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Journal of Hepatology Aug 2023Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Ischemia-reperfusion injury (IRI) has thus far been considered as an inevitable component of organ transplantation, compromising outcomes, and limiting organ availability. Ischemia-free organ transplantation is a novel approach designed to avoid IRI, with the potential to improve outcomes.
METHODS
In this randomized-controlled clinical trial, recipients of livers from donors after brain death were randomly assigned to receive either an ischemia-free or a 'conventional' transplant. The primary endpoint was the incidence of early allograft dysfunction. Secondary endpoints included complications related to graft IRI.
RESULTS
Out of 68 randomized patients, 65 underwent transplants and were included in the analysis. 32 patients received ischemia-free liver transplantation (IFLT), and 33 received conventional liver transplantation (CLT). Early allograft dysfunction occurred in two recipients (6%) randomized to IFLT and in eight (24%) randomized to CLT (difference -18%; 95% CI -35% to -1%; p = 0.044). Post-reperfusion syndrome occurred in three recipients (9%) randomized to IFLT and in 21 (64%) randomized to CLT (difference -54%; 95% CI -74% to -35%; p <0.001). Non-anastomotic biliary strictures diagnosed with protocol magnetic resonance cholangiopancreatography at 12 months were observed in two recipients (8%) randomized to IFLT and in nine (36%) randomized to CLT (difference, -28%; 95% CI -50% to -7%; p = 0.014). The comprehensive complication index at 1 year after transplantation was 30.48 (95% CI 23.25-37.71) in the IFLT group vs. 42.14 (95% CI 35.01-49.26) in the CLT group (difference -11.66; 95% CI -21.81 to -1.51; p = 0.025).
CONCLUSIONS
Among patients with end-stage liver disease, IFLT significantly reduced complications related to IRI compared to a conventional approach.
CLINICAL TRIAL REGISTRATION
chictr.org. ChiCTR1900021158.
IMPACT AND IMPLICATIONS
Ischemia-reperfusion injury has thus far been considered as an inevitable event in organ transplantation, compromising outcomes and limiting organ availability. Ischemia-free liver transplantation is a novel approach of transplanting donor livers without interruption of blood supply. We showed that in patients with end-stage liver disease, ischemia-free liver transplantation, compared with a conventional approach, led to reduced complications related to ischemia-reperfusion injury in this randomized trial. This new approach is expected to change the current practice in organ transplantation, improving transplant outcomes, increasing organ utilization, while providing a clinical model to delineate the impact of organ injury on alloimmunity.
Topics: Humans; Liver Transplantation; End Stage Liver Disease; Ischemia; Liver; Reperfusion Injury; Perfusion; Organ Preservation
PubMed: 37086919
DOI: 10.1016/j.jhep.2023.04.010 -
In vivo development of immune tissue in human intestinal organoids transplanted into humanized mice.Nature Biotechnology Jun 2023Human intestinal organoids (HIOs) derived from pluripotent stem cells provide a valuable model for investigating human intestinal organogenesis and physiology, but they...
Human intestinal organoids (HIOs) derived from pluripotent stem cells provide a valuable model for investigating human intestinal organogenesis and physiology, but they lack the immune components required to fully recapitulate the complexity of human intestinal biology and diseases. To address this issue and to begin to decipher human intestinal-immune crosstalk during development, we generated HIOs containing immune cells by transplanting HIOs under the kidney capsule of mice with a humanized immune system. We found that human immune cells temporally migrate to the mucosa and form cellular aggregates that resemble human intestinal lymphoid follicles. Moreover, after microbial exposure, epithelial microfold cells are increased in number, leading to immune cell activation determined by the secretion of IgA antibodies in the HIO lumen. This in vivo HIO system with human immune cells provides a framework for future studies on infection- or allergen-driven intestinal diseases.
Topics: Humans; Animals; Mice; Intestines; Intestinal Mucosa; Organoids; Pluripotent Stem Cells; Transplants
PubMed: 36702898
DOI: 10.1038/s41587-022-01558-x -
EBioMedicine Jun 2023Peritoneal metastasis is a challenging aspect of clinical practice for gastric cancer. Animal models are crucial in understanding molecular mechanisms, assessing drug... (Review)
Review
Peritoneal metastasis is a challenging aspect of clinical practice for gastric cancer. Animal models are crucial in understanding molecular mechanisms, assessing drug efficacy, and conducting clinical intervention studies, including those related to gastric cancer peritoneal metastasis. Unlike other xenograft models, peritoneal metastasis models should not only present tumor growth at the transplant site, but also recapitulate tumor cell metastasis in the abdominal cavity. Developing a reliable model of gastric cancer peritoneal metastasis involves several technical aspects, such as the selection of model animals, source of xenograft tumors, technology of transplantation, and dynamic monitoring of the tumor progression. To date, challenges remain in developing a reliable model that can completely recapitulate peritoneal metastasis. Thus, this review aims to summarize the techniques and strategies used to establish animal models of gastric cancer peritoneal metastasis, providing a reference for future model establishment.
Topics: Animals; Humans; Peritoneal Neoplasms; Stomach Neoplasms; Peritoneum; Transplantation, Heterologous; Heterografts; Cell Line, Tumor
PubMed: 37182268
DOI: 10.1016/j.ebiom.2023.104601 -
Transplant International : Official... 2024
Topics: Humans; Liver Transplantation; Transplants; Perfusion; Organ Preservation; Graft Survival; Liver
PubMed: 38544563
DOI: 10.3389/ti.2024.12853 -
Annual Review of Animal Biosciences Feb 2024End-stage organ failure can result from various preexisting conditions and occurs in patients of all ages, and organ transplantation remains its only treatment. In... (Review)
Review
End-stage organ failure can result from various preexisting conditions and occurs in patients of all ages, and organ transplantation remains its only treatment. In recent years, extensive research has been done to explore the possibility of transplanting animal organs into humans, a process referred to as xenotransplantation. Due to their matching organ sizes and other anatomical and physiological similarities with humans, pigs are the preferred organ donor species. Organ rejection due to host immune response and possible interspecies infectious pathogen transmission have been the biggest hurdles to xenotransplantation's success. Use of genetically engineered pigs as tissue and organ donors for xenotransplantation has helped to address these hurdles. Although several preclinical trials have been conducted in nonhuman primates, some barriers still exist and demand further efforts. This review focuses on the recent advances and remaining challenges in organ and tissue xenotransplantation.
Topics: Animals; Humans; Swine; Transplantation, Heterologous; Organ Transplantation; Genetic Engineering; Transplants
PubMed: 37906838
DOI: 10.1146/annurev-animal-021122-102606 -
Nature Communications Jul 2023Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better...
Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the cell-to-cell interactions of the alloreactive inflammatory infiltrate. Here, we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies with varying phenotypes and severities of rejection and without rejection, and identified cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived FCGR3A+ monocytes, FCGR3A+ NK cells and the severity of intragraft inflammation. Activated FCGR3A+ monocytes overexpressed CD47 and LILR genes and increased paracrine signaling pathways promoting T cell infiltration. FCGR3A+ NK cells overexpressed FCRL3, suggesting that antibody-dependent cytotoxicity is a central mechanism of NK-cell mediated graft injury. Multiplexed immunofluorescence using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results highlight the central involvement of innate immune cells in the pathogenesis of allograft rejection and identify several potential therapeutic targets that might improve allograft longevity.
Topics: Graft Rejection; Kidney; Transplantation, Homologous; Antibodies; Allografts; Immunity, Innate
PubMed: 37468466
DOI: 10.1038/s41467-023-39859-7 -
Ugeskrift For Laeger Apr 2024Due to degeneration, homografts were since the 1950s only used strictly for replacement of complex arterial segments and lesions incl. the aortic valve, replacement of... (Review)
Review
Due to degeneration, homografts were since the 1950s only used strictly for replacement of complex arterial segments and lesions incl. the aortic valve, replacement of infected arterial prostheses, and vascular access for patients on haemodialysis. During the 1990s, rate-differentiated freezing methods and anti-crystallization agents proved to prevent crystallisation, and more widespread use with expanded indications incl. coronary and lower limb bypasses began justified by promising midterm results. In 2021, the first Scandinavian homograft biobank was founded in Odense in Denmark. This review summarises the history and the experiences from this biobank.
Topics: Humans; Cryopreservation; Allografts; Blood Vessel Prosthesis; Denmark
PubMed: 38708698
DOI: 10.61409/V07230454 -
Periodontology 2000 Feb 2024Bone grafting is routinely performed in periodontology and oral surgery to fill bone voids. While autogenous bone is considered the gold standard because of its... (Review)
Review
Bone grafting is routinely performed in periodontology and oral surgery to fill bone voids. While autogenous bone is considered the gold standard because of its regenerative properties, allografts and xenografts have more commonly been utilized owing to their availability as well as their differential regenerative/biomechanical properties. In particular, xenografts are sintered at high temperatures, which allows for their slower degradation and resorption rates and/or nonresorbable features. As a result, clinicians have combined xenografts with other classes of bone grafts (most notably allografts and autografts in various ratios) for procedures requiring better long-term stability, such as contour grafting, sinus elevation procedures, and vertical bone augmentations. This review addresses the regenerative properties of each class of bone grafts and then highlights the importance of understanding each of their biomechanical and regenerative properties for clinical applications, including extraction site management, contour augmentation, sinus grafting, and horizontal and vertical augmentation procedures. Thereafter, an introduction toward the novel production of nonresorbable bone allografts (NRBAs) via high-temperature sintering is presented. These NRBAs not only pose the advantage of being more biocompatible than xenografts owing to their origin (human vs. animal bone) but also display nonresorbable properties similar to those of xenografts. Thus, while packaging allografts with xenografts in premixtures specific to various clinical indications has never been permitted owing to cross-species contamination and FDA/CE requirements, the discovery and production of NRBAs allows premixing with standard allografts in various ratios without regulatory restrictions. Therefore, premixtures of allografts with NRBAs can be produced in various ratios for specific indications (e.g., a 1:1 ratio similar to an allograft/xenograft mixture for sinus grafting) without the need for purchasing separate classes of bone grafts. This optimized form of bone grafting could theoretically provide clinicians more precise ratios without the need to purchase separate bone grafts. This review highlights the future potential for simplified and optimized bone grafting in periodontology and implant dentistry.
Topics: Humans; Bone Transplantation; Animals; Bone Regeneration; Allografts; Heterografts; Alveolar Ridge Augmentation; Biomechanical Phenomena
PubMed: 37610202
DOI: 10.1111/prd.12517 -
American Journal of Transplantation :... Mar 2024The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of...
The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell-mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized. This paper summarizes the key Banff Meeting 2022 sessions not covered in the Banff Kidney Meeting 2022 Report paper and also provides an update on other Banff Working Group activities relevant to kidney allografts.
Topics: Kidney Transplantation; Canada; Graft Rejection; Kidney; Allografts
PubMed: 37931753
DOI: 10.1016/j.ajt.2023.10.031 -
Current Opinion in Organ Transplantation Jun 2024In recent years, the xenotransplantation science has advanced tremendously, with significant strides in both preclinical and clinical research. This review intends to... (Review)
Review
PURPOSE OF REVIEW
In recent years, the xenotransplantation science has advanced tremendously, with significant strides in both preclinical and clinical research. This review intends to describe the latest cutting-edge progress in knowledge and methodologies developed to overcome potential obstacles that may preclude the translation and successful application of clinical xenotransplantation.
RECENT FINDINGS
Preclinical studies have demonstrated that it is now possible to extend beyond two years survival of primate recipients of life saving xenografts. This has been accomplished thanks to the utilization of genetic engineering methodologies that have allowed the generation of specifically designed gene-edited pigs, a careful donor and recipient selection, and appropriate immunosuppressive strategies.In this light, the compassionate use of genetically modified pig hearts has been authorized in two human recipients and xenotransplants have also been achieved in human decedents. Although encouraging the preliminary results suggest that several challenges have yet to be fully addressed for a successful clinical translation of xenotransplantation. These challenges include immunologic, physiologic and biosafety aspects.
SUMMARY
Recent progress has paved the way for the initial compassionate use of pig organs in humans and sets the scene for a wider application of clinical xenotransplantation.
Topics: Animals; Humans; Animals, Genetically Modified; Graft Rejection; Graft Survival; Heterografts; Immunosuppressive Agents; Swine; Transplantation, Heterologous; Treatment Outcome
PubMed: 38529696
DOI: 10.1097/MOT.0000000000001146