Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and emerging allogeneic T cell therapies offer curative potential for hematologic malignancies, but their benefits remain constrained by graft-versus-host disease (GvHD). Although multiple signaling pathways contribute to GvHD, their effects are determined by dynamic interactions among immune cell subsets, tissue compartments, and disease stages rather than by isolated pathway activation. Here, we provide a network centered synthesis of major GvHD signaling pathways, including JAK/STAT, BTK/ITK, PI3K/AKT/mTOR, NF-κB, NFAT, MAPK, and Notch, with emphasis on pathway crosstalk, feedback, cellular and tissue context, and the distinct yet overlapping biology of acute and chronic GvHD. We further examine how network connectivity and context dependent signaling influence therapeutic responses and the challenge of suppressing pathogenic alloimmunity while preserving beneficial graft-versus-leukemia (GvL) activity. This framework highlights GvHD as a dynamically interconnected signaling disorder and provides a context aware basis for interpreting pathway directed therapies according to cellular context, disease stage, and the level of clinical evidence supporting each therapeutic approach.

In the clinical practice of hematopoietic stem cell transplantation (HSCT), we find ourselves in a thought-provoking paradox. On one hand, hematologists strive to create an sterility paradigm for patients through systemic drug baths before admission, prophylactic use of broad-spectrum antibiotics during the conditioning phase, and sterile diets during transplantation. The core goal of these strategies is to minimize the risk of infection for patients. However, from a microbiological perspective, a completely different picture emerges; the gut microbiota is a virtual organ that co-evolved with the host and possesses critical metabolic and immune regulatory functions. Microbiologists point out that indiscriminate antibiotic clearing strategies, while attempting to eradicate a few pathogens, also destroy the diversity and ecological functions of the microbiota necessary for maintaining gut homeostasis, leading to the collapse of intestinal barrier, disruption of intestinal epithelial energy metabolism, and loss of immune regulatory signals. Increasing evidence suggests that this pursuit of aseptic ideal, particularly the extensive suppression of the gut microbiome by broad-spectrum antibiotics, may be opening another Pandora's box: severe gut dysbiosis, which is not only associated with unexplained fever and diarrhea but may also affect the overall reconstruction and regulation of the patient's immune system, thus correlating with the occurrence and development of challenging complications such as graft-versus-host disease (GVHD). The divergence of views between hematologists and microbiologists highlights a core cognitive conflict in contemporary HSCT management: are we treating a patient, or are we regulating a superorganism composed of human cells and symbiotic microorganisms? This comment aims to analyze this contradiction based on existing evidence and advocate for a more refined and ecologically-oriented new model of clinical management.

Ischemia-reperfusion injury (IRI) after transplantation causes early and late graft dysfunction. Ezetimibe (Eze) is a lipid-reducing agent that has been reported to attenuate oxidative stress and inflammation in non-pulmonary models of ischemia-reperfusion. We examined its effect in a rat lung transplantation model. Lewis rats (n = 8/group) underwent left lung transplantation without pretreatment (LT) or with Eze pretreatment of the donor (LT-D), recipient (LT-R), or both (LT-DR). Eze (1 mg/kg) was given orally three times weekly for 2 weeks, and donor lungs were transplanted after 6 h of cold storage. Graft gas exchange, histology, inflammation, and apoptosis were assessed after 2 h of reperfusion. Graft PaO2/FiO2, measured with the contralateral hilum clamped, differed among the groups (176.8 ± 149.6, 265.1 ± 124.3, 321.9 ± 130.2, and 412.6 ± 142.3 mmHg in LT, LT-D, LT-R, and LT-DR; p = 0.015) and was significantly higher than in LT only in LT-DR. All treatment groups had lower lung injury scores than LT (16.62 ± 0.65 vs 12.25 ± 0.78, 10.95 ± 0.46, and 10.72 ± 0.40; p < 0.001). Plasma inflammatory cytokines and lung tissue myeloperoxidase were also lower in the treatment groups, and TUNEL positivity was significantly lower only in LT-DR. In conclusion, Eze pretreatment attenuated early IRI in a rat model of lung transplantation. Because the AMPK/Nrf2 pathway and direct indices of oxidative stress were not measured, the mechanism of this protection remains undetermined, and the findings are confined to the first 2 h after reperfusion.

In the context of allogeneic hematopoietic cell transplantation (allo-HCT), misclassifying null- and low-expression alleles could result in an HLA mismatch with life-threatening clinical consequences. HLA-C*04:09N was considered one of the most frequent null alleles, but it was recently reclassified as a low-expression allele, HLA-C*04:09L, based on a recent work which described that could be detected at the cell surface and capable of inducing peptide-specific T-cell activation in vitro. The authors suggested that these findings could imply clinical consequences in the field of transplantation, but without including any real clinical case. In this report we describe a patient carrying HLA-C*02:02:02,04:09N (now C*04:09L) who underwent an allo-HCT from a mismatched unrelated donor HLA-C*02:02:02,- that was considered functionally 10/10 matched due to the supposed lack of expression of HLA-C*04:09N. The post-transplant clinical course was complicated by graft-versus-host-disease, progression to secondary acute myeloid leukemia, and death.

Degenerative diseases continue to impose a substantial global health burden with limited curative options. Neurodegenerative diseases, the principal focus of this review, are among the largest contributors to this burden. Stem cell therapies have emerged as a promising approach, offering the potential to replace lost cells, modulate pathological microenvironments, and restore tissue function through both direct cell replacement and paracrine mechanisms. However, conventional stem cell strategies encounter persistent obstacles including immune rejection, tumorigenicity, poor engraftment, and limited long-term efficacy in chronic disease settings. This narrative review synthesizes recent and emerging innovations in stem cell therapy for neurodegenerative diseases across four major domains: (i) emerging mechanisms of stem cell action, including activation of dormant neural stem cells (NSCs), exosome-based cell-free therapies, and rejuvenation of aged stem cells; (ii) emerging cell types such as pre-morula stem cells (PMSCs), perinatal stem cells, SSEA-4+ human umbilical cord mesenchymal stem cells (hUC-MSCs), and iPSC-derived mesenchymal progenitor cells (MiMPCs); (iii) advanced delivery platforms including three-dimensional (3D) biomaterial scaffolds, injectable hydrogels, and stem cell membrane-coated nanoparticles (CMNPs); and (iv) gene-editing strategies, particularly CRISPR/Cas9-mediated generation of hypoimmunogenic induced pluripotent stem cell (iPSC) lines for allogeneic, off-the-shelf cell therapies. Key translational gaps, including standardization of exosome isolation and scaffold fabrication protocols, long-term safety and immunogenicity assessment, and ethical and regulatory frameworks, are critically evaluated, and future research directions are proposed. In addition, the review states the level of evidence (in vitro, animal, or human) supporting each approach and summarizes their clinical status in a single table. Addressing these challenges through interdisciplinary collaboration will be essential to realizing the full potential of stem cell-based regenerative medicine for degenerative diseases.

Upon recognition of alloantigen, T cells rely on an array of costimulatory and coinhibitory receptors to shape their activation and function. The surface receptor CD43 has been reported to provide myriad functions on T cell related to adhesion, trafficking, and intracellular signaling. We investigated the role of CD43 on CD8[+] T cells in vitro and in a fully allogeneic model of acute allograft rejection. Following polyclonal activation, CD43 did not impact the initial proliferation of CD8[+] T cells, although CD43 deficient CD8[+] T cells had mildly enhanced expression of IL-2Rα and PD-1 relative to CD43 wild-type CD8[+] T cells (***p = 0.0008 and **p = 0.006, respectively). Following 7-9 days of in vitro culture, CD43 deficient CD8[+] T cells had a stronger effector phenotype, displaying greater expression of Granzyme B, CD69, IL-2Rα, and PD-1. Following fully allogeneic skin grafting, alloantigen-specific CD43 deficient CD8[+] T cells accumulated at greater numbers in the secondary lymphoid tissue and the allograft relative to CD43 wild-type CD8[+] T cells (draining lymph nodes ***p = 0.007, spleen *p = 0.03). Hierarchical clustering and manual gating of revealed that CD43 deficient had an elevated frequency of effector populations with a CD62L[lo], KLRG-1[+], and CD49d[hi] phenotype, and that CD43 KO CD49d[hi] cells preferentially infiltrated the allograft tissue (***p = 0.0001). Together, these data provide evidence that CD43 acts as a checkpoint of alloantigen-specific CD8[+] T cell differentiation after transplantation.

Vascularized Composite Allotransplantation (VCA) requires immunosuppression to prevent allosensitization and subsequent allograft rejection. This study evaluated the prevalence, characteristics, and clinical implications of donor-specific antibodies (DSA) in VCA recipients. Thirty-seven VCA recipients (median age 32.5 years) from six international centers, grafted between 2000 and 2019, were studied. They included 23 upper extremity transplantations (UETs), 13 face transplantations and one patient with simultaneous UET and face transplantation. A total of 402 pre-transplant and follow-up sera were screened for DSA using a centralized assay. Among the 31 evaluable recipients, DSA appeared in a range of time between 7 and 2740 days post-transplantation with a median time of 360 days. The cumulative incidence of de novo DSA was 26% at five years and 48% at ten years. The incidence of de novo DSA did not differ between UET and face recipients. Both preformed and de novo DSA displayed comparable disappearance kinetics. A higher incidence of chronic rejection was observed in patients with DSA when an MFI cutoff of 500 was used (46.7% vs. 17.6% in patients with and without DSA, respectively), which became significant (p = 0.02) when the cutoff was increased to 1000. In conclusion, humoral immunization is a common event following VCA. DSA positivity was associated with chronic rejection and graft vasculopathy. Further mechanistic studies are needed to confirm the role of DSA in VCA rejection.