Yong-Guang Yang

Swine leukocyte antigens (SLA) may be a new type of xenoantigen. Previous studies on SLA have primarily focused on their cross‐reactivity with HLA. However, the role of SLA in stimulating xenogeneic immune responses after xenotransplantation remains unclear. In our recent kidney xenotransplantation study in rhesus monkeys using GTKO/hCD55 or GTKO/β4GalNT2KO/hCD55/hTBM pigs as donors, 5 of 13 recipients experienced early AMR accompanied by a marked increase in anti‐donor pig antibodies. Flow cytometry analysis showed that the terminal sera of these recipients contained significant de novo anti‐SLA antibodies, as evidenced by reduced antibody binding to GTKO/SLA‐I/II KO pig PBMCs. Using GTKO/β4GalNT2KO pAECs with or without pIFN‐γ stimulation as target cells, we found that the binding levels of the terminal sera to pAECs were positively correlated with SLA expression. IP‐MS analysis identified multiple SLA class I and class II epitopes targeted by recipient IgG antibodies, with SLA‐2 emerging as a dominant immunogenic antigen. In addition, xenogeneic MLR assays revealed that deletion of SLA, particularly SLA class II, markedly attenuated human anti‐pig T‐cell proliferation. These results demonstrate that induced anti‐SLA antibodies can be generated in the early period after pig‐to‐monkey kidney xenotransplantation and may play a significant role in the development of AMR.

Background: Virus-induced asthma exacerbation is a major cause of hospitalization and mortality in patients with asthma, yet the underlying immunopathology remains incompletely understood owing to the lack of human-relevant in vivo models. Humanized mice are powerful tools for biomedical investigation, but their application in studying asthma exacerbation has not yet been explored.Methods: We established a cytokine-optimized Thy/HSC humanized mouse model by combining transplantation of human fetal thymic tissue and CD34⁺ fetal liver cells with adeno-associated virus (AAV)-mediated delivery of human GM-CSF, IL-3, and IL-5. Asthmatic airway inflammation was induced by intranasal IL-33 administration, followed by H1N1 influenza infection to model viral-induced asthma exacerbation. Immunological, histopathological, and transcriptomic analyses were performed to characterize disease progression and therapeutic responses. Findings: AAV-mediated cytokine complementation markedly enhanced human myeloid reconstitution in vivo and enabled robust IL-33-driven airway inflammation characterized by peribronchial inflammatory cell infiltration, goblet cell hyperplasia, mucus hypersecretion, and elevated human type 2 cytokines. Subsequent influenza infection triggered severe asthma exacerbation accompanied by weight loss, mortality, neutrophilic inflammatory conversion, cytokine hyperproduction, and extensive lung injury, closely recapitulating clinical features observed in uncontrolled asthma exacerbation patients. Transcriptomic analyses identified IL-6 signaling as a central driver of inflammatory amplification and pathological remodeling. Therapeutic blockade of the IL-6 receptor with tocilizumab suppressed inflammatory cytokine production, reduced immune cell infiltration, alleviated lung pathology, promoted macrophage transition toward an anti-inflammatory phenotype, and significantly improved animal survival.Interpretation: We establish a humanized mouse model that recapitulates viral-induced asthma exacerbation through functional reconstruction of the human myeloid compartment. This platform provides a clinically relevant system for mechanistic investigation and preclinical therapeutic evaluation, while identifying IL-6 signaling as a potential therapeutic target in severe asthma exacerbation.

Over the past several decades, humanized mouse models have undergone significant refinement and become essential tools in biomedical research. Advances in genetic engineering, particularly the targeted knock‐in of human cytokines, have enabled robust development and function of human immune cells in these models. Recent breakthroughs—including the directed differentiation of human pluripotent stem cells into thymic epithelial cells and the efficient expansion of hematopoietic stem cells—have alleviated the constraint of scarce human tissue sources. Furthermore, the reconstruction of lymph node structures and successful engraftment of solid organ tissues have significantly improved the efficiency and physiological relevance of human immune system reconstitution. These models now provide a unique platform for in vivo studies in cancer immunotherapy, infectious diseases, regenerative medicine, and autoimmune disorders under near‐physiological conditions. Beyond rodents, substantial progress in humanized large animals, such as pigs, offers promising avenues for large‐scale immune system reconstruction and mass production of immunotherapeutic cells. This review presents a comprehensive overview of the development, optimization, and expanding applications of humanized animal models, highlighting their transformative role in advancing translational medicine.

The thrombospondin‐1 (TSP‐1)/CD47 signaling axis plays a critical role in endothelial injury during hepatic ischemia‐reperfusion (IR). Targeting this pathway represents a promising strategy to prevent liver IR injury; however, existing CD47 antagonists cause severe hematologic side effects due to nonspecific binding to erythrocytes. This study developed TAX2 (CD47‐derived peptide with the sequence CEVSQLLKGDAC)‐functionalized biodegradable nanoparticles (TAX2‐NPs) that specifically capture TSP‐1 and block its interaction with CD47 on liver sinusoidal endothelial cells (LSECs). TAX2‐NPs are composed of PLGA and DSPE‐PEG‐Mal and are conjugated with the cyclic peptide TAX2, derived from the TSP‐1‐binding domain of CD47. Upon systemic administration, TAX2‐NPs preferentially accumulate in the injured liver, where they competitively bind TSP‐1, preventing endothelial apoptosis and preserving sinusoidal integrity. Captured TSP‐1 is subsequently internalized by macrophages and degraded via the autophagy‐lysosome pathway, thereby eliminating residual extracellular TSP‐1 and mitigating its prolonged pathogenic effects. Collectively, this study presents a ligand‐targeted nanotherapeutic strategy that integrates TSP‐1 sequestration, signaling blockade, and autophagy‐mediated degradation, offering a safe and effective approach to protect the liver from ischemia‐reperfusion injury.

Natural and artificial enzymes have emerged as promising candidates for biomedical applications, possessing the potential to address redox imbalances and metabolic disorders in liver diseases. However, their clinical translation remains limited by challenges in biocompatibility, targeted delivery, dose‐response balance, and long‐term stability. Nanozymes, novel nanomaterials with potent enzyme‐like catalytic activity, exhibit promising capacities to overcome these challenges. In this review, we discuss nanozymes applied to liver diseases, including metabolic disorders, tissue repair, hepatic tumors, and viral infections. Under physiological and pathological liver conditions, diverse targeting strategies can be applied for the precise delivery of nanozymes. We demonstrate the fundamental mechanisms of nanozymes in scavenging reactive oxygen species (ROS), alleviating oxidative stress, and remodeling the immune microenvironment. The structural features, including size, morphology, composition, and surface modifications of nanozymes, critically influence catalytic performance and targeting efficiency at disease sites. These design criteria improve catalytic activity and reduce drug‐induced toxicity, thereby achieving a balance between dosage and therapeutic effects. We highlight the Artificial Intelligence (AI)‐driven revolution, in which machine learning contributes to predicting catalytic activity, optimizing structural design, and enabling intelligent applications of nanozymes. Finally, we outline the potential strategies and the limitations of nanozymes for clinical translation in liver disease therapy.