Xenotransplantation最新文献

{"title":"Xenotransplantation in China: Past, Present, and Future.","authors":"Kai Xing, Yuan Chang, Xiulin Zhang, Xingchao Du, Jiangping Song","doi":"10.1111/xen.70038","DOIUrl":"https://doi.org/10.1111/xen.70038","url":null,"abstract":"<p><p>Organ failure poses a substantial global health challenge, and xenotransplantation emerges as one of the most promising avenues to mitigate the critical shortage of donor organs. In recent years, numerous research institutions have undertaken clinical and preclinical xenotransplantation in humans, instilling hope for notable progress. Nevertheless, formidable obstacles persist before success can be fully achieved. Chinese researchers have been at the forefront of xenotransplantation studies, actively contributing to several pivotal areas: the identification of critical genes essential for xenotransplantation and the creation of genetically modified pigs; preclinical studies on pig-to-nonhuman primate organ and tissue xenotransplantation, as well as the utilization of genetically engineered pig-derived biomaterials; contributions to both preclinical and clinical xenotransplantation research; and the formulation and refinement of xenotransplantation policies and ethical guidelines in China. In conclusion, this review seeks to not only acknowledge the contributions of Chinese researchers but also to encourage further collaboration between Chinese scholars and their international counterparts in advancing the field of xenotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 2","pages":"e70038"},"PeriodicalIF":3.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038318","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":"Treatment of Presumptive Rejection After Orthotopic Pig-to-Baboon Cardiac Xenotransplantation.","authors":"Chace B Mitchell, Sarah J Neal, Joe H Simmons, Sriram Chitta, David K C Cooper, David C Cleveland, John D Cleveland","doi":"10.1111/xen.70044","DOIUrl":"https://doi.org/10.1111/xen.70044","url":null,"abstract":"<p><strong>Background: </strong>Significant progress has been made in the long-term survival of non-human primates after orthotopic gene-edited pig cardiac xenotransplantation. However, to our knowledge, there are no reports of the successful reversal of an acute rejection episode in such an experiment. We present evidence suggesting that rejection can be reversed with corticosteroids and complement inhibition.</p><p><strong>Methods: </strong>Orthotopic transplantation of a pig heart (with 69 gene-edits) was carried out in a baboon. The immunosuppressive regimen was based on CD40/CD154 T cell co-stimulation pathway blockade and rapamycin. Cardiac function remained excellent until Day 162, when there were increases in heart rate, ventricular septal wall thickness, left ventricular end-diastolic pressures (LVEDP), and troponin level, which were associated with a low serum level of rapamycin (<4 ng/mL). Anti-rejection treatment was begun with an increase in rapamycin dosage, steroid bolus therapy, two doses of a C1-esterase inhibitor, and an extra dose of the anti-CD154mAb.</p><p><strong>Results: </strong>There was a rapid correction of all hemodynamic parameters, and the troponin T level (which had risen to 139 ng/L) returned to pre-rejection levels. Ventricular septal thickness and LVEDP returned to pre-rejection levels after treatment. The baboon remains well with normal graft function. Baseline heart rate remains faster than before the rejection episode.</p><p><strong>Conclusions: </strong>As we transition to the clinical application of gene-edited pig cardiac xenotransplantation, the ability to treat rejection is of vital importance. The optimal treatment for rejection remains uncertain but we suggest that systemic complement inhibition is important.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 2","pages":"e70044"},"PeriodicalIF":3.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000532","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":"Dendritic Cells in Xenotransplantation: Shaping the Cellular Immune Response Toward Tolerance.","authors":"Gisella L Puga Yung, Tom Wakley, Athanasios Kouklas, Jörg D Seebach","doi":"10.1111/xen.70037","DOIUrl":"https://doi.org/10.1111/xen.70037","url":null,"abstract":"<p><p>The molecular barriers that cause acute xenograft rejection have been identified and addressed by generating genetically modified (GM) animals, knocked out for specific xenoantigens (xenoAgs), and expressing regulatory molecules for both complement and coagulation pathways among others. The focus of xenotransplantation research now lies in delayed xenograft rejection. Dendritic cells (DC) are a specific subpopulation of professional antigen-presenting cells (APC) that play a crucial role in the context of organ transplantation. DCs, originating from both the xenograft and the recipient, have the capacity to present xenoAgs to the recipient's immune system via their respective major histocompatibility complex (MHC) molecules leading to rejection. These processes are known as direct and indirect presentation, respectively. However, under certain microenvironmental conditions, DC develops into anti-inflammatory regulatory cells that can induce immunological tolerance. The purpose of this review is to summarize current knowledge on the general characteristics and functions of DC from species relevant to xenotransplantation, specifically humans, non-human primates (NHP), and pigs. It will also cover the process of xenoAg presentation, different methods for generating DC with regulatory properties in vitro, and finally, discuss the current strategies for using regulatory DC to improve xenograft acceptance by inducing tolerance.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 2","pages":"e70037"},"PeriodicalIF":3.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144030688","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":"Defect in Sensing Human Thrombin by Porcine Endothelial Protease-Activated Receptor-1: Molecular Incompatibility Between Porcine PAR-1 and Human Thrombin.","authors":"Thi Xoan Hoang, Ju-Young Bang, Vinh Phuoc Nguyen, Phu Chi Vu, Ik Jin Yun, Hee Jung Kang, Jae Young Kim","doi":"10.1111/xen.70041","DOIUrl":"10.1111/xen.70041","url":null,"abstract":"<p><p>Xenotransplantation, the transplantation of organs from pigs to humans, presents significant challenges due to immune rejection, which is driven by molecular incompatibilities between species. This study investigates the compatibility between human thrombin and porcine protease-activated receptor-1 (PAR-1), a key regulator of both coagulation and inflammatory responses. Human thrombin activates PAR-1 in human vascular endothelial cells, but our results demonstrate that human thrombin does not effectively activate PAR-1 in porcine vascular endothelial cells due to differences in amino acid sequences, particularly at the thrombin cleavage site and the Hir domain. Protein-protein docking analysis further reveals that porcine PAR-1 forms less stable interactions with human thrombin compared to human PAR-1, resulting in reduced activation. This molecular incompatibility likely contributes to impaired nitric oxide (NO) production, endothelial dysfunction, and increased inflammation, which are critical for the survival of transplanted organs. Additionally, experiments using the PAR-1 inhibitor vorapaxar (Vor) show that inhibiting PAR-1 signaling can suppress inflammatory cytokine and chemokine expression in co-cultures of human macrophages and porcine endothelial cells. These findings suggest that selective PAR-1 inhibitors or targeted therapies regulating thrombin-PAR-1 signaling may improve the success rate of xenotransplantation. However, further in vivo studies are needed to validate these findings and explore therapeutic interventions targeting thrombin-PAR-1 interactions to enhance xenograft survival.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 2","pages":"e70041"},"PeriodicalIF":4.1,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035049","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":"International Xenotransplantation Association (IXA) Position Paper on Infectious Disease Considerations in Xenotransplantation.","authors":"Jay A Fishman, Joachim Denner, Linda Scobie","doi":"10.1111/xen.70001","DOIUrl":"10.1111/xen.70001","url":null,"abstract":"<p><p>Clinical xenotransplantation has the potential to address shortages of human organs for patients with end-stage organ failure. Advances in genetic engineering, immunosuppressive regimens, and infectious disease diagnostics have improved prospects for clinical xenotransplantation. Management of the infectious risks posed by clinical xenotransplantation requires biosecure breeding and validated methods for microbiological surveillance of source animals and recipients. Novel infection control protocols may complement biosafety requirements. Infectious risks in xenotransplantation include both known human pathogens common to immunosuppressed organ recipients and from porcine organisms or xenozoonoses for which the clinical manifestations are less well defined and for which microbial assays and therapies are more limited. Some pig-specific organisms do not infect human cells but have systemic manifestations when active within the xenograft. The human risk posed by porcine endogenous retroviruses (PERV) is uncertain. There are no documented transmissions of PERV in humans and swine are available with inactivated genomic PERV loci. Metagenomic sequencing will complement more traditional diagnostic tools in the detection of any unknown pathogens in xenotransplantation recipients. Such data are required for the development of protocols for donor and recipient microbiological surveillance, infection control, and antimicrobial therapies that will enhance the safety of clinical xenotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 2","pages":"e70001"},"PeriodicalIF":3.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804239","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":"Desensitization With Proteasome Inhibition and Costimulation Blockade Modulates the Xenoreactive Humoral Response in Nonhuman Primate Xenotransplantation.","authors":"Brendan P Lovasik, Abraham J Matar, Jakob Habib, David A Faber, Cynthia P Breeden, Alton B Farris, A Joseph Tector, Andrew B Adams","doi":"10.1111/xen.70045","DOIUrl":"https://doi.org/10.1111/xen.70045","url":null,"abstract":"<p><strong>Introduction: </strong>\"Delayed\" antibody-mediated xenograft rejection is one of the most important obstacles to clinical application of pig organ xenografts. The aim of this study was to assess the impact of a structured desensitization regimen including proteasome inhibition and next-generation costimulation blockade on xenoreactive antibodies.</p><p><strong>Methods: </strong>Rhesus macaques with moderate-high pre-treatment xenoreactive antibody titers (N = 2) were selected. Recipients received twice-weekly carfilzomib (20 mg/m²), anti-CD154 (20 mg/kg) every other week, and CD4 and CD20 lymphocyte cell depletion. Bone marrow was acquired to assess plasma cell depletion in response to proteasome inhibition. A flow cytometry-based xenoreactive crossmatch assay was performed to assess levels of circulating xenoreactive antibodies.</p><p><strong>Results: </strong>The desensitization regimen resulted in a >50% depletion of CD38+CD27+ bone marrow plasma cells; these changes were progressive over the duration of the desensitization treatment period. The desensitization strategy and plasma cell depletion resulted in a progressive reduction in anti-pig IgG antibodies. Following xenotransplantation, both desensitized recipients demonstrated superior graft survival to a highly xenoreactive recipient (MST 30 days vs. 6 days), but neither desensitized recipient experienced prolonged graft survival.</p><p><strong>Conclusions: </strong>A structured desensitization regimen including proteasome inhibition and costimulation blockade results in plasma cell depletion and resultant reduction in circulating xenoreactive anti-pig IgG antibodies, with a modest improvement in xenograft survival. This desensitization regimen has promise for pig-to-NHP xenotransplant models.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 2","pages":"e70045"},"PeriodicalIF":3.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12012413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988988","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":"International Xenotransplantation Association (IXA) Position Paper on the History, Current Status, and Regulation of Xenotransplantation.","authors":"Wayne J Hawthorne, Richard N Pierson, Leo Buhler, Peter J Cowan, Jay Fishman, Rita Bottino, Raphael P H Meier, Paolo Brenner, Eckhard Wolf, Emanuele Cozzi, Muhammad M Mohiuddin","doi":"10.1111/xen.70002","DOIUrl":"10.1111/xen.70002","url":null,"abstract":"<p><p>Recent landmark clinical translation of xenotransplantation depended upon multiple innovations by the xenotransplant community, including the introduction of a variety of source pig genetic modifications, technical innovations, and novel immunosuppressive strategies, as well as the development of ethical and regulatory frameworks to support translation to the clinic. Each organ, tissue, or cell type intended for xenotransplantation will require application-specific preclinical milestones to be met in order to predict \"success\", as measured by ethical, safe, and efficacious translation to the clinic. Based on successful pre-clinical results and emerging evidence from decedent studies and initial clinical cases, evidence-based infectious disease, ethical, and regulatory considerations are emerging, and will be the foundations for the application-specific position papers that are currently under development. Here, we describe significant landmark events focusing upon safe and efficacious results underpinned by appropriate guidance documents developed over the past three decades that enabled recent translation to the clinic for heart and kidney xenografts. These steps have been undertaken over the past three decades by the xenotransplant community specifically led by the International Xenotransplantation Association (IXA) in consultation with the Transplantation Society (TTS) and the World Health Organization (WHO) to usher xenotransplantation to the clinic.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 2","pages":"e70002"},"PeriodicalIF":3.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11977855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812482","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":"How to Detect Porcine Endogenous Retrovirus (PERV) Infections in Patients After Transplantation of Pig Organs.","authors":"Joachim Denner, Hina Jhelum, Jinzhao Ban, Ludwig Krabben, Benedikt B Kaufer","doi":"10.1111/xen.70028","DOIUrl":"10.1111/xen.70028","url":null,"abstract":"<p><p>Porcine endogenous retroviruses (PERVs) are integrated into the genome of all pigs and can infect human cells in culture. However, no PERV infections have been reported in recipients following preclinical or clinical xenotransplantation or deliberate infection experiments. Detection of PERV infection in transplanted recipients is challenging due to microchimerism, such as the presence of pig cells containing PERV proviruses in the recipient. Based on our previous publications on PERV detection in xenotransplant recipients, particularly from the first clinical trials, we developed a comprehensive strategy to screen for PERV infections. Recipients can be monitored for increasing levels of viral genomic RNA and mRNA using real-time reverse transcriptase (RT)-PCR, which can indicate PERV expression and replication. To test this strategy, explanted pig hearts and organs from baboons after pig heart transplantation were analyzed. No PERV genomic RNA or mRNA was detected in these tissues, although both were found in PERV-producing human control cells. Screening for antibodies against PERV as indirect evidence of infection is the method of choice. Recombinant viral proteins were prepared for use in Western blot assays. Animal antisera generated through immunization with recombinant PERV proteins served as positive controls. No antibodies against PERV were detected in transplanted baboons, even though microchimerism was observed in many of the animals' organs. For effective antibody screening, at least two PERV proteins should be used as antigens.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"32 1","pages":"e70028"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493936","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":"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}