Xenotransplantation最新文献

{"title":"Novel factors potentially initiating acute antibody‐mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen","authors":"Kohei Kinoshita, Akihiro Maenaka, Ivy A. Rosales, Ahmad Karadagi, Toshihide Tomosugi, David Ayares, Seth Lederman, Robert B. Colvin, Tatsuo Kawai, Richard N. Pierson, Takaaki Kobayashi, David K. C. Cooper","doi":"10.1111/xen.12859","DOIUrl":"https://doi.org/10.1111/xen.12859","url":null,"abstract":"Antibody‐mediated rejection (AMR) is a common cause of graft failure after pig‐to‐nonhuman primate organ transplantation, even when the graft is from a pig with multiple genetic modifications. The specific factors that initiate AMR are often uncertain. We report two cases of pig kidney transplantation into immunosuppressed baboons in which we identify novel factors associated with the initiation of AMR. In the first, membranous nephropathy was the initiating factor that was then associated with the apparent loss of the therapeutic anti‐CD154 monoclonal antibody in the urine when severe proteinuria was present. This observation suggests that proteinuria may be associated with the loss of any therapeutic monoclonal antibody, for example, anti‐CD154 or eculizumab, in the urine, resulting in xenograft rejection. In the second case, the sequence of events and histopathology tentatively suggested that pyelonephritis may have initiated acute‐onset AMR. The association of a urinary infection with graft rejection has been well‐documented in ABO‐incompatible kidney allotransplantation based on the expression of an antigen on the invading microorganism shared with the kidney graft, generating an immune response to the graft. To our knowledge, these potential initiating factors of AMR in pig xenografts have not been highlighted previously.","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140803509","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":"Call for applications for the Dr. med. vet. Dr. med. Ernst von Wnuck Award 2024 for Cardiovascular Research","authors":"Eckhard Wolf","doi":"10.1111/xen.12856","DOIUrl":"https://doi.org/10.1111/xen.12856","url":null,"abstract":"<p>The call for applications for the Dr. med. vet. Dr. med. Ernst von Wnuck Award, endowed with 3000 EUR, is aimed at heads of research groups and young scientists working in the field of xenogeneic heart transplantation. The spectrum of relevant work includes basic research, development of suitable donor pigs, preclinical transplantation models, and innovative approaches to clinical translation. Applicants should have relevant, outstanding research and demonstrate a scientific focus in their career. Please send your application documents of maximum two pages on the current status of your scientific work, planned own projects in the field as well as five representative publications together with your CV by May 31, 2024 to Prof. Dr. Eckhard Wolf, Gene Center, LMU Munich, Germany (ewolf@genzentrum.lmu.de).</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561950","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 clinical trials: Should patients with diminished capacity be permitted to enroll?","authors":"Daniel Rodger, James Mack, Christopher Bobier, Luz Padilla, Daniel J. Hurst","doi":"10.1111/xen.12857","DOIUrl":"https://doi.org/10.1111/xen.12857","url":null,"abstract":"<h2>1 INTRODUCTION</h2>\u0000<p>Before xenotransplantation clinical trials begin, it is essential to establish clear and equitable participant selection criteria. Selection criteria have been suggested in the literature, as well as in a proposed kidney xenotransplantation phase 1 clinical trial.<span>^1-4</span> In each, inclusion criteria is predicated on patients possessing clinical decision-making capacity. Ensuring informed consent for xenotransplantation clinical trials with patients who have decision-making capacity is recognized as complex for the following reasons: the possibility of therapeutic misconception, potential for xenozoonosis, and the potentially burdensome requirement for lifelong biosurveillance.<span>^{5, 6}</span> Informed consent for enrollment in a xenotransplantation trial with adult persons who have diminished capacity would involve additional complexities. By diminished capacity, we mean to describe someone who—for various medical reasons—does not have the ability to provide informed consent. To our knowledge, no xenotransplantation investigator, nor the proposed kidney xenotransplantation phase I clinical trial in the United States, currently proposes including persons with diminished capacity. Nonetheless, the topic has been broached, and we believe it requires additional independent scrutiny.</p>\u0000<h3>1.1 Current recommendations for including persons with diminished capacity</h3>\u0000<p>Xenotransplantation clinical trials with persons who lack decision-making capacity have not been considered at length and would likely be controversial. The Nuffield Council on Bioethics recommended that “the first xenotransplantation trials should not involve adults incapable of consenting to participation on their own behalf” (7.25).<span>⁷</span> It made an exception, however: “The Medical Research Council has recommended that the participation of incapacitated adults in therapeutic research may be justified if, in addition to evidence that the procedure will benefit the individual, it relates to their incapacitating condition and the relevant knowledge could not be gained by research in adults able to consent” (7.26).<span>⁷</span> Similarly, the United States Department of Health and Human Services (DHHS) stated: “enrollment of mentally impaired individuals into xenotransplantation protocols should be limited to those in whom mental capacity is likely to be restored by the procedure.”<span>⁸</span> Additionally, in the DHHS guidelines, a surrogate must confirm that the clinical trial aligns with the person's preferences or would promote their best interests and that they are “likely to adhere to lifelong follow-up requirements.”<span>⁸</span></p>\u0000<p>In 2012, the American Medical Association (AMA) Council on Ethical and Judicial Affairs posited that it “would be ethical to include children and incompetent adults in xenotransplantation research protocols only when the patients ar","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561955","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":"Human ST3Gal II and ST6GalNAc IV genes increase human serum‐mediated cytotoxicity to xenogeneic cells","authors":"Hyunju Choi, Kwon‐Ho Song, Hee‐Do Kim, Jun‐Young Park, Young‐Choon Lee, Hee‐Jung Choi, Cheorl‐Ho Kim","doi":"10.1111/xen.12855","DOIUrl":"https://doi.org/10.1111/xen.12855","url":null,"abstract":"Carbohydrate‐antigens widely existed on glycoproteins and glycosphingolipids of all mammalian cells play a crucial role in self‐defense and immunity. Xeno‐reactive antibodies included in natural human sera play a protecting role in an acute phase‐rejection of xenotransplantation. In this study, we investigated the effect of an alteration of glycosylation‐pattern, caused by human sialyltransferases such as hST3Gal II or hST6GalNAc IV, on human serum mediated cytotoxicity in pig kidney PK15 cells. From LDH cytotoxicity assay, cytotoxicity to human serum was significantly increased in hST3Gal II and hST6GalNAc IV‐transfected PK15 cells, as compared to the control. In the hST6Gal I‐carrying cells, the cytotoxicity to human serum was rather decreased. Moreover, flow cytometry analysis revealed that an alteration of pig glycosylation‐pattern by hST3Gal II or hST6GalNAc IV influences on a binding of human IgM or IgG, respectively, in pig kidney cells, regardless of Gal antigen alteration. Finally, we found that hST6GalNAc IV contributed to increase of terminal disialylated tetrasaccharide structure, disialyl T antigen, as evidenced by increase of the MAL II lectin binding capacity in the hST6GalNAc IV‐transfected PK15 cells, compared with control. Therefore, our results suggest that carbohydrate antigens, such as disialyl T antigen, newly synthesized by the ST3Gal II‐ and ST6GalNAc IV are potentially believed to be new xeno‐reactive elements.","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140561963","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":"Emergence of novel circoviruses in humans and pigs and their possible importance for xenotransplantation and blood transfusions.","authors":"Tanja Opriessnig, Chao-Ting Xiao, Nicolas J Mueller, Joachim Denner","doi":"10.1111/xen.12842","DOIUrl":"10.1111/xen.12842","url":null,"abstract":"<p><strong>Background: </strong>As sequencing is becoming more broadly available, virus discovery continues. Small DNA viruses contribute to up to 60% of the overall virus load in pigs. Porcine circoviruses (PCVs) are small DNA viruses with a single-stranded circular genome. They are common in pig breeds and have not been properly addressed for their potential risk in xenotransplantation. Whereas PCV1 is non-pathogenic in pigs, PCV2 has been associated with various disease manifestations. Recently two new circoviruses have been described, PCV3 and PCV4. While PCV4 is currently present mainly in Asia, PCV3 is widely distributed, and has been identified in commercial pigs, wild boars, and pigs generated for xenotransplantation. In one case PCV3 was transmitted by pigs to baboons via heart transplantation. PCV3 pathogenicity in pigs was controversial initially, however, the virus was found to be associated with porcine dermatitis and nephropathy syndrome (PDNS), reproductive failure, and multisystemic inflammation. Inoculation studies with PCV3 infectious clones confirmed that PCV3 is pathogenic. Most importantly, recently discovered human circoviruses (CV) are closely related to PCV3.</p><p><strong>Methods: </strong>Literature was evaluated and summarized. A dendrogram of existing circoviruses in pigs, humans, and other animal species was created and assessed at the species level.</p><p><strong>Results: </strong>We found that human circoviruses can be divided into three species, human CV1, CV2, and CV3. Human CV2 and CV3 are closest to PCV3.</p><p><strong>Conclusions: </strong>Circoviruses are ubiquitous. This communication should create awareness of PCV3 and the newly discovered human circoviruses, which may be a problem for blood transfusions and xenotransplantation in immune suppressed individuals.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159146","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":"Incidence of serum antibodies to xenoantigens on triple-knockout pig cells in different human groups.","authors":"Songzhe He, Tao Li, Hao Feng, Jiaxiang Du, David K C Cooper, Hidetaka Hara, Hongtao Jiang, Dengke Pan, Gang Chen, Yi Wang","doi":"10.1111/xen.12818","DOIUrl":"10.1111/xen.12818","url":null,"abstract":"<p><strong>Background: </strong>Xenoantigens other than Gal, Neu5Gc, and Sda may be playing a role in pig graft rejection. We investigated the incidence of antibodies to unknown pig xenoantigen in different human groups.</p><p><strong>Methods: </strong>We collected blood from TKO/hCD55 pigs (n = 3), and isolated PBMCs and RBCs. Serum samples were collected from (i) healthy human volunteers (n = 43), (ii) patients with end-stage renal disease (ESRD) (n = 87), (iii) the same patients after kidney allotransplantation (n = 50), and (iv) renal allotransplant recipients experiencing T cell-mediated rejection (allo-TCMR, n = 10). The sera were initially incubated with TKO/hCD55 pRBCs (1 × 10⁸ cells) for 1 h to absorb anti-pig antibodies (except against SLA and possibly other antigens not expressed on pRBCs) and then the serum (absorbed or unabsorbed) was tested for antibody binding and complement-dependent cytotoxicity (CDC) to TKO/hCD55 pig PBMCs.</p><p><strong>Results: </strong>A significant reduction in IgM/IgG binding and CDC was observed in the absorbed sera. Serum obtained before and after renal allotransplantation showed no significant difference in IgM or IgG binding to, or in CDC of, TKO/hCD55 pig cells. IgM antibodies (but rarely IgG) against unknown xenoantigens expressed on TKO/hCD55 PBMCs, possibly against swine leukocyte antigens, were documented in healthy humans, patients with ESRD, and those with renal allografts undergoing acute T cell rejection. IgM (but not CDC) was higher in patients experiencing allo-TCMR.</p><p><strong>Conclusion: </strong>Human sera contain IgM antibodies against unknown pig xenoantigens expressed on TKO/hCD55 pPBMCs. Although not confirmed in the present study, the targets for these antibodies may include swine leukocyte antigens.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9922992","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":"Barriers toward xenotransplantation in Arab World.","authors":"Maya Ghazi, Aalaa Saleh, Malak Abdallah, Diala El Masri, Jad El Masri, Lemir Majed El Ayoubi, Jihad Hawi, Abdo Jurjus","doi":"10.1111/xen.12852","DOIUrl":"10.1111/xen.12852","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140207662","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":"A murine groin site cardiac transplantation model-applicable tool for studying roles of peripheral lymph nodes in transplantation.","authors":"Yaguang Li, Wenjia Yuan, Mingda Zhong, Julia Qi, Xinguo Zheng, Xubiao Xie, Tengfang Li, Hedong Zhang, Xin Jiang, Longkai Peng, Helong Dai","doi":"10.1111/xen.12817","DOIUrl":"10.1111/xen.12817","url":null,"abstract":"<p><p>The murine heterotopic cardiac transplantation model has been widely used to study antigen-specific immune responses or new immunosuppressive agents, which have a strong correlation with peripheral lymph nodes. Thus, a new organ transplantation model that is applicable to related studies is needed. Here, we describe a groin-site murine heart transplantation model using a cuff technique, in which the donor aorta and pulmonary artery are anastomosed to the truncated femoral vessels of the recipient. The mean survival time (MST) of the grafts in BALB/c-to-C57BL/6 allo-transplant group was 7.2 ± 0.3 days, and 1.9 ± 0.2 days in BALB/c-to-Sprague-Dawley (SD) rat xeno-transplant group. H&E results show that donor hearts from both groups demonstrate typical pathological features at the endpoint. Evans Blue tracing revealed that the popliteal lymph nodes of the grafted side hindlimb are larger than those of the contralateral side. Moreover, IHC staining for CD3, CD20 shows that the germinal center and cortex region of the grafted side of popliteal lymph nodes is apparently increased than that of the contralateral side. To sum up, this model may serve as an ideal model to study the role of peripheral lymph nodes in organ transplant rejection. In addition, extra-peritoneal grafting makes a step forward in animal welfare under the 3Rs' principle (Replacement, Reduction, Refinement).</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10319342","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":"Long-term control of diabetes by tofacitinib-based immunosuppressive regimen after allo islet transplantation in diabetic rhesus monkeys that rejected previously transplanted porcine islets.","authors":"Jong-Min Kim, Seong-Jun Kang, So-Hee Hong, Hyunwoo Chung, Jun-Seop Shin, Byoung-Hoon Min, Hyun Je Kim, Jongwon Ha, Chung-Gyu Park","doi":"10.1111/xen.12850","DOIUrl":"10.1111/xen.12850","url":null,"abstract":"<p><p>Porcine islet xenotransplantation has been highlighted as an alternative to allo islet transplantation. Despite the remarkable progress that has been made in porcine-islet pre-clinical studies in nonhuman primates, immunological tolerance to porcine islets has not been achieved to date. Therefore, allo islet transplantation could be required after the failure of porcine islet xenotransplantation. Here, we report the long-term control of diabetes by allogeneic pancreatic islet transplantation in diabetic rhesus monkeys that rejected previously transplanted porcine islets. Four diabetic male rhesus monkeys received the porcine islets and then allo islets (5700-19 000 IEQ/kg) were re-transplanted for a short or long period after the first xeno islet rejection. The recipient monkeys were treated with an immunosuppressive regimen consisting of ATG, humira, and anakinra for induction, and sirolimus and tofacitinib for maintenance therapy. The graft survival days of allo islets in these monkeys were >440, 395, >273, and 127, respectively, similar to that in allo islet transplanted cynomolgus monkeys that received the same immunosuppressive regimen without xeno sensitization. Taken together, it is likely that prior islet xenotransplantation does not affect the survival of subsequent allo islets under clinically applicable immunosuppressants.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159084","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":"Close contacts of xenograft recipients: Ethical considerations due to risk of xenozoonosis.","authors":"Daniel J Hurst, Luz Padilla, Daniel Rodger, Tamar Schiff, David K C Cooper","doi":"10.1111/xen.12847","DOIUrl":"10.1111/xen.12847","url":null,"abstract":"<p><p>With decades of pre-clinical studies culminating in the recent clinical application of xenotransplantation, it would appear timely to provide recommendations for operationalizing oversight of xenotransplantation clinical trials. Ethical issues with clinical xenotransplantation have been described for decades, largely centering on animal welfare, the risks posed to the recipient, and public health risks posed by potential spread of xenozoonosis. Much less attention has been given to considerations relating to potentially elevated risks faced by those who may care for or otherwise have close contact with xenograft recipients. This paper examines the ethical and logistical issues raised by the potential exposure to xenozoonotic disease faced by close contacts of xenotransplant recipients-defined herein as including but not limited to caregivers, household contacts, and sexual partners-which warrants special attention given their increased risk of exposure to infection compared to the general public. We discuss implications of assent or consent by these close contacts to potentially undergo, along with the recipient, procedures for infection screening and possible quarantine. We then propose several options and recommendations for operationalizing oversight of xenotransplantation clinical trials that could account for and address close contacts' education on and agency regarding the risk of xenozoonosis.</p>","PeriodicalId":23866,"journal":{"name":"Xenotransplantation","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140102524","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}