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EBioMedicine Oct 2023The power to predict kidney allograft outcomes based on non-invasive assays is limited. Assessment of operational tolerance (OT) patients allows us to identify...
BACKGROUND
The power to predict kidney allograft outcomes based on non-invasive assays is limited. Assessment of operational tolerance (OT) patients allows us to identify transcriptomic signatures of true non-responders for construction of predictive models.
METHODS
In this observational retrospective study, RNA sequencing of peripheral blood was used in a derivation cohort to identify a protective set of transcripts by comparing 15 OT patients (40% females), from the TOMOGRAM Study (NCT05124444), 14 chronic active antibody-mediated rejection (CABMR) and 23 stable graft function patients ≥15 years (STA). The selected differentially expressed transcripts between OT and CABMR were used in a validation cohort (n = 396) to predict 3-year kidney allograft loss at 3 time-points using RT-qPCR.
FINDINGS
Archetypal analysis and classifier performance of RNA sequencing data showed that OT is clearly distinguishable from CABMR, but similar to STA. Based on significant transcripts from the validation cohort in univariable analysis, 2 multivariable Cox models were created. A 3-transcript (ADGRG3, ATG2A, and GNLY) model from POD 7 predicted graft loss with C-statistics (C) 0.727 (95% CI, 0.638-0.820). Another 3-transcript (IGHM, CD5, GNLY) model from M3 predicted graft loss with C 0.786 (95% CI, 0.785-0.865). Combining 3-transcripts models with eGFR at POD 7 and M3 improved C-statistics to 0.860 (95% CI, 0.778-0.944) and 0.868 (95% CI, 0.790-0.944), respectively.
INTERPRETATION
Identification of transcripts distinguishing OT from CABMR allowed us to construct models predicting premature graft loss. Identified transcripts reflect mechanisms of injury/repair and alloimmune response when assessed at day 7 or with a loss of protective phenotype when assessed at month 3.
FUNDING
Supported by the Ministry of Health of the Czech Republic under grant NV19-06-00031.
PubMed: 37660534
DOI: 10.1016/j.ebiom.2023.104782 -
JCI Insight Nov 2023Chronic lung allograft dysfunction (CLAD) is a major complication after lung transplantation that results from a complex interplay of innate inflammatory and alloimmune...
Chronic lung allograft dysfunction (CLAD) is a major complication after lung transplantation that results from a complex interplay of innate inflammatory and alloimmune factors, culminating in parenchymal and/or obliterative airway fibrosis. Excessive IL-17A signaling and chronic inflammation have been recognized as key factors in these pathological processes. Herein, we developed a model of repeated airway inflammation in mouse minor alloantigen-mismatched single-lung transplantation. Repeated intratracheal LPS instillations augmented pulmonary IL-17A expression. LPS also increased acute rejection, airway epithelial damage, and obliterative airway fibrosis, similar to human explanted lung allografts with antecedent episodes of airway infection. We then investigated the role of donor and recipient IL-17 receptor A (IL-17RA) in this context. Donor IL-17RA deficiency significantly attenuated acute rejection and CLAD features, whereas recipient IL-17RA deficiency only slightly reduced airway obliteration in LPS allografts. IL-17RA immunofluorescence positive staining was greater in human CLAD lungs compared with control human lung specimens, with localization to fibroblasts and myofibroblasts, which was also seen in mouse LPS allografts. Taken together, repeated airway inflammation after lung transplantation caused local airway epithelial damage, with persistent elevation of IL-17A and IL-17RA expression and particular involvement of IL-17RA on donor structural cells in development of fibrosis.
Topics: Mice; Humans; Animals; Interleukin-17; Receptors, Interleukin-17; Lipopolysaccharides; Pulmonary Fibrosis; Lung; Inflammation; Fibrosis; Respiratory Tract Infections; Allografts
PubMed: 37937643
DOI: 10.1172/jci.insight.158002 -
Journal of Medicine and Life Jul 2023The D antigen of the Rh blood group is considered clinically significant due to its ability to cause hemolytic transfusion reactions and hemolytic disease in the fetus... (Meta-Analysis)
Meta-Analysis Review
The D antigen of the Rh blood group is considered clinically significant due to its ability to cause hemolytic transfusion reactions and hemolytic disease in the fetus and newborn. This systematic review discusses the prevalence of RhD variants among pregnant women and the importance of including RhD genotyping for prenatal testing to detect RhD variants and prevent anti-D alloimmunization. A comprehensive literature search was conducted using scientific search engines, including PubMed and MEDLINE databases, with the keywords 'anti-D alloimmunization', 'RhD variant', and 'pregnant women.' The review adhered to the PRISMA guidelines. Meta-analysis was performed using MedCalc version 20. A significance level of p≤0.05 was considered statistically significant for all two-tailed tests. The meta-analysis included four articles that met the inclusion criteria. The total prevalence of RhD positivity (RhD+) was 61% (95% CI:34%-85%). The prevalence ranged from 22% to 82%, indicating a high degree of heterogeneity between studies (I2=98.71%, p<0.0001). The overall prevalence of D variants was 15% (95% CI, 9%-23%) with a prevalence of 0.05% to 100%, showing a high degree of heterogeneity between studies (I2=99.89%, p<0.0001). Anti-D alloimmunization could occur in pregnant women with some types of RhD variants. All four studies focused on molecular testing of samples showing inconsistent or weak results with at least two anti-D antibodies using serological methods.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Pregnant Women; Fetus; Prevalence
PubMed: 37900088
DOI: 10.25122/jml-2023-0004 -
Immunological platelet transfusion refractoriness: current insights from mechanisms to therapeutics.Platelets Dec 2024Although there have been tremendous improvements in the production and storage of platelets, platelet transfusion refractoriness (PTR) remains a serious clinical issue... (Review)
Review
Although there have been tremendous improvements in the production and storage of platelets, platelet transfusion refractoriness (PTR) remains a serious clinical issue that may lead to various severe adverse events. The burden of supplying platelets is worsened by rising market demand and limited donor pools of compatible platelets. Antibodies against platelet antigens are known to activate platelets through FcγR-dependent or complement-activated channels, thereby rapidly eliminating foreign platelets. Recently, other mechanisms of platelet clearance have been reported. The current treatment strategy for PTR is to select appropriate and compatible platelets; however, this necessitates a sizable donor pool and technical assistance for costly testing. Consolidation of these mechanisms should be of critical significance in providing insight to establish novel therapeutics to target immunological platelet refractoriness. Therefore, the purposes of this review were to explore the modulation of the immune system over the activation and elimination of allogeneic platelets and to summarize the development of alternative approaches for treating and avoiding alloimmunization to human leukocyte antigen or human platelet antigen in PTR.
Topics: Humans; Platelet Transfusion; Blood Platelets; Thrombocytopenia; Antigens, Human Platelet; HLA Antigens
PubMed: 38314765
DOI: 10.1080/09537104.2024.2306983 -
Frontiers in Immunology 2023Despite the advances in therapeutic interventions, solid organ transplantation (SOT) remains the "gold standard" treatment for patients with end-stage organ failure.... (Review)
Review
Despite the advances in therapeutic interventions, solid organ transplantation (SOT) remains the "gold standard" treatment for patients with end-stage organ failure. Recently, vascularized composite allotransplantation (VCA) has reemerged as a feasible treatment option for patients with complex composite tissue defects. In both SOT and VCA, ischemia reperfusion injury (IRI) is inevitable and is a predominant factor that can adversely affect transplant outcome by potentiating early graft dysfunction and/or graft rejection. Restoration of oxygenated blood supply to an organ which was previously hypoxic or ischemic for a period of time triggers cellular oxidative stress, production of both, pro-inflammatory cytokines and chemokines, infiltration of innate immune cells and amplifies adaptive alloimmune responses in the affected allograft. Currently, Food and Drug Administration (FDA) approved drugs for the treatment of IRI are unavailable, therefore an efficacious therapeutic modality to prevent, reduce and/or alleviate allograft damages caused by IRI induced inflammation is warranted to achieve the best-possible transplant outcome among recipients. The tolerogenic capacity of CD4CD25FOXP3 regulatory T cells (Tregs), have been extensively studied in the context of transplant rejection, autoimmunity, and cancer. It was not until recently that Tregs have been recognized as a potential cell therapeutic candidate to be exploited for the prevention and/or treatment of IRI, owing to their immunomodulatory potential. Tregs can mitigate cellular oxidative stress, produce anti-inflammatory cytokines, promote wound healing, and tissue repair and prevent the infiltration of pro-inflammatory immune cells in injured tissues. By using strategic approaches to increase the number of Tregs and to promote targeted delivery, the outcome of SOT and VCA can be improved. This review focuses on two sections: (a) the therapeutic potential of Tregs in preventing and mitigating IRI in the context of SOT and VCA and (b) novel strategies on how Tregs could be utilized for the prevention and/or treatment of IRI.
Topics: Humans; Allografts; Cytokines; Forkhead Transcription Factors; Reperfusion Injury; T-Lymphocytes, Regulatory
PubMed: 37868962
DOI: 10.3389/fimmu.2023.1270300 -
The Journal of Heart and Lung... May 2024Engineering donor organs to better tolerate the harmful non-immunological and immunological responses inherently related to solid organ transplantation would improve... (Review)
Review
Engineering donor organs to better tolerate the harmful non-immunological and immunological responses inherently related to solid organ transplantation would improve transplant outcomes. Our enhanced knowledge of ischemia-reperfusion injury, alloimmune responses and pathological fibroproliferation after organ transplantation, and the advanced toolkit available for gene therapies, have brought this goal closer to clinical reality. Ex vivo organ perfusion has evolved rapidly especially in the field of lung transplantation, where clinicians routinely use ex vivo lung perfusion (EVLP) to confirm the quality of marginal donor lungs before transplantation, enabling safe transplantation of organs originally considered unusable. EVLP would also be an attractive platform to deliver gene therapies, as treatments could be administered to an isolated organ before transplantation, thereby providing a window for sophisticated organ engineering while minimizing off-target effects to the recipient. Here, we review the status of lung transplant first-generation gene therapies that focus on inducing transgene expression in the target cells. We also highlight recent advances in next-generation gene therapies, that enable gene editing and epigenetic engineering, that could be used to permanently change the donor organ genome and to induce widespread transcriptional gene expression modulation in the donor lung. In a future vision, dedicated organ repair and engineering centers will use gene editing and epigenetic engineering, to not only increase the donor organ pool, but to create superior organs that will function better and longer in the recipient.
Topics: Lung Transplantation; Humans; Genetic Therapy; Perfusion; Lung; Organ Preservation; Animals
PubMed: 38310996
DOI: 10.1016/j.healun.2024.01.016 -
Frontiers in Immunology 2023Antibody-mediated rejection is the leading cause of kidney graft dysfunction. The process of diagnosing it requires the performance of an invasive biopsy and subsequent... (Review)
Review
Antibody-mediated rejection is the leading cause of kidney graft dysfunction. The process of diagnosing it requires the performance of an invasive biopsy and subsequent histological examination. Early and sensitive biomarkers of graft damage and alloimmunity are needed to identify graft injury and eventually limit the need for a kidney biopsy. Moreover, other scenarios such as delayed graft function or interstitial fibrosis and tubular atrophy face the same problem. In recent years, interest has grown around extracellular vesicles, specifically exosomes actively secreted by immune cells, which are intercellular communicators and have shown biological significance. This review presents their potential as biomarkers in kidney transplantation and alloimmunity.
Topics: Kidney Transplantation; Extracellular Vesicles; Kidney; Exosomes; Biomarkers
PubMed: 37662919
DOI: 10.3389/fimmu.2023.1154650 -
Cureus Aug 2023Neutropenia, characterized by a decrease in peripheral blood neutrophil count less than 1500/µL, poses significant clinical challenges due to its association with...
Neutropenia, characterized by a decrease in peripheral blood neutrophil count less than 1500/µL, poses significant clinical challenges due to its association with recurrent infections. This paper presents a rare and intriguing case of alloimmune neonatal neutropenia (ANN), an uncommon variant of neutropenia instigated by the transplacental transfer of maternal anti-neutrophil antibodies that consequently induce opsonization and phagocytosis of the neonate's neutrophils within the reticuloendothelial system. The patient, an 18-day-old boy, was born at 36 weeks five days of gestation and weighed 2465 g, an attribute considered appropriate for gestational age (AGA). He experienced multiple episodes of skin and respiratory infections, coupled with delayed umbilical cord separation and demonstrated a significant reduction in neutrophil count. Despite these symptoms, the patient did not develop bacteremia and his condition improved with antibiotic therapy, leading to his discharge from the hospital. Crucially, both the patient and his mother tested positive for anti-HNA (human neutrophil alloantigen)-1a and anti-HNA-1b antibodies, indicative of a diagnosis of ANN. ANN is intriguing in its clinical course, where despite neutropenia, severe infections are relatively uncommon, and the majority of cases resolve spontaneously within several months post-birth as the maternal antibodies diminish. Nevertheless, there have been reports of moderate to severe infections, demanding clinical intervention and close patient monitoring. The patient in our case was treated with prophylactic antibiotics for six weeks, until a rise in neutrophil count was confirmed, stemming from the severity and recurrence of infections. The issue of using antibiotics and granulocyte colony-stimulating factor (G-CSF) agents in the treatment of ANN remains contentious, with contrasting reports regarding their efficacy and safety. The balance between the prospective therapeutic advantages, potential risks such as antibiotic resistance, and the possibility of inducing leukemia with long-term administration of G-CSF agents necessitates meticulous deliberation. This case underscores the crucial role of early recognition of ANN in neonates presenting with neutropenia. Prompt diagnosis enables a more targeted approach to treatment, reduction in unnecessary antibiotic administration, and specific testing, thus impacting the overall patient management and potentially improving outcomes. Furthermore, in the event of delayed umbilical cord separation in neonates, healthcare providers should consider ANN and other immunodeficiencies related to neutrophil functional abnormalities as potential diagnoses. This patient's story accentuates the need for further investigations to elucidate the precise etiology and pathogenesis of ANN, paving the way for improved diagnostic tools and effective therapeutic strategies.
PubMed: 37791226
DOI: 10.7759/cureus.44409 -
Transplantation Direct Nov 2023Despite advances in posttransplant care, long-term outcomes for liver transplant recipients remain unchanged. Approximately 25% of recipients will advance to graft... (Review)
Review
Despite advances in posttransplant care, long-term outcomes for liver transplant recipients remain unchanged. Approximately 25% of recipients will advance to graft cirrhosis and require retransplantation. Graft fibrosis progresses in the context of de novo or recurrent disease. Recurrent hepatitis C virus infection was previously the most important cause of graft failure but is now curable in the majority of patients. However, with an increasing prevalence of obesity and diabetes and nonalcoholic fatty liver disease as the most rapidly increasing indication for liver transplantation, metabolic dysfunction-associated liver injury is anticipated to become an important cause of graft fibrosis alongside alloimmune hepatitis and alcoholic liver disease. To better understand the landscape of the graft fibrosis literature, we summarize the associated epidemiology, cause, potential mechanisms, diagnosis, and complications. We additionally highlight the need for better noninvasive methods to ameliorate the management of graft fibrosis. Some examples include leveraging the microbiome, genetic, and machine learning methods to address these limitations. Overall, graft fibrosis is routinely seen by transplant clinicians, but it requires a better understanding of its underlying biology and contributors that can help inform diagnostic and therapeutic practices.
PubMed: 37854023
DOI: 10.1097/TXD.0000000000001547