Xenotransplantation最新文献

{"title":"Patient informed consent for a clinical trial of gene-edited pig kidney transplantation: A representative consent form.","authors":"David K C Cooper","doi":"10.1111/xen.12790","DOIUrl":"https://doi.org/10.1111/xen.12790","url":null,"abstract":"<p><p>When clinical trials of gene-edited pig organ transplantation are initiated, the consent form that the patient is requested to sign will be an important document. Consent to receive a pig xenograft will have significant differences when compared with the requirements of most experimental clinical procedures. We here suggest a consent form for pig kidney transplantation that addresses the major points that will be required and hope it will provide a basis for discussion and future modification, if necessary. There is purposely some repetition in the document, but we believe this is necessary to ensure that the patient has a clear understanding of what he/she is consenting to.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"30 1","pages":"e12790"},"PeriodicalIF":3.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9786717","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":"In vivo induction of regulatory T cells by anti-CD45RB antibody causes transferable tolerance to discordant human xenogenic islets.","authors":"Yanling Zhang,&nbsp;Maozhu Yang,&nbsp;Guiqing Jia,&nbsp;Shaoping Deng,&nbsp;Ji Lei,&nbsp;James Markmann,&nbsp;Gaoping Zhao","doi":"10.1111/xen.12778","DOIUrl":"https://doi.org/10.1111/xen.12778","url":null,"abstract":"<p><strong>Background: </strong>The treatment of diabetes by islet cell transplantation has become an accepted therapy, with transplantation of xenogeneic islet cells an attractive alternative to the problem. Previous studies in mice have demonstrated that anti-CD45RB induce immune tolerance in human pancreatic islet cells. The current study was to define the mechanism of action of anti-CD45RB induced nonspecific immune tolerance to heteroantigens.</p><p><strong>Methods: </strong>A total of 1500 IEQ human islets were transplanted to diabetic B6μMT-/- mice, B6 mice, and μMT-/- diabetic mice undergoing thymectomy. These mice were treated short-term with doses of anti-CD45RB. CD4+Foxp3+Tregs were detected in the blood, peripheral lymphatic organs by flow cytometry, and immunohistochemistry. In addition, anti-CD25 mAb was administered to tolerant human islet cells B6μMT-/-mice. Mice then were transplanted with other human islet cells and received CD4+CD25+Tregs isolated from tolerant human islets mice to observe islet destruction.</p><p><strong>Results: </strong>Anti-CD45RB treatment-induced tolerance to islets in both immunocompetent and B-cell-deficient mice (μMT-/- mice) by processes that were dependent on CD25+ Tregs, but not B cells. Anti-CD45RB treatment increased the number of CD4+Foxp3+Tregs cells. Anti-CD45RB treatment-induced immune tolerance that was antigen nonspecific, with Tregs playing an important role. Anti-CD45RB treatment-induced tolerance generated Tregs that could be transferred to another individual to manifest nonspecific immune tolerance.</p><p><strong>Conclusion: </strong>The results of the experiment suggest that anti-CD45RB induced tolerance to human islet xenografts is mediated by the proliferation of Tregs. These tolerogenic Tregs can be transferred to other mice and induce nonspecific immune tolerance.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"29 6","pages":"e12778"},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9073210","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":"Issue Information","authors":"","doi":"10.1111/xen.12699","DOIUrl":"https://doi.org/10.1111/xen.12699","url":null,"abstract":"","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43523332","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":"Genetic modifications designed for xenotransplantation attenuate sialoadhesin-dependent binding of human erythrocytes to porcine macrophages.","authors":"Kaitlyn Petitpas,&nbsp;Zahra Habibabady,&nbsp;Veronica Ritchie,&nbsp;Margaret R Connolly,&nbsp;Lars Burdorf,&nbsp;Wenning Qin,&nbsp;Yinan Kan,&nbsp;Jacob V Layer,&nbsp;Juliet N Crabtree,&nbsp;Michele E Youd,&nbsp;William F Westlin,&nbsp;Diogo M Magnani,&nbsp;Richard N Pierson,&nbsp;Agnes M Azimzadeh","doi":"10.1111/xen.12780","DOIUrl":"10.1111/xen.12780","url":null,"abstract":"<p><p>The phenomenon of diminishing hematocrit after in vivo liver and lung xenotransplantation and during ex vivo liver xenoperfusion has largely been attributed to action by resident liver porcine macrophages, which bind and destroy human erythrocytes. Porcine sialoadhesin (siglec-1) was implicated previously in this interaction. This study examines the effect of porcine genetic modifications, including knockout of the CMAH gene responsible for expression of Neu5Gc sialic acid, on the adhesion of human red blood cells (RBCs) to porcine macrophages. Wild-type (WT) porcine macrophages and macrophages from several strains of genetically engineered pigs, including CMAH gene knockout and several human transgenes (TKO+hTg), were incubated with human RBCs and \"rosettes\" (≥3 erythrocytes bound to one macrophage) were quantified by microscopy. Our results show that TKO+hTg genetic modifications significantly reduced rosette formation. The monoclonal antibody 1F1, which blocks porcine sialoadhesin, significantly reduced rosette formation by WT and TKO+hTg macrophages compared with an isotype control antibody. Further, desialation of human RBCs with neuraminidase before addition to WT or TKO+hTg macrophages resulted in near-complete abrogation of rosette formation, to a level not significantly different from porcine RBC rosette formation on porcine macrophages. These observations are consistent with rosette formation being mediated by binding of sialic acid on human RBCs to sialoadhesin on porcine macrophages. In conclusion, the data predict that TKO+hTg genetic modifications, coupled with targeting of porcine sialoadhesin by the 1F1 mAb, will attenuate erythrocyte sequestration and anemia during ex vivo xenoperfusion and following in vivo liver, lung, and potentially other organ xenotransplantation.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"29 6","pages":"e12780"},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10152518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9399392","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":"Knock-out of N-glycolylneuraminic acid attenuates antibody-mediated rejection in xenogenically perfused porcine lungs.","authors":"Ryan Chaban, Zahra Habibabady, Wessam Hassanein, Margaret R Connolly, Lars Burdorf, Emily Redding, Christopher Laird, Jolene Ranek, Gheorghe Braileanu, Selin Sendil, Xiangfei Cheng, Wenji Sun, Natalie A O'Neill, Kasinath Kuravi, Sunghoon Hurh, David L Ayares, Agnes M Azimzadeh, Richard N Pierson","doi":"10.1111/xen.12784","DOIUrl":"10.1111/xen.12784","url":null,"abstract":"<p><strong>Background: </strong>Antibody-mediated rejection has long been known to be one of the major organ failure mechanisms in xenotransplantation. In addition to the porcine α1,3-galactose (α1,3Gal) epitope, N-Glycolylneuraminic acid (Neu5Gc), a sialic acid, has been identified as an important porcine antigen against which most humans have pre-formed antibodies. Here we evaluate GalTKO.hCD46 lungs with an additional cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) gene knock-out (Neu5GcKO) in a xenogeneic ex vivo perfusion model METHODS: Eleven GalTKO.hCD46.Neu5GcKO pig lungs were perfused for up to 6 h with fresh heparinized human blood. Six of them were treated with histamine (H) blocker famotidine and 1-thromboxane synthase inhibitor Benzylimidazole (BIA) and five were left untreated. GalTKO.hCD46 lungs without Neu5GcKO (n = 18: eight untreated and 10 BIA+H treated) served as a reference. Functional parameters, blood, and tissue samples were collected at pre-defined time points throughout the perfusion RESULTS: All but one Neu5GcKO organs maintained adequate blood oxygenation and \"survived\" until elective termination at 6 h whereas two reference lungs failed before elective termination at 4 h. Human anti-Neu5Gc antibody serum levels decreased during the perfusion of GalTKO.hCD46 lungs by flow cytometry (∼40% IgM, 60% IgG), whereas antibody levels in Neu5GcKO lung perfusions did not fall (IgM p = .007; IgG p < .001). Thromboxane elaboration, thrombin generation, and histamine levels were significantly reduced with Neu5GcKO lungs compared to reference in the untreated groups (p = .007, .005, and .037, respectively); treatment with BIA+H masked these changes. Activation of platelets, measured as CD62P expression on circulating platelets, was lower in Neu5GcKO experiments compared to reference lungs (p = .023), whereas complement activation (as C3a rise in plasma) was not altered. MCP-1 and lactotransferin level elevations were blunted in Neu5GcKO lung perfusions (p = .007 and .032, respectively). Pulmonary vascular resistance (PVR) rise was significantly attenuated and delayed in untreated GalTKO.hCD46.Neu5GcKO lungs in comparison to the untreated GalTKO.hCD46 lungs (p = .003) CONCLUSION: Additional Neu5GcKO in GalTKO.hCD46 lungs significantly reduces parameters associated with antibody-mediated inflammation and activation of the coagulation cascade. Knock-out of the Neu5Gc sialic acid should be beneficial to reduce innate immune antigenicity of porcine lungs in future human recipients.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"29 6","pages":"e12784"},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11093624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10516938","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":"What is the clinical relevance of deviant serum calcium and phosphate levels after pig-to-primate kidney xenotransplantation?","authors":"Aaron C K Lucander,&nbsp;Eric Judd,&nbsp;David K C Cooper","doi":"10.1111/xen.12785","DOIUrl":"10.1111/xen.12785","url":null,"abstract":"<p><p>Experience from human renal allotransplantation informs us that disturbances in serum calcium and phosphate levels are relatively common. Post-transplant hypercalcemia is associated with an increased risk of recipient mortality, but not of graft loss or nephropathy, and post-transplant hyperphosphatemia with an increased risk of both recipient mortality and death-censored graft failure, but neither post-transplant hypocalcemia nor hypophosphatemia is associated with adverse outcome. Studies after pig-to-nonhuman primate kidney xenotransplantation have demonstrated consistent supranormal serum calcium and subnormal serum phosphate levels. If these trends in serum electrolyte levels were to occur following pig-to-human kidney xenotransplantation, the data from allotransplant studies would indicate an increased risk of recipient mortality (associated with hypercalcemia) but not of graft loss or nephropathy, and no adverse outcome from hypophosphatemia. Furthermore, some nonhuman primates are now surviving in a healthy state for longer than a year after life-supporting pig kidney transplantation, suggesting that chronic hypercalcemia and/or hypophosphatemia are not detrimental to long-term survival, and should not prevent clinical trials of pig kidney transplantation from being undertaken.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"29 6","pages":"e12785"},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10154070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9749312","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":"A compositional analysis of native and decellularized porcine nasal septum cartilage.","authors":"Katharina Tluczynski,&nbsp;Roman Breiter","doi":"10.1111/xen.12781","DOIUrl":"https://doi.org/10.1111/xen.12781","url":null,"abstract":"<p><strong>Objectives: </strong>Decellularization of porcine septum cartilage is necessary for its application as xenogenic replacement material. The aim of this study was to investigate spatial differences of structure and composition in the whole native and decellularized porcine nasal septum. Subsequently, the results shall be compared with studies of human nasal septum.</p><p><strong>Methods: </strong>Ten porcine nasal septa were divided into six regions from caudal to cephalic and four regions from dorsal to ventral to create a grid of 24 approximately equal segments. All segments of five septal cartilages were decellularized separately by a wet chemical multistep procedure. The segments were analyzed to determine quantitative amounts of total collagen, chondrocytes, and sulfated glycosaminoglycans (sGAG).</p><p><strong>Results: </strong>The distribution of cell number showed no significant differences between the individual regions. For the distribution of collagen and sGAG, no significant differences could be identified from caudal to cephalic, both in native and decellularized tissue. From dorsal to ventral, native and decellularized nasal septum showed significant differences between individual regions. In native septum, linear regression analysis indicated a decreasing collagen and an increasing sGAG content from dorsal to ventral. After decellularization, an increasing collagen and a decreasing sGAG content was detected.</p><p><strong>Conclusion: </strong>The results of this study showed slightly but significant differences in the distribution of collagen and sGAG from dorsal to ventral. From caudal to cephalic, no differences could be observed. Compared to human, nasal septum differences in cell, collagen, and sGAG content were detected. Despite this, human and porcine nasal septum showed similar distributions and a consistently inverse linearity of collagen and sGAG content. Nevertheless, the midcaudal and midcephalic regions showed the highest porosity and a high stability and thus offer the best conditions for the revitalization of porcine tissue by human cells.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"29 6","pages":"e12781"},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9089235","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":"Recellularized bovine pericardium with autologous mesenchymal stem cells reduces immune activation.","authors":"Sabin J Bozso,&nbsp;Jimmy J H Kang,&nbsp;Ryaan El-Andari,&nbsp;Dana Boe,&nbsp;Hannah Hedtke,&nbsp;Michael C Moon,&nbsp;Darren H Freed,&nbsp;Jayan Nagendran,&nbsp;Jeevan Nagendran","doi":"10.1111/xen.12774","DOIUrl":"https://doi.org/10.1111/xen.12774","url":null,"abstract":"<p><strong>Introduction: </strong>Current bioprosthetic heart valve replacement options are limited by structural valvular deterioration (SVD) due to an immune response to the xenogenic scaffold. Autologous mesenchymal stem cell (MSC) recellularization is a method of concealing xenogenic scaffolds, preventing recipient immune recognition of xenogenic tissue heart valves, and potentially leading to reduction in SVD incidence. The purpose of this study is to examine the effects of autologous MSC recellularized tissue on the immune response of human whole blood to bovine pericardium (BP). We hypothesized that autologous MSC recellularization of BP will result in reduced pro-inflammatory cytokine production equivalent to autologous human pericardium.</p><p><strong>Methods: </strong>Bone marrow, human pericardium, and whole blood were collected from adult patients undergoing elective cardiac surgery. Decellularized BP underwent recellularization with autologous MSCs, followed by co-incubation with autologous whole blood. Immunohistochemical, microscopic, and quantitative immune analysis approaches were used.</p><p><strong>Results: </strong>We demonstrated that native BP, exposed to human whole blood, results in significant TNF-α and IL1β production. When decellularized BP is recellularized with autologous MSCs and exposed to whole blood, there is a significant reduction in TNF-α and IL1β production. Importantly, recellularized BP exposed to whole blood had similar production of TNF-α and IL1β when compared to autologous human pericardium exposed to human whole blood.</p><p><strong>Conclusion: </strong>Our results suggest that preventing initial immune activation with autologous MSC recellularization may be an effective approach to decrease the recipient immune response, preventing recipient immune recognition of xenogeneic tissue engineered heart valves, and potentially leading to reduction in SVD incidence.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"29 6","pages":"e12774"},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10523245","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":"Observations on hydronephrosis after pig kidney transplantation in baboons.","authors":"Jeremy B Foote,&nbsp;Mohamed H Bikhet,&nbsp;Christophe Hansen-Estruch,&nbsp;Mariyam Javed,&nbsp;David Ayares,&nbsp;Hidetaka Hara,&nbsp;Abhinav Humar,&nbsp;Devin E Eckhoff,&nbsp;David K C Cooper","doi":"10.1111/xen.12779","DOIUrl":"10.1111/xen.12779","url":null,"abstract":"<p><p>We have seen hydronephrosis (obstructive nephropathy) at necropsy in 3 of 11 (21%) genetically-engineered pig kidneys that functioned in baboons for >36 days, even when the clinical and histopathological features of rejection were minimal. We briefly report one such case and illustrate the macroscopic and microscopic appearances of such a kidney and ureter. The causes of the observed changes remain uncertain. In our small experience, there seems to be no correlation between the development of hydronephrosis and (i) the surgical technique, (ii) the genotype of the pig, (iii) the length of the pig ureter, or (iv) the immunosuppressive and anti-inflammatory therapy administered. We suggest that the distal ureteric thickening may be the result of an inflammatory response. In two cases, we resolved the problem by carrying out a secondary side-to-side anastomosis between the proximal pig ureter and the baboon bladder.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"29 6","pages":"e12779"},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9771893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9234127","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":"Early testing of porcine organ xenotransplantation products in humans: Microbial safety as illustrated for porcine cytomegalovirus.","authors":"Joachim Denner,&nbsp;Henk-Jan Schuurman","doi":"10.1111/xen.12783","DOIUrl":"https://doi.org/10.1111/xen.12783","url":null,"abstract":"Sincemid-2021, a number of exploratory studies have been conducted to test porcine solid organs in humans, representing a new step in moving xenotransplantation towards clinical application. These studies are summarized below and attracted wide interest in the media and scientific community, resulting in commentaries in scientific journals (referenced below). We focus in this commentary on safety, that is, the potential of transspecies transmission of infectious agents, in particular viruses.1 Transspecies transmission of endogenous retrovirus, that is, porcineendogenous retrovirus (PERV)hasbeen subject of much research during the last decades; this research resulted, amongst others, in studies using pig donors that are negative for the PERV-C subtype, or in generation of pigs in which PERV-A and PERV-B subtypes were genetically inactivated (on a PERV-C negative platform).2 Although PERV-C infects only pig cells but not human cells, its presence allows recombination between PERV-C and PERV-A, resulting in high titer PERV-A/C recombinants.3 However, such a recombination is a rare event in vivo.4 The item of PERV risk was not addressed in the exploratory studies, and will not be discussed in this manuscript. But, one exogenous virus, porcine cytomegalovirus (PCMV), popped up in","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":"29 6","pages":"e12783"},"PeriodicalIF":3.9,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10526248","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}