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Cell Death and Differentiation Jun 2021Upregulation of programmed death ligand 1 (PD-L1) helps tumor cells escape from immune surveillance, and therapeutic antibodies targeting PD-1/PD-L1 have shown better...
Upregulation of programmed death ligand 1 (PD-L1) helps tumor cells escape from immune surveillance, and therapeutic antibodies targeting PD-1/PD-L1 have shown better patient outcomes only in several types of malignancies. Recent studies suggest that the clinical efficacy of anti-PD-1/PD-L1 treatments is associated with PD-L1 levels; however, the underlying mechanism of high PD-L1 protein levels in cancers is not well defined. Here, we report that the deubiquitinase OTUB1 positively regulates PD-L1 stability and mediates cancer immune responses through the PD-1/PD-L1 axis. Mechanistically, we demonstrate that OTUB1 interacts with and removes K48-linked ubiquitin chains from the PD-L1 intracellular domain in a manner dependent on its deubiquitinase activity to hinder the degradation of PD-L1 through the ERAD pathway. Functionally, depletion of OTUB1 markedly decreases PD-L1 abundance, reduces PD-1 protein binding to the tumor cell surface, and causes increased tumor cell sensitivity to human peripheral blood mononuclear cells (PBMCs)-mediated cytotoxicity. Meanwhile, OTUB1 ablation-induced PD-L1 destabilization facilitates more CD8 T cells infiltration and increases the level of IFN-γ in serum to enhance antitumor immunity in mice, and the tumor growth suppression by OTUB1 silencing could be reversed by PD-L1 overexpression. Furthermore, we observe a significant correlation between PD-L1 abundance and OTUB1 expression in human breast carcinoma. Our study reveals OTUB1 as a deubiquitinating enzyme that influences cancer immunosuppression via regulation of PD-L1 stability and may be a potential therapeutic target for cancer immunotherapy.
Topics: Adult; Animals; Cell Line, Tumor; Cysteine Endopeptidases; Deubiquitinating Enzymes; Disease Models, Animal; Healthy Volunteers; Humans; Immunosuppression Therapy; Immunotherapy; Mice; Programmed Cell Death 1 Receptor; Transfection; Up-Regulation; Young Adult
PubMed: 33328570
DOI: 10.1038/s41418-020-00700-z -
Clinical Journal of the American... Dec 2021Cardiovascular disease remains a leading cause of death and morbidity in kidney transplant recipients and a common reason for post-transplant hospitalization. Several...
Cardiovascular disease remains a leading cause of death and morbidity in kidney transplant recipients and a common reason for post-transplant hospitalization. Several traditional and nontraditional cardiovascular risk factors exist, and many of them present pretransplant and worsened, in part, due to the addition of immunosuppression post-transplant. We discuss optimal strategies for identification and treatment of these risk factors, including the emerging role of sodium-glucose cotransporter 2 inhibitors in post-transplant diabetes and cardiovascular disease. We present common types of cardiovascular disease observed after kidney transplant, including coronary artery disease, heart failure, pulmonary hypertension, arrhythmia, and valvular disease. We also discuss screening, treatment, and prevention of post-transplant cardiac disease. We highlight areas of future research, including the need for goals and best medications for risk factors, the role of biomarkers, and the role of screening and intervention.
Topics: Humans; Cardiovascular Diseases; Diabetes Mellitus; Risk Factors; Kidney Transplantation; Immunosuppression Therapy
PubMed: 34556500
DOI: 10.2215/CJN.00520121 -
Lancet (London, England) May 2020Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment.
METHODS
The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232.
FINDINGS
The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT.
INTERPRETATION
Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression.
FUNDING
The 7th EU Framework Programme.
Topics: Cell- and Tissue-Based Therapy; Dendritic Cells; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Macrophages; T-Lymphocytes, Regulatory
PubMed: 32446407
DOI: 10.1016/S0140-6736(20)30167-7 -
Cells Oct 2023Type 1 Diabetes (T1D) is an autoimmune destruction of pancreatic beta cells. The development of the Edmonton Protocol for islet transplantation in 2000 revolutionized... (Review)
Review
Type 1 Diabetes (T1D) is an autoimmune destruction of pancreatic beta cells. The development of the Edmonton Protocol for islet transplantation in 2000 revolutionized T1D treatment and offered a glimpse at a cure for the disease. In 2022, the 20-year follow-up findings of islet cell transplantation demonstrated the long-term safety of islet cell transplantation despite chronic immunosuppression. The Edmonton Protocol, however, remains limited by two obstacles: scarce organ donor availability and risks associated with chronic immunosuppression. To overcome these challenges, the search has begun for an alternative cell source. In 2006, pluripotency genomic factors, coined "Yamanaka Factors," were discovered, which reprogram mature somatic cells back to their embryonic, pluripotent form (iPSC). iPSCs can then be differentiated into specialized cell types, including islet cells. This discovery has opened a gateway to a personalized medicine approach to treating diabetes, circumventing the issues of donor supply and immunosuppression. In this review, we present a brief history of allogenic islet cell transplantation from the early days of pancreatic remnant transplantation to present work on encapsulating stem cell-derived cells. We review data on long-term outcomes and the ongoing challenges of allogenic islet cell and stem cell-derived islet cell transplant.
Topics: Humans; Islets of Langerhans Transplantation; Diabetes Mellitus, Type 1; Islets of Langerhans; Insulin-Secreting Cells; Immunosuppression Therapy
PubMed: 37887267
DOI: 10.3390/cells12202423 -
Frontiers in Immunology 2023Molecular carcinogenesis is a multistep process that involves acquired abnormalities in key biological processes. The complexity of cancer pathogenesis is best... (Review)
Review
Molecular carcinogenesis is a multistep process that involves acquired abnormalities in key biological processes. The complexity of cancer pathogenesis is best illustrated in the six hallmarks of the cancer: (1) the development of self-sufficient growth signals, (2) the emergence of clones that are resistant to apoptosis, (3) resistance to the antigrowth signals, (4) neo-angiogenesis, (5) the invasion of normal tissue or spread to the distant organs, and (6) limitless replicative potential. It also appears that non-resolving inflammation leads to the dysregulation of immune cell metabolism and subsequent cancer progression. The present article delineates immunometabolic reprogramming as a critical hallmark of cancer by linking chronic inflammation and immunosuppression to cancer growth and metastasis. We propose that targeting tumor immunometabolic reprogramming will lead to the design of novel immunotherapeutic approaches to cancer.
Topics: Humans; Neoplasms; Immunosuppression Therapy; Inflammation
PubMed: 37275901
DOI: 10.3389/fimmu.2023.1125874 -
British Journal of Anaesthesia Mar 2024Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) is a clinical endotype of chronic critical illness. PICS consists of a self-perpetuating cycle... (Review)
Review
Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) is a clinical endotype of chronic critical illness. PICS consists of a self-perpetuating cycle of ongoing organ dysfunction, inflammation, and catabolism resulting in sarcopenia, immunosuppression leading to recurrent infections, metabolic derangements, and changes in bone marrow function. There is heterogeneity regarding the definition of PICS. Currently, there are no licensed treatments specifically for PICS. However, findings can be extrapolated from studies in other conditions with similar features to repurpose drugs, and in animal models. Drugs that can restore immune homeostasis by stimulating lymphocyte production could have potential efficacy. Another treatment could be modifying myeloid-derived suppressor cell (MDSC) activation after day 14 when they are immunosuppressive. Drugs such as interleukin (IL)-1 and IL-6 receptor antagonists might reduce persistent inflammation, although they need to be given at specific time points to avoid adverse effects. Antioxidants could treat the oxidative stress caused by mitochondrial dysfunction in PICS. Possible anti-catabolic agents include testosterone, oxandrolone, IGF-1 (insulin-like growth factor-1), bortezomib, and MURF1 (muscle RING-finger protein-1) inhibitors. Nutritional support strategies that could slow PICS progression include ketogenic feeding and probiotics. The field would benefit from a consensus definition of PICS using biologically based cut-off values. Future research should focus on expanding knowledge on underlying pathophysiological mechanisms of PICS to identify and validate other potential endotypes of chronic critical illness and subsequent treatable traits. There is unlikely to be a universal treatment for PICS, and a multimodal, timely, and personalised therapeutic strategy will be needed to improve outcomes for this growing cohort of patients.
Topics: Animals; Humans; Critical Illness; Syndrome; Immunosuppression Therapy; Inflammation; Chronic Disease; Research
PubMed: 38177003
DOI: 10.1016/j.bja.2023.11.052 -
Frontiers in Immunology 2020Vascular composite allotransplantation (VCA) is a field under research and has emerged as an alternative option for the repair of severe disfiguring defects that result... (Review)
Review
Vascular composite allotransplantation (VCA) is a field under research and has emerged as an alternative option for the repair of severe disfiguring defects that result from infections or traumatic amputation in a selected group of patients. VCA is performed in centers with appropriate expertise, experience and adequate resources to effectively manage the complexity and complications of this treatment. Lifelong immunosuppressive therapy, immunosuppression associated complications, and the effects of the host immune response in the graft are major concerns in VCA. VCA is considered a quality of life transplant and the risk-benefit ratio is dissimilar to life saving transplants. Belatacept seems a promising drug that prolongs patient and graft survival in kidney transplantation and it could also be an alternative approach to VCA immunosuppression. In this review, we are summarizing current literature about the role of costimulation blockade, with a focus on belatacept in VCA.
Topics: Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Transplantation Immunology; Transplantation, Homologous; Vascularized Composite Allotransplantation
PubMed: 33042138
DOI: 10.3389/fimmu.2020.544186 -
Progress in Retinal and Eye Research Jan 2021The search for alternatives to allotransplants is driven by the shortage of corneal donors and is demanding because of the limitations of the alternatives. Indeed,... (Review)
Review
The search for alternatives to allotransplants is driven by the shortage of corneal donors and is demanding because of the limitations of the alternatives. Indeed, current progress in genetically engineered (GE) pigs, the introduction of gene-editing technology by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, and advanced immunosuppressants have made xenotransplantation a possible option for a human trial. Porcine corneal xenotransplantation is considered applicable because the eye is regarded as an immune-privileged site. Furthermore, recent non-human primate studies have shown long-term survival of porcine xenotransplants in keratoplasty. Herein, corneal immune privilege is briefly introduced, and xenogeneic reactions are compared with allogeneic reactions in corneal transplantation. This review describes the current knowledge on special issues of xenotransplantation, xenogeneic rejection mechanisms, current immunosuppressive regimens of corneal xenotransplantation, preclinical efficacy and safety data of corneal xenotransplantation, and updates of the regulatory framework to conduct a clinical trial on corneal xenotransplantation. We also discuss barriers that might prevent xenotransplantation from becoming common practice, such as ethical dilemmas, public concerns on xenotransplantation, and the possible risk of xenozoonosis. Given that the legal definition of decellularized porcine cornea (DPC) lies somewhere between a medical device and a xenotransplant, the preclinical efficacy and clinical trial data using DPC are included. The review finally provides perspectives on the current standpoint of corneal xenotransplantation in the fields of regenerative medicine.
Topics: Animals; Animals, Genetically Modified; Cornea; Corneal Transplantation; Gene Editing; Gene Regulatory Networks; Genetic Engineering; Graft Survival; Humans; Immunosuppression Therapy; Transplantation, Heterologous
PubMed: 32755676
DOI: 10.1016/j.preteyeres.2020.100876 -
Pathologica Jun 2021Autoimmune hepatitis (AIH) is a relatively rare non-resolving chronic liver disease, which mainly affects women. It is characterized by hypergammaglobulinemia,... (Review)
Review
Autoimmune hepatitis (AIH) is a relatively rare non-resolving chronic liver disease, which mainly affects women. It is characterized by hypergammaglobulinemia, circulating autoantibodies, interface hepatitis on liver histology and a favourable response to immunosuppression. The putative mechanism for the development of autoimmune hepatitis is thought to be the interaction between genetic predisposition, environmental triggers and failure of the native immune system. AIH still remains a major diagnostic and therapeutic challenge, mainly because it is a very heterogeneous disease. Prompt and timely diagnosis is crucial since, if left untreated, AIH has a high mortality rate. Histological demonstration of hepatitis is required for the diagnosis of AIH and, therefore, liver biopsy is mandatory in the initial diagnostic work-up, before treatment. In this review, we summarize the histological features of AIH with the main aim of highlighting the most important clinical-pathological hallmarks useful in the routine diagnostic practice.
Topics: Autoantibodies; Female; Hepatitis, Autoimmune; Humans; Immunosuppression Therapy
PubMed: 34294936
DOI: 10.32074/1591-951X-241 -
Journal of Nephrology Apr 2021A large number of neurological disorders can affect renal transplant recipients, potentially leading to disabling or life-threatening complications. Prevention, early... (Review)
Review
A large number of neurological disorders can affect renal transplant recipients, potentially leading to disabling or life-threatening complications. Prevention, early diagnosis and appropriate management of these conditions are critical to avoid irreversible lesions. A pivotal role in the pathogenesis of common post-transplant neurological disorders is played by immunosuppressive therapy. The most frequently administered regimen consists of triple immunosuppression, which comprises a calcineurin inhibitor (CNI), a purine synthesis inhibitor and glucocorticoids. Some of these immunosuppressive drugs may lead to neurological signs and symptoms through direct neurotoxic effects, and all of them may be responsible for the development of tumors or opportunistic infections. In this review, after a brief summary of neurotoxic pathogenetic mechanisms encompassing recent advances in the field, we focus on the clinical presentation of more common and severe immunosuppression-related neurological complications, classifying them by characteristics of urgency and anatomic site. Our goal is to provide a general framework that addresses such clinical issues with a multidisciplinary approach, as these conditions require.
Topics: Calcineurin Inhibitors; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Nervous System Diseases
PubMed: 33481222
DOI: 10.1007/s40620-020-00956-1