Activity Of Allografts Research Articles

P40 homodimers bridge ischemic tissue inflammation and heterologous alloimmunity in mice via IL-15 transpresentation.

Virus-induced memory T cells often express functional cross-reactivity, or heterologous immunity, to other viruses and to allogeneic MHC molecules that is an important component of pathogenic responses to allogeneic transplants. During immune responses, antigen-reactive naive and central memory T cells proliferate in secondary lymphoid organs to achieve sufficient cell numbers to effectively respond, whereas effector memory T cell proliferation occurs directly within the peripheral inflammatory microenvironment. Mechanisms driving heterologous memory T cell proliferation and effector function expression within peripheral tissues remain poorly understood. Here, we dissected proliferation of heterologous donor-reactive memory CD8+ T cells and their effector functions following infiltration into heart allografts with low or high intensities of ischemic inflammation. Proliferation within both ischemic conditions required p40 homodimer-induced IL-15 transpresentation by graft DCs, but expression of effector functions mediating acute allograft injury occurred only in high-ischemic allografts. Transcriptional responses of heterologous donor-reactive memory CD8+ T cells were distinct from donor antigen-primed memory CD8+ T cells during early activation in allografts and at graft rejection. Overall, the results provide insights into mechanisms driving heterologous effector memory CD8+ T cell proliferation and the separation between proliferation and effector function that is dependent on the intensity of inflammation within the tissue microenvironment.

Single-cell analysis of graft-infiltrating host cells identifies caspase-1 as a potential therapeutic target for heart transplant rejection.

Understanding the cellular mechanisms underlying early allograft rejection is crucial for the development of effective immunosuppressant strategies. This study aims to investigate the cellular composition of graft-infiltrating cells during the early rejection stage at a single-cell level and identify potential therapeutic targets. A heterotopic heart transplant model was established using enhanced green fluorescent protein (eGFP)-expressing mice as recipients of allogeneic or syngeneic grafts. At 3 days post-transplant, eGFP-positive cells infiltrating the grafts were sorted and subjected to single-cell RNA-seq analysis. Potential molecular targets were evaluated by assessing graft survival and functions following administration of various pharmacological inhibitors. A total of 27,053 cells recovered from syngrafts and allografts were classified into 20 clusters based on expression profiles and annotated with a reference dataset. Innate immune cells, including monocytes, macrophages, neutrophils, and dendritic cells, constituted the major infiltrating cell types (>90%) in the grafts. Lymphocytes, fibroblasts, and endothelial cells represented a smaller population. Allografts exhibited significantly increased proportions of monocyte-derived cells involved in antigen processing and presentation, as well as activated lymphocytes, as compared to syngrafts. Differential expression analysis revealed upregulation of interferon activation-related genes in the innate immune cells infiltrating allografts. Pro-inflammatory polarization gene signatures were also enriched in these infiltrating cells of allografts. Gene profiling and intercellular communication analysis identified natural killer cells as the primary source of interferon-γ signaling, activating inflammatory monocytes that displayed strong signals of major histocompatibility complexes and co-stimulatory molecules. The inflammatory response was also associated with promoted T cell proliferation and activation in allografts during the early transplant stages. Notably, caspase-1 exhibited specific upregulation in inflammatory monocytes in response to interferon signaling. The regulon analysis also revealed a significant enrichment of interferon-related motifs within the transcriptional regulatory network of downstream inflammatory genes including caspase-1. Remarkably, pharmacological inhibition of caspase-1 was shown to reduce immune infiltration, prevent acute graft rejection, and improve cardiac contractile function. The single-cell transcriptional profile highlighted the crucial role of caspase-1 in interferon-mediated inflammatory monocytes infiltrating heart transplants, suggesting its potential as a therapeutic target for attenuating rejection.

Obliterative airway disease in rat tracheal allografts requires tumor necrosis factor alpha

Obliterative bronchiolitis is the major complication affecting long-term lung transplant survivors. Tumor necrosis factor-alpha (TNF-α) promotes inflammation and fibrosis in chronic lung injury models. These experiments defined the role of TNF-α in an established model of obliterative airway disease (OAD). Rat tracheas were transplanted from Brown–Norway donors into Lewis recipients, and explanted on days 7 and 14. Treated groups received either anti-TNF-α antibodies or a novel TNF-α translational inhibitor, RDP-58, beginning either immediately or on post-transplant day 7. Morphometry assessed epithelial loss and luminal obliteration, while separate tracheas were processed for TNF-α mRNA expression by RQRT-PCR or protein localization/expression by immunohistochemistry. EMSAs evaluated NFκB activation. 14-day control allografts averaged 58% occlusion and 98% epithelial loss. These parameters were significantly improved with TNF-α inhibition, averaging 32% luminal obliteration and 37% epithelial preservation. TNF-α mRNA expression increased at 14-days relative to native tracheas, and was unchanged by RDP-58 treatment. However, TNF-α protein expression, localized to the mucosa/submucosa, was markedly reduced with RDP-58, and resulted in diminished global NFκB activation in allografts. Delayed RDP treatment reduced disease progression during the second week, as luminal occlusion increased from 26% to only 35%, while respiratory epithelium persisted at 21%. TNF-α promotes the development of OAD in tracheal allografts via an NFκB-dependent mechanism, and its inhibition may prove beneficial clinically.

Antioxidant treatment inhibits activation of myocardial nuclear factor kappa B and inhibits nitrosylation of myocardial heme protein in cardiac transplant rejection.

Nitric oxide production via inducible nitric oxide synthase (iNOS) is believed to play a role in cardiac allograft rejection. Previously, we showed that antioxidants can significantly prolong cardiac graft survival, but the nature of this protection is unknown. In the present study, we examined the protective effect of another antioxidant, dimethylthiourea (DMTU), in a model of cardiac allograft rejection. Specifically, we hypothesized that DMTU would prolong graft survival and decrease activation of nuclear factor-kappa B (NF-kappa B), an important redox-sensitive transcription factor necessary for iNOS gene expression. NF-kappa B was activated by twofold as early as postoperative day 2 in allografts. NF-kappa B activation in allografts progressed to a peak of ninefold by postoperative day and remained increased until postoperative day 6. No activation of NF-kappa B was observed in isografts for comparable time periods. Treatment with DMTU resulted in a significant prolongation of graft survival. This beneficial effect was associated with diminished activation of myocardial NF-kappa B. Treatment with DMTU also resulted in decreased formation of iron-nitrosylprotein complexes as evidenced by electron paramagnetic resonance spectroscopy. These studies provide evidence that reactive oxygen plays a significant role in signal transduction for activation via the transcription factor, NF-kappa B, thereby modulating distal actions and consequences of iNOS-derived nitric oxide.

Complement as a mediator of vascular inflammation and activation in allografts

Complement as a mediator of vascular inflammation and activation in allografts