Transplant immunology最新文献

Objective

Sepsis has a high incidence, morbidity, and mortality rate and is a great threat to human safety. Gut health plays an important role in sepsis development. Qi Huang Fang (QHF) contains astragalus, rhubarb, zhishi, and atractylodes. It is used to treat syndromes of obstructive qi and deficiency of righteousness. This study aimed to investigate whether QHF improves intestinal barrier function and microorganisms in mice through NLRP3 inflammatory vesicle-mediated cellular focal death.

Methods

A mouse model of sepsis was constructed by cecal ligation and puncture (CLP) of specific pathogen-free (SPF)-grade C57BL/6 mice after continuous gavage of low, medium, and high doses of astragalus formula or probiotics for 4 weeks. Twenty-four hours postoperatively, the mechanism of action of QHF in alleviating septic intestinal dysfunction and restoring intestinal microecology, thereby alleviating intestinal injury, was evaluated by pathological observation, immunohistochemistry, western blotting, ELISA, and 16S rDNA high-throughput sequencing.

Results

Different doses of QHF and probiotics ameliorated intestinal injury and reduced colonic apoptosis in mice to varying degrees (P < 0.05). Meanwhile, different doses of QHF and probiotics were able to reduce the serum levels of IL-6, IL-1β, and TNF-α (P < 0.05); down-regulate the protein expression of NLRP3, caspase-1, and caspase-11 (P < 0.05); and up-regulate the protein expression of zonula occluden-1 (ZO-1) and occludin (P < 0.05), which improved the intestinal barrier function in mice. In addition, QHF decreased the relative abundance of harmful bacteria (Firmicutes, Muribaculaceae, Campilobacterota, Helicobacter, and Alistipes) and increased the relative abundance of beneficial bacteria (Bacteroidetes and Actinobacteria) (P < 0.05).

Conclusion

QHF improves intestinal barrier function and gut microbiology in mice via NLRP3 inflammasome-mediated cellular pyroptosis.

In the last decade, cell therapies have revolutionized the treatment of some diseases, earning the definition of being the “third pillar” of therapeutics. In particular, the infusion of regulatory T cells (Tregs) is explored for the prevention and control of autoimmune reactions and acute/chronic allograft rejection. Such an approach represents a promising new treatment for autoimmune diseases to recover an immunotolerance against autoantigens, and to prevent an immune response to alloantigens. The efficacy of the in vitro expanded polyclonal and antigen-specific Treg infusion in the treatment of a large number of autoimmune diseases has been extensively demonstrated in mouse models. Similarly, experimental work documented the efficacy of Treg infusions to prevent acute and chronic allograft rejections. The Treg therapy has shown encouraging results in the control of type 1 diabetes (T1D) as well as Crohn's disease, systemic lupus erythematosus, autoimmune hepatitis and delaying graft rejection in clinical trials. However, the best method for Treg expansion and the advantages and pitfalls with the different types of Tregs are not fully understood in terms of how these therapeutic treatments can be applied in the clinical setting. This review provides an up-to-date overview of Treg infusion-based treatments in autoimmune diseases and allograft transplantation, the current technical challenges, and the highlights and disadvantages of this therapeutic approaches.”

As a consequence of increased lifespan and rising number of elderly individuals developing end-stage organ disease, the higher demand for organs along with a growing availability for organs from older donors pose new challenges for transplantation. During aging, dynamic adaptations in the functionality and structure of the biological systems occur. Consistently, immunosenescence (IS) accounts for polydysfunctions within the lymphocyte subsets, and the onset of a basal but persistent systemic inflammation characterized by elevated levels of pro-inflammatory mediators. There is an emerging consensus about a causative link between such hallmarks and increased susceptibility to morbidities and mortality, however the role of IS in solid organ transplantation (SOT) remains loosely addressed. Dissecting the immune-architecture of immunologically-privileged sites may prompt novel insights to extend allograft survival. A deeper comprehension of IS in SOT might unveil key standpoints for the clinical management of transplanted patients.

Background

Acute myocardial infarction (AMI) is a global health problem with high mortality. Early diagnosis can prevent the development of AMI and provide valuable information for subsequent treatment. Angiogenesis has been shown to be a critical factor in the development of infarction and targeting this process may be a potential protective strategy for preventing myocardial injury and improving the prognosis of AMI patients. This study aimed to screen and verify diagnostic markers related to angiogenesis in AMI and to investigate the molecular mechanisms of action associated with AMI in terms of immune cell infiltration.

Methods

The GSE66360 and the GSE60993 datasets were both downloaded from the GEO database and were used as the training cohort and the external validation cohort, respectively. Angiogenesis-related genes (ARGs) were downloaded from the MSigDB database. The hub ARGs were identified via LASSO, RF, and SVM-RFE algorithms. ROC curves were used to assess the accuracy of the hub ARGs. The potential mechanisms of the hub ARGs were analyzed by GSEA. The ssGSEA algorithm was used to determine differences in immune cell infiltration and immune function. The CIBERSORT algorithm was used for immune cell infiltration analysis. In addition, we constructed a ceRNA network map of differentially expressed ARGs.

Results

We identified the thrombomodulin (THBD) gene from ARGs as a potential diagnostic marker for AMI based on the LASSO, SVM-RFE, and RF algorithms. THBD was differentially expressed and had a potential diagnostic value (area under the curve [AUC] = 0.931 and 0.765 in the training and testing datasets, respectively). GSEA showed that the MAPK signaling pathway was more enriched in the high-expression group of THBD (P < 0.05). Immune cell infiltration analysis demonstrated that THBD was mainly positively correlated with monocytes (R = 0.48, P = 0.00055) and neutrophils (R = 0.36, P = 0.013). Finally, in the ceRNA regulatory network, THBD was closely associated with 9 miRNAs and 42 lncRNAs involved in AMI.

Conclusion

THBD can be used as a potential diagnostic marker for AMI. This study provides new insights for future AMI diagnosis and molecular mechanism research. Moreover, immune cell infiltration plays an essential role in the occurrence and development of AMI.

Introduction

Multiple sclerosis (MS), as a destructive pathology of myelin in central nervous system (CNS), causes physical and mental complications. Experimental autoimmune encephalomyelitis (EAE) is laboratory model of MS widely used for CNS-associated inflammatory researches. Cell therapy using macrophage M2 (MPM2) is a cell type with anti-inflammatory characteristics for all inflammatory-based neuropathies. This experimental study investigated the probable therapeutic anti-inflammatory effects of intraperitoneal (IP) injection of MPM2 on alleviation of motor defect in EAE-affected animals.

Materials and methods

24 C57/BL6 female mice were divided into four groups of EAE, EAE + Dexa, EAE + PBS, and EAE + MP2. EAE was induced through deep cervical injection of spinal homogenate of guinea pigs. MPM2 cells were harvested from bone marrow and injected (10⁶cells/ml) in three days of 10, 13 and 16 post-immunizations (p.i). Clinical score (CS), anti-inflammatory cytokines (IL-4, IL-10), pro-inflammatory gene expression (TNF-α, IL-1β) and histopathological investigations (HE, Nissl and Luxol Fast Blue) were considered. Data were analyzed using SPSS software (v.19) and p < 0.05 was considered significant level.

Results

During EAE induction, the mean animal weight was decreased (p < 0.05); besides, following MPM2 injection, the weight gain was applied (p < 0.05) in EAE + MPM2 groups than control. Increased (p < 0.05) levels of CS was found during EAE induction in days 17–28 in EAE animals; besides, CS was decreased (p < 0.05) in EAE + MPM2 group than EAE animals. Also, in days 25–28 of experiment, the CS was decreased (p < 0.05) in EAE + MPM2 than EAE + Dexa. Histopathological assessments revealed low density of cell nuclei in corpus callosum, microscopically. LFB staining also showed considerable decrease in white matter density of corpus callosum in EAE group. Acceleration of white matter density was found in EAE + MPM2 group following cell therapy procedure. Genes expression of TNF-α, IL-1β along with IL-4 and IL-10 were decreased (p < 0.05) in EAE + MPM2 group.

Conclusion

IP injection of MPM2 to EAE-affected female mice can potentially reduce the CNS inflammation, neuronal death and myelin destruction. MPM2 cell therapy can improve animal motor defects.

Background

Macrophage type 1 (M1) cells are associated with both acute kidney injury (AKI) during kidney transplantation and acute rejection (AR) after kidney transplantation. Our study explored M1-related biomarkers involved in both AKI and AR and their potential biological functions.

Methods

Based on the Gene Expression Omnibus (GEO) database, the immune cell infiltration levels and differentially expressed genes were examined in AKI and AR in the kidney transplantation; M1-related genes shared in AKI and AR were identified using weighted gene co-expression analysis (WGCNA) system. Subsequently, protein-protein interaction (PPI) networks and machine learning methods to identify Hub genes and construct diagnostic models. Both AKI model and AR rat models were built to validate the expressions of Hub genes and test the injury phenotype, oxidative stress markers, and inflammatory factors. Finally, the transcription factor (TF)-Hub gene and micro-RNA (miRNA)-Hub gene regulatory networks were constructed based on identified Hub genes.

Results

Out of 2167 differential expression genes (DEGs) in AKI and 2100 DEGs in AR, four M1-related Hub genes were obtained by PPI networks and machine learning methods, namely GBP2, TYROBP, CCR5, and TLR8. The calibration curves in the nomogram diagnostic model for these four Hub genes suggested the same predictive probability as an ideal model for AKI and AR after kidney transplantation (AUC values of the area under the ROC curve were all >0.7). The same observations were confirmed in ischemia reperfusion injury (IRI) and AR rat models by identifying common four Hub genes (GBP2, TYROBP, TLR8, and CCR5). Western blots showed that these four Hub genes were significantly different in rat models of IRI and AR (all p<0.05). Compared with the control group, IRI and AR groups showed aggravated histopathological damage and increased secretion of oxidative stress markers and inflammatory factors in rat kidneys (all p<0.05). Finally, TF-Hub and miRNA-Hub gene regulatory networks were constructed to provide a theoretical basis for the regulation of Hub genes.

Conclusion

We identified four macrophage M1-related Hub genes shared among AKI and AR after kidney transplantation. These genes may be considered for diagnosis of AKI and AR after kidney transplantation.

Introduction

This study examines the effect of belatacept based salvage regimens on kidney transplant outcomes.

Methods

This single-center retrospective study included all adult kidney transplant recipients between 2011 and 2022 who were converted to belatacept salvage therapy during their follow up. eGFR, graft survival, incidence of infections and neoplasia, histology and DSA data were collected through systematic review of the medical record.

Results

Patients were divided into 3 groups based on salvage regimen: Mycophenolate mofetil/belatacept (MMF/Bela) (n = 28), low-dose Calcineurin inhibitors/belatacept (CNI/Bela) (n = 22), and low-dose Calcineurin inhibitors/ Mycophenolate mofetil /belatacept (CNI/MMF/Bela) (n = 13). Patients with antibody-mediated rejection were more likely to receive CNIs in addition to belatacept (low-dose CNI/MMF/Bela 54%, low-dose CNI/Bela 45%, MMF/Bela 3.6%, p < 0.001). DSA decreased in all groups after transition to belatacept by 15.67% (p = 0.15). No difference in Glomerular filtration rate (eGFR) over time was observed between the groups, and eGFR remained stable over the first year after transition to belatacept. The incidence of death and allograft failure was similar between the groups (low- dose CNI/MMF/Bela n = 3, low-dose CNI/Bela n = 7, MMF/Bela n = 4; p = 0.41). Patients in the low-dose CNI/Bela cohort who were transitioned to belatacept within 6 months from transplant showed a decline in eGFR over the first year after transition, while the other treatment cohorts demonstrated stable or slight increase in eGFR.

Conclusions

The present study demonstrates comparable transplant outcomes in terms of eGFR, graft survival, incidence of infections and neoplasia, rejection rate and donor specific antibody (DSA) in three belatacept-based maintenance immunosuppression regimens supporting the safety and efficacy of these therapeutic options.

The ATP-binding cassette subfamily A member 3 (ABCA3) protein plays a fundamental role in surfactant homeostasis. Most children with ABCA3 gene mutations develop pulmonary interstitial fibrosis leading to the development of interstitial lung disease. Since traditional medicine does not offer effective therapy, the best option is lung transplantations, especially bilateral lung transplantations. We are reporting the case of a successful bilateral lung transplantation in a five-year-old child with pulmonary interstitial fibrosis caused by ABCA3 gene mutations. This successful transplantation enabled the patient to get rid of chronic cough and tachypnea.

Introduction

Despite significant progress over the last decades in the survival of kidney allografts, several risk factors remain contributing to worsening kidney function or even loss of transplants. We aimed to evaluate a new machine learning method to identify these variables which may predict the early graft loss in kidney transplant patients and to assess their usefulness for improving clinical decisions.

Material and methods

A retrospective cohort study was carried out with 627 kidney transplant patients followed at least three months. All these data were pre-processed, and their selected features were used to develop an automatically working a machine learning algorithm; this algorithm was then applied for training and parameterization of the model; and finally, the tested model was then used for the analysis of patients' features that were the most impactful for the prediction of clinical outcomes. Our models were evaluated using the Area Under the Curve (AUC), and the SHapley Additive exPlanations (SHAP) algorithm was used to interpret its predictions.

Results

The final selected model achieved a precision of 0.81, a sensitivity of 0.61, a specificity of 0.89, and an AUC value of 0.84. In our model, serum creatinine levels of kidney transplant patients, evaluated at the hospital discharge, proved to be the most important factor in the decision-making for the allograft loss. Patients with a weight equivalent to a BMI closer to the normal range prior to a kidney transplant are less likely to experience graft loss compared to patients with a BMI below the normal range. The age of patients at transplantation and Polyomavirus (BKPyV) infection had significant impact on clinical outcomes in our model.

Conclusions

Our algorithm suggests that the main characteristics that impacted early allograft loss were serum creatinine levels at the hospital discharge, as well as the pre-transplant values such as body weight, age of patients, and their BKPyV infection. We propose that machine learning tools can be developed to effectively assist medical decision-making in kidney transplantation.

Background

Immune-mediated rejection is the most common cause of allograft failure in kidney transplant (KT) patients. Exposure to alloantigen, including human leukocyte antigen (HLA), results in the production of donor-specific antibodies (DSA). There are limited data about low levels of mean fluorescence intensity (MFI) DSA, especially post-transplantation. This study evaluated allograft outcomes in KT patients with low MFI DSA.

Methods

From January 2007 to December 2021, KT patients who were tested for post-transplant DSA at Ramathibodi Hospital, Bangkok, Thailand, with the DSA MFI ≤ 1000 were evaluated. These KT patients were categorized into two groups: very low DSA (VLL; MFI = 1–500) and low DSA (LL; MFI = 501–1000). All KT patients were evaluated for the primary outcomes, such as the incidence of acute rejection, serum creatinine levels at one and five years after transplantation as well as allograft and patient survivals.

Results

Among 36 KT patients 25 were included as those with VLL and 11 as those with LL. The LL group had significantly higher T-cell mediated allograft rejection (TCMR) than the VLL group (45% vs. 12%, P = 0.04). In addition, 10 patients, 5 in the VLL group and 5 in the LL group developed antibody-mediated allograft rejection (ABMR). Both TCMR and ABMR were confirmed by biopsy results. There was a trend toward higher MFI in KT patients with ABMR than without ABMR (P = 0.22). At 5 post-transplant years, serum creatinine, allograft and patient survivals were comparable between these two groups. Furthermore, the univariate and multivariate analyzes revealed that the LL group was a high risk for rejection.

Conclusion

Low MFI DSA values after transplantation may be associated with a higher incidence of rejection, but this finding did not show differences in allograft and patient survival in this study's analysis.