American Journal of Transplantation最新文献

Antibody-mediated rejection remains a leading cause of graft loss during kidney transplantation. Ischemia reperfusion injury (IRI) has been reported to promote T cell proliferation, leading to B cell activation and subsequent production of donor-specific antibodies, which target antigens on the vascular endothelium. We hypothesize that a novel therapeutic strategy targeting highly toxic reactive oxygen species could mitigate oxidative stress and immune responses associated with IRI. Our previous study demonstrated that oral administration of a silicon (Si)-based agent consistently generates substantial amounts of hydrogen, effectively suppressing IRI-induced oxidative stress and acute kidney injury in a rat renal clamp model. Here, we investigated the effect of the Si-based agent on immune responses in an allogeneic kidney transplant setting. Using both short-term and long-term evaluation models, we found that the Si-based agent suppressed oxidative stress and acquired immunity activation. Furthermore, early suppression of donor-specific antibody production and amelioration of chronic antibody-mediated rejection were observed. These findings indicate that the Si-based agent offers protective effects on graft function and survival, highlighting its potential clinical application to improve outcomes for kidney transplant recipients.

Regulatory T cells (Tregs) have been shown to be involved in the induction of transplantation tolerance in numerous models. Our previous work demonstrated that methyltransferase-like 14 (METTL14) loss impaired Treg function and hindered the establishment of transplantation tolerance. However, the underlying mechanisms remain unclear. In this study, we found that METTL14 knockdown in Tregs significantly impaired their regulatory function, leading to poor allograft function and accelerated transplant rejection. Using methylated RNA immunoprecipitation- and mRNA-sequencing approaches, we discovered that METTL14 deficiency fostered the expression of semaphorin 4D (Sema4D) mRNA, a key semaphorin family member with immunoregulatory activity. Methylation of target adenosines reduced Sema4D mRNA degradation, a process mediated by the METTL14-YTH N6-methyladenosine RNA binding protein 2 axis. Inhibition of Sema4D suppressed its interaction with its receptor, thereby preserving Treg immunoregulation capability and prolonging allograft survival through the p21-activated kinase-signal transducer and activator of transcription 5signaling pathway. Importantly, Sema4D expression in kidney transplant biopsies were negatively correlated with renal allograft survival. In summary, our findings suggest that METTL14 deficiency in Tregs leads to transplant rejection and reveal for the first time that Sema4D may serve as a potential therapeutic target to enhance Treg function in transplantation.

Rejection monitoring in facial vascularized composite allotransplantation traditionally focuses on skin biopsies. However, mucosal rejection frequently presents with more pronounced signs of immune activity. To explore mechanistic differences between skin and mucosal rejection, rejection and nonrejection biopsies from allograft skin and oral mucosa of 9 facial vascularized composite allotransplantation recipients were retrospectively analyzed using histology, multiplex immunostaining, and gene expression profiling, with peripheral blood mononuclear cells quantified via mass cytometry. Both skin and mucosa exhibited similar patterns of granzyme B expressing (GZMB⁺) T cells, indicating T cell-mediated rejection in both tissues. However, mucosa demonstrated additional CD19⁺ B cell infiltration and occasional plasma cells, which were absent in skin. These intramucosal B cells expressed AHNAK and CD43, suggesting they may be innate-like B cells (Bin cells). CD8⁺/GZMB⁺ cells and B cell populations were enriched in peripheral blood mononuclear cells during combined skin and mucosal rejection but not isolated skin rejection. These findings suggest distinct rejection mechanisms in skin and mucosa, with mucosa uniquely involving B cells. Current skin-focused rejection monitoring may overlook important mucosal rejection events, emphasizing the need to monitor both tissues concurrently. Mucosal biopsies could improve the accuracy in detecting acute rejection.