Xenotransplantation最新文献

Introduction: Cardiac xenotransplantation (CXTx) has the potential to increase the supply of donor organs; however, compared with clinical application research, studies on the mechanisms of injury following CXTx remain severely lacking. Plasma metabolite levels can accurately reflect the body's physiological state and serve as early predictors of potential adverse events. In this study, we established a heterotopic pig-to-non-human primate model and consecutively collected plasma samples for metabolomic analysis.

Methods: Based on the type of donor porcine heart and postoperative management strategy, the experiment was divided into three groups: Group I, wild-type (WT) donor heart; Group II, alpha-1,3-galactosyltransferase gene knockout (GTKO) donor heart without immunosuppression; and Group III, GTKO donor heart with immunosuppression.

Results: A total of 1215 metabolites were identified in recipient plasma following CXTx. Survival time was divided into three stages by hierarchical clustering, and that partial least squares discriminant analysis (PLS-DA) was used to visualize and rank metabolites contributing to these differences. Trajectory analysis identified six clusters with distinct temporal fluctuations in plasma metabolite levels after CXTx. Several plasma metabolites were found to rise prior to increases in troponin I levels, suggesting their potential as early biomarkers for predicting cardiac xenograft failure.

Conclusion: In summary, this novel approach to studying CXTx revealed previously unrecognized characteristics and offers a potential strategy for the early prediction of xenograft failure.

Recent advances in gene-edited pig organ xenotransplantation offer a promising solution to the critical shortage of human donor organs. Differences in physiology, drug metabolism, excretion, and responses between species require careful consideration for posttransplant medication management in human recipients. This brief review compares the anatomical, physiological, and biochemical features of pig and human organs, particularly in relation to the liver, kidney, heart, and lungs, and their potential implications on drug exposure, response, and efficacy after xenotransplantation. The transplantation of gene-edited organs from pigs to humans will result in a complex metabolic interplay, depending on the organ being transplanted. For example, if a pig liver is transplanted into a human, the drugs metabolized by the pig liver may be excreted in the bile or by the human kidney. There may be breed-specific metabolism of drugs, and genetic polymorphism in pigs may contribute to variability in drug exposure similar to what is observed among humans. Furthermore, there may be significant size differences between pigs and human organs, and their functional capabilities may change over time as the pig organs age within the recipient's body. In this article, we review how pig organ xenotransplantation may impact physiology, drug exposure, and response to immunosuppressive agents, anti-infective drugs, and other medications commonly used for posttransplant medical conditions. There is limited data available on the specific breeds of pigs used in xenotransplantation, and further research is required to ensure appropriate drug dosing, minimize toxicity, and optimize long-term graft function in recipients of pig organ xenografts.

Glucose-responsive insulin-secreting stem cell-derived islet-like cells (SC-islets) are a promising source for beta cell replacement to treat type 1 diabetes (T1D). However, immune rejection and limited function of SC-islets post-transplantation are key barriers to this treatment. We previously reported glycemic control and prolonged function of SC-islets microencapsulated in alginate that incorporates the pro-survival and immunomodulatory chemokine CXCL12 in immunocompetent diabetic mice without systemic immune suppression. Here, in a pilot study, we translated this SC-islet microencapsulation approach in nonhuman primates (NHPs) via transplantation of a therapeutic dose of SC-islets microencapsulated in alginate incorporating CXCL12 into the greater omental sac of a healthy and a diabetic NHP. We demonstrate that treatment did not cause metabolic dysfunction over a 6-month period in the NHPs. The healthy NHP maintained stable C-peptide and blood glucose levels, while the diabetic NHP had detectable serum C-peptide through 13 weeks post-transplant and a significant reduction in exogenous insulin requirements compared with a corresponding diabetic NHP recipient in the absence of immunosuppressive treatment. Serum biochemistry as well as hematological and immunological parameters of the NHPs remained normal throughout the post-transplantation period. At termination, the retrieved microencapsulated SC-islets were predominantly free floating without pericapsular fibrotic overgrowth and were glucose-responsive, expressing all major endocrine cell markers, albeit a significant decrease in viability compared with pre-transplant levels. Overall, these findings demonstrate feasibility, safety, and function of microencapsulated SC-islets in two NHPs in this small pilot study and our dataset supports further investigation of this approach toward clinical translation.

OMICS analyses have the potential to greatly enhance our understanding of rejection and other processes in xenotransplantation. These approaches may therefore contribute to extending the survival time of xenotransplants. Initial OMICS studies in brain-dead patients following transplantation of pig kidneys or hearts revealed increased expression of genes associated with humoral immune responses. This included activation of monocytes, macrophages, and natural killer (NK) cells, as well as endothelial activation, complement activation, and T cell development. Such multimodal deep phenotyping has been proposed as a potential game-changer in the field of xenotransplantation. However, it is essential to consider that viral infections may significantly influence the results of these analyses. Viruses are known to alter gene expression patterns, not only within the immune system but also in endothelial cells and other tissue compartments. Depending on the type of virus, the immune response may either be stimulated-as the host reacts against the infection-or suppressed, in cases involving immunosuppressive viruses. Therefore, integration of comprehensive virus screening is essential in such studies.

If cardiac xenotransplantation (XTx) can resolve the critical shortage of human organs, then we have an ethical obligation to reconsider it for select pediatric patients who are currently ineligible for allotransplantation but who may still benefit from a transplanted organ. This is especially true for children with genetic diseases who are often excluded due to unfavorable risk-benefit assessments rooted in the scarcity of donor hearts. While the overall potential of XTx remains uncertain, its ability to mitigate scarcity forces us to reevaluate who might benefit from a transplant. This commentary argues that if XTx resolves at least some concerns regarding immediate organ availability and quantity, then we should support further evaluation for transplantation in pediatric patients who may benefit but who were previously deemed ineligible for cardiac allotransplantation. While not all patients may cross the risk-benefit threshold, many deserve at least this evaluation, and failing to even evaluate is rooted in disability bias. Primarily focusing on the precedent trisomy 21 (T21) patients and the evolution in perceptions of transplantation suitability, we argue that if these patients will physiologically be stable after XTx, then we should consider the benefits XTx could provide-prolonged survival, symptom resolution, and improved quality of life (QOL) even if baseline QOL is limited (as in patients with other disabilities)-as justifying the attendant risks. This argument may also extend beyond T21 to other patient populations with genetic conditions, including select patients with trisomy 18 (T18).

Tissue engineering using decellularized liver scaffolds presents a promising approach in regenerative medicine, offering a potential alternative to donor organ transplantation. The use of human livers as a bioscaffold is restricted by their limited availability and quality. Porcine livers offer an alternative due to their anatomical and physiological similarities to human livers. However, applying porcine-derived biomaterials in a clinical setting poses a risk of pathogen transmission, which is a noteworthy concern. Porcine endogenous retroviruses (PERVs), which are integrated into the genome of all pig breeds, are of particular concern, as subclasses PERV-A and PERV-B have shown to infect human cells in vitro. It is therefore essential to effectively remove all PERVs when manufacturing porcine scaffolds. In this study, we assessed the presence of PERV-specific DNA, RNA, and protein in decellularized porcine livers. Our findings prove that genetic and protein PERV material was effectively removed from porcine livers during our decellularization procedure. This finding substantiates the potential of using decellularized scaffolds of porcine origin for clinical applications without risk of PERV transmission.

Using pig islet cells for transplants shows great promise for addressing the shortage of human donor organs in type 1 diabetes. However, it comes with unique risks from porcine endogenous retroviruses (PERV), which are found in all pig genomes and cannot be eliminated through breeding or biosecure rearing. Although there have been no reported cases of PERV transmission in early studies, the fact that PERV is a retrovirus requires strict safety measures. To minimize this risk, donor pigs are sourced from herds that are free from known pathogens and undergo rigorous screening for viruses like PERV. Regulatory bodies around the world acknowledge these concerns, with the World Health Assembly setting the "highest standards" for xenotransplant trials, the FDA requiring testing for active PERV, and the EMA and WHO guidelines recommending comprehensive screening protocols. Despite this, there are still regional differences in how long pigs are quarantined and how often they are tested, making it harder to compare data. A recent trial in South Korea, approved in 2024, is a good example of this variability, limiting the number of patients who can participate and requiring close monitoring for PERV. We suggest creating a global framework with standardized criteria for sourcing pigs and validated tests, which would allow for the mutual acceptance of safety data, improve patient protection, and speed up the translation of these treatments to clinical practice.

Background: Induction therapy is necessary to prevent acute rejection of xenografts. At present, basiliximab is rarely used as an induction therapy agent in solid organ xenotransplantation. In this study, we conducted in vitro experiments to investigate the inhibitory effect of basiliximab on human anti-porcine xenogeneic immune responses.

Methods: A xenogeneic and allogeneic mixed lymphocyte reaction (MLR) system was established using peripheral blood mononuclear cells (PBMCs) isolated from GTKO/CMAHKO/β4GalNT2KO (triple-knockout, TKO) pigs or humans as stimulator cells, and another group of human PBMCs as responder cells. Various concentrations of basiliximab were added to the MLR systems as interventions. The inhibitory effects of basiliximab on the proliferation and cytokine production of human T cells were compared.

Results: PBMCs from TKO pigs or humans stimulated significant proliferation of human T cells. Basiliximab inhibited human CD4⁺ and CD8⁺ T-cell proliferation in a typical dose-dependent manner in both xenogeneic and allogeneic MLR. When the concentration of basiliximab reached 1 µg/mL, the proliferation rates of xenoreactive CD4⁺ and CD8⁺ T cells decreased by more than 72%, which was quite similar to the effect in the allogeneic MLR. The inhibitory effects of basiliximab on xenogeneic T-cell responses were further confirmed by the detection of CD25 expression and supernatant cytokines (IFN-γ, TNF-α), and the results were similar to those for allogeneic MLR.

Conclusions: Basiliximab can significantly reduce the xenoreactivity of human lymphocytes against TKO pig cells, and its inhibitory effect is no less than that on allogeneic T cell responses, supporting its potential as induction therapy in xenotransplantation.

Corneal opacities affect millions worldwide, with corneal transplantation as the primary treatment. However, donor shortages remain a challenge, leaving thousands waiting for transplants. Xenotransplantation using porcine corneas has emerged as a promising alternative due to anatomical and physiological similarities with human corneas. Advances in CRISPR/Cas technology enable genetic modifications to address immune rejection and zoonotic risks. A key concern is xenozoonosis, the transmission of infectious agents from pigs to humans. Pathogens such as porcine endogenous retroviruses (PERVs), porcine cytomegalovirus (PCMV), and bacteria pose potential risks. While PERVs can infect human cells in vitro, no transmission has been documented in vivo. Regulatory bodies, including the WHO and IXA, have established guidelines for monitoring and clinical trials. The first human corneal xenotransplantation trials in South Korea and China are underway. Enhanced biosecurity measures in tissue banks have reduced microbial contamination, improving safety. Corneal xenotransplantation presents lower risks compared to solid organ xenotransplants. With ongoing research, stringent regulations, and improved pathogen-free animal models, this technique could become a viable clinical option. Future human trials will provide crucial insights into its long-term safety and effectiveness.