Background: Adoptive transfer of autologous regulatory T cells (Tregs) is a promising therapeutic strategy aimed at enabling immunosuppression minimization following kidney transplantation. In our phase 1 clinical trial of Treg therapy in living donor renal transplantation, the ONE Study (ClinicalTrials.gov: NCT02129881), we observed focal lymphocytic infiltrates in protocol kidney transplant biopsies that are not regularly seen in biopsies of patients receiving standard immunosuppression.
View Article and Find Full Text PDFBackground And Aims: The intrahepatic processes associated with chronic hepatitis B (CHB), especially in the context of hepatitis delta virus (HDV) and HIV co-infection, require a better understanding. Spatial transcriptomics can provide new insights into the complex intrahepatic biological processes, guiding new personalised treatments. Our aim is to evaluate this method characterising the intrahepatic transcriptional landscape, cellular composition and biological pathways in liver biopsy samples from patients with hepatitis B virus (HBV) and HDV or HIV co-infection.
View Article and Find Full Text PDFObjective: To identify the effects of patient risk factors and pelvic venous reflux (PVR) patterns on treatment outcomes of Pelvic Vein Embolisation (PVE) for Pelvic Venous Disorder (PeVD).
Methods: We performed a retrospective cohort review assessing population, intervention, comparison, and outcomes (PICO) for women undergoing PVE for PVR January 2017-January 2021. We identified 190 patients who had completed both questionnaires and who had given consent for their information to be used for research (Median age 46, IQR 40-52).
Evaluating the contribution of the tumour microenvironment (TME) in tumour progression has proven a complex challenge due to the intricate interactions within the TME. Multiplexed imaging is an emerging technology that allows concurrent assessment of multiple of these components simultaneously. Here we utilise a highly multiplexed dataset of 61 markers across 746 colorectal tumours to investigate how complex mTOR signalling in different tissue compartments influences patient prognosis.
View Article and Find Full Text PDFSingle cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium.
View Article and Find Full Text PDFTransplantation
December 2023
The last 5 y have seen the development and widespread adoption of high-plex spatial transcriptomic technology. This technique detects and quantifies mRNA transcripts in situ, meaning that transcriptomic signatures can be sampled from specific cells, structures, lesions, or anatomical regions while conserving the physical relationships that exist within complex tissues. These methods now frequently implement next-generation sequencing, enabling the simultaneous measurement of many targets, up to and including the whole mRNA transcriptome.
View Article and Find Full Text PDFSevere lung damage resulting from COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways, and genes present across the spectrum of histopathological damage in COVID-19-affected lung tissue. We applied correlation network-based approaches to deconvolve gene expression data from 46 areas of interest covering more than 62,000 cells within well-preserved lung samples from 3 patients.
View Article and Find Full Text PDFHermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking. The mechanism for Crohn's disease-like inflammation, lung fibrosis, and macrophage lipid accumulation in these patients remains enigmatic. The aim of this study is to understand the cellular basis of inflammation in HPS-1.
View Article and Find Full Text PDFLow-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells.
View Article and Find Full Text PDFLow plasma iron (hypoferremia) induced by hepcidin is a conserved inflammatory response that protects against infections but inhibits erythropoiesis. How hypoferremia influences leukocytogenesis is unclear. Using proteomic data, we predicted that neutrophil production would be profoundly more iron-demanding than generation of other white blood cell types.
View Article and Find Full Text PDFBackground & Aims: CD4CD25Foxp3 regulatory T cells (Tregs) are essential to maintain immunological tolerance and have been shown to promote liver allograft tolerance in both rodents and humans. Low-dose IL-2 (LDIL-2) can expand human endogenous circulating Tregs in vivo, but its role in suppressing antigen-specific responses and promoting Treg trafficking to the sites of inflammation is unknown. Likewise, whether LDIL-2 facilitates the induction of allograft tolerance has not been investigated in humans.
View Article and Find Full Text PDFUnderstanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in the Syrian hamster model.
View Article and Find Full Text PDFBackground: Excessive inflammation is pathogenic in the pneumonitis associated with severe COVID-19. Neutrophils are among the most abundantly present leukocytes in the inflammatory infiltrates and may form neutrophil extracellular traps (NETs) under the local influence of cytokines. NETs constitute a defense mechanism against bacteria, but have also been shown to mediate tissue damage in a number of diseases.
View Article and Find Full Text PDFThe severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Genome-wide association studies identified the 3p21.31 region as conferring a twofold increased risk of respiratory failure.
View Article and Find Full Text PDFCurrent endovenous laser ablation (EVLA) practice favours 1470 nm, as water is a major chromophore for this wavelength. Water has a greater affinity for 1940 nm, leading to claims that lower powers or linear endovenous energy densities (LEEDs) are needed. We compared the thermal spread and carbonisation of EVLA using these two wavelengths, in the porcine liver model.
View Article and Find Full Text PDFClinical trials of Treg therapy in transplantation are currently entering phases IIa and IIb, with the majority of these employing polyclonal Treg populations that harbor a broad specificity. Enhancing Treg specificity is possible with the use of chimeric antigen receptors (CARs), which can be customized to respond to a specific human leukocyte antigen (HLA). In this study, we build on our previous work in the development of HLA-A2 CAR-Tregs by further equipping cells with the constitutive expression of interleukin 10 (IL-10) and an imaging reporter as additional payloads.
View Article and Find Full Text PDFDuring allotransplantation, the endothelium acts as semi-professional antigen-presenting cells with the ability to activate proliferation and to promote differentiation of CD4-T subsets. These abilities are dependent on the luminal expression of HLA class II antigens by microvascular endothelial cells, which is regulated by inflammatory cytokines. The upregulation of HLA-DR and HLA-DQ during rejection implies significant intragraft inflammation.
View Article and Find Full Text PDFTo compare outcomes when pesticides are used to control bed bugs by professionals and nonprofessionals. All US National Pesticide Information Center inquiries from 2013 to 2017 were assessed to identify scenarios involving bed bugs and pesticide applications. Cases were evaluated with respect to types of applicators, misapplications, and human pesticide exposures.
View Article and Find Full Text PDFOrgan transplantation is a life-saving treatment for end-stage organ failure. However, despite advances in immunosuppression, donor matching, tissue typing, and organ preservation, many organs are still lost each year to rejection. Ultimately, tolerance in the absence of immunosuppression is the goal, and although this seldom occurs spontaneously, a deeper understanding of alloimmunity may provide avenues for future therapies which aid in its establishment.
View Article and Find Full Text PDFThis case report describes the diagnosis and treatment of a pre-pubertal (onset at age 7) Caucasian female with serological evidence of Lyme disease accompanied by multiple neuropsychiatric symptoms 6 months following a vacation in a tick endemic area of the United States. Prior to the diagnosis of Lyme disease, the patient also met the clinical diagnostic criteria for PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Strep), with serological evidence of three distinct episodes of streptococcal pharyngitis. All three episodes of strep occurred during the 6-months interval between suspected Lyme disease exposure and the onset of multiple neuropsychiatric symptoms.
View Article and Find Full Text PDFThe humanization of animals is a powerful tool for the exploration of human disease pathogenesis in biomedical research, as well as for the development of therapeutic interventions with enhanced translational potential. Humanized models enable us to overcome biologic differences that exist between humans and other species, while giving us a platform to study human processes in vivo. To become humanized, an immune-deficient recipient is engrafted with cells, tissues, or organoids.
View Article and Find Full Text PDFObjective: This retrospective study examined whether changes in patient pre- and post-treatment symptoms correlated with changes in anti-neuronal autoantibody titers and the neuronal cell stimulation assay in the Cunningham Panel in patients with Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection (PANDAS), and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS).
Methods: In an analysis of all tests consecutively performed in Moleculera Labs' clinical laboratory from April 22, 2013 to December 31, 2016, we identified 206 patients who were prescribed at least one panel prior to and following treatment, and who met the PANDAS/PANS diagnostic criteria. Patient follow-up was performed to collect symptoms and treatment or medical intervention.
Development of donor-specific antibodies is associated with reduced allograft survival in renal transplantation. Recent clinical studies highlight the prevalence of human leukocyte antigen (HLA)-DQ antibodies amongst de novo donor-specific antibodies (DSAs), yet the specific contribution of these DSAs to rejection has not been examined. Antibody-mediated rejection primarily targets the microvasculature, so this study explored how patient HLA-DQ alloantibodies can modulate endothelial activation and so immunoregulation.
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