after the first skin transplantation to assess in vivo IgM cleavage. Total IgG and IgM were quantified with western blot, and anti-pig (xenoreactive) IgG/IgM were evaluated using flowcrossmatch. B cell and its subpopulations were assessed using flow cytometry.</p><p><strong>Results: </strong>IceM selectively cleaved human IgM, while showing no cleavage activity toward other isotypes including IgG, IgA, IgD, and IgE. Additionally, IceM cleaves only human and non-human primate IgM in vitro, but not in sera from other species. At a dose of 0.5 mg/kg, IceM reduced xenoreactive IgM levels to 13.76% ± 4.98% of baseline (B cell flow crossmatch) at 24 h post-administration, with baseline levels restored approximately 2 weeks after treatment. Additionally, animals showed similar kinetics of xenoreative IgM degradation with the repeated dose of IceM.</p><p><strong>Conclusion: </strong>In this study, we report a recombinant bacterial enzyme that selectively cleaves IgM in human and non-human primate sera. Repeat administration of IceM in macaques enables selective, robust clearance of circulating xenoreactive IgM. This approach will be useful in treating preformed natural and rebound IgM in xenotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70015"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transplant Patients' Perceptions About Participating in First-in-Human Pig Kidney Xenotransplant Clinical Trials: A Mixed Methods Study.","authors":"Elisa J Gordon, Karen J Maschke, Jessica Gacki-Smith, Hannah L Brooks, Margaret M Matthews, Karen Traboulsi, Dahlya Manning, Joseph Leventhal, Michael K Gusmano","doi":"10.1111/xen.70013","DOIUrl":"10.1111/xen.70013","url":null,"abstract":"<p><p>First-in-human pig xenotransplant clinical trials may soon begin, which raises ethical concerns about patients' decision-making to participate in such trials. We assessed kidney transplant candidates' attitudes and hypothetical decision-making about participating in xenotransplant trials through semi-structured telephone interviews and an online survey. We analyzed qualitative data by thematic analysis and quantitative data by descriptive statistics. Twenty-eight patients participated in interviews; 142 patients participated in the survey. Most interview and survey respondents were male (68%, 56%), White (54%, 61%), or Black (36%, 22%). Although interview participants appreciated xenotransplantation research's potential to advance science, they expressed concerns about infection transmission and graft function. Few survey respondents were willing to participate in a pig kidney trial to test the safety of pig kidneys (12.6%) or pig kidney function (16.9%). Interview participants would be more likely to participate in a first-in-human pig kidney trial if receiving a human kidney was unlikely and their health status declined. Willingness would also depend on how long the pig kidney would function. Most interview participants were receptive to long-term monitoring, but not to family monitoring. Transplant programs planning xenotransplant trials should anticipate these types of concerns for optimizing human subject protections and conducting a robust informed consent process.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70013"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11800742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic Review and Comparative Outcomes Analysis of NHP Liver Allotransplants and Xenotransplants.","authors":"Kasra Shirini, Raphael P H Meier","doi":"10.1111/xen.70017","DOIUrl":"10.1111/xen.70017","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70017"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asking the Right Questions: Larry Faucette's Journey Through Xenotransplant.","authors":"Muhammad M Mohiuddin","doi":"10.1111/xen.70014","DOIUrl":"https://doi.org/10.1111/xen.70014","url":null,"abstract":"","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70014"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Xenotransplantation, Ethics, and Pediatric Decedent Studies.","authors":"Daniel J Hurst, Luz A Padilla, Anthony Merlocco","doi":"10.1111/xen.70024","DOIUrl":"https://doi.org/10.1111/xen.70024","url":null,"abstract":"","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70024"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Religion and Attitudes Toward Xenotransplantation: Results of a Nationwide Survey in the United States.","authors":"Daniel J Hurst, Luz A Padilla, Amanda Zink, Brendan Parent, Laura L Kimberly","doi":"10.1111/xen.70020","DOIUrl":"10.1111/xen.70020","url":null,"abstract":"<p><p>Religious viewpoints have been shown to influence the ways in which many persons approach medical decision-making and have been noted as a potential barrier to xenotransplantation acceptance. This study sought to explore how attitudes toward xenotransplantation differ among various religious beliefs. A national Likert-scale survey was conducted in 2023 with a representative sample in the United States. Religious belief was self-reported. Regression analysis was used to identify associations with religious belief and hesitations about xenotransplantation. Five thousand and eight individuals across the United States responded to the survey. The two biggest concerns about xenotransplantation across religious groups were the current lack of evidence about success and the risk of xenozoonosis. Although they still expressed concerns about certain issues, Catholic and Muslim respondents were most comfortable with xenotransplantation for all. On average, the risk of xenozoonosis was a concern among 25% across all religious beliefs (p <0.0001). Orthodox Christians expressed the highest rate of negative feelings toward the recent xenotransplantation experiments on brain dead and living individuals. Those who reported no religion were most likely to have negative feelings about killing pigs for human organ transplant (OR 1.26; 95% CI: 1.08-1.46). As xenotransplantation progresses from pre-clinical studies to clinical trials, and potentially to clinical therapy, hesitations among religious groups exist. Specific studies should be designed to investigate how religious viewpoints can affect xenotransplantation acceptance.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70020"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preservation of Cardiac Xenografts in a Model of Infant Human Cardiac Transplantation.","authors":"Chace B Mitchell, Joe Simmons, Clementine Vo, Kanwarpal Bakshi, Julie Juliani, Julie Fenske, Carolyn L Hodo, David C Cleveland, John D Cleveland","doi":"10.1111/xen.70009","DOIUrl":"10.1111/xen.70009","url":null,"abstract":"<p><strong>Introduction: </strong>There is no standard protocol for management of organ preservation for orthotopic, life-sustaining cardiac xenotransplantation, particularly for hearts from pediatric sized donors. Standard techniques and solutions successful in human allotransplantation are not viable. We theorized that a solution commonly used in reparative cardiac surgery in human children would suffice by exploiting the advantages inherent to xenotransplantation, namely the ability to reduce organ ischemic times by co-locating the donor and recipient.</p><p><strong>Methods: </strong>Orthotopic cardiac xenotransplantation was performed from genetically engineered pigs to size matched baboons. A dose of modified Del Nido cardioplegia initiated donor heart arrest and was followed by a second dose mixed with recipient blood prior to implant. Hemodynamics and cardiac function were tracked with a combination of invasive and non-invasive measures.</p><p><strong>Results: </strong>Mean ischemic time and cardiopulmonary bypass times were 54.1 ± 14.6 and 84.1 ± 14 min respectively. The ejection fraction following chest closure was preserved at >50% for all animals. This finding persisted at 48hours. Mean inotropic score at 24 h post-implant was 9.7 ± 3.</p><p><strong>Conclusion: </strong>Del Nido cardioplegia solution when combined with short graft ischemic times demonstrates promising outcomes to avoid primary graft dysfunction for cardiac xenografts in a small animal model of life-sustaining orthotopic cardiac xenotransplantation. Ex vivo perfusion systems may be unnecessary for successful clinical implementation of this evolving technology.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70009"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of Brain Death Recipients in Xenotransplantation: A Double-Edged Sword.","authors":"Xingchao Du, Yuan Chang, Jiangping Song","doi":"10.1111/xen.70010","DOIUrl":"10.1111/xen.70010","url":null,"abstract":"<p><p>Organ transplants are used to treat many end-stage diseases, but a shortage of donors means many patients cannot be treated. Xenogeneic organs have become an important part of filling the donor gap. Many current studies of kidney, heart, and liver xenotransplantation have used gene-edited pig organs on brain-dead recipients. However, the endocrine system, immune system, and nervous system of brain-dead people are changed, which are different from that of real patients transplanted, and the current research results of brain death (BD) recipients are also different. So there are drawbacks to using brain-dead people for xenotransplantation. In addition, although the policy requires the use of non-human primate (NHP) experiments as the research standard for xenotransplantation, there are still differences between NHP and humans in terms of immunity. Therefore, to better study xenotransplantation, new models may be needed in addition to NHP and brain-dead individuals. Humanized animal models or organoids may be able to fill this gap.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70010"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}