Advances In Immunology Research Articles

Extreme immunotherapy: emergency immunology to defeat pandemics

The ongoing global COVID-19 pandemic has thrown into sharp relief the gap between modern biology’s ability to investigate and respond to a novel pathogen and modern medicine’s ability to marshal effective front-line interventions to limit its immediate health impact. While we have witnessed the rapid development of innovative vaccines against SARS-CoV-2 using novel molecular platforms, these have yet to alter the pandemic’s long-term trajectory in all but a handful of high-income countries. Health workers at the clinical front lines have little more in their clinical armamentarium than was available a century ago—chiefly oxygen and steroids—and yet advances in modern immunology and immunotherapeutics suggest an underuse of extant and effective, if unorthodox, therapies, which we now call “Extreme Immunotherapies for Pandemics (EIPs).”

Changes in expression of PD-L1 on peripheral T cells in patients with melanoma and lung cancer treated with PD-1 inhibitors

Advances in cancer immunology have increased the use of immune checkpoint inhibitors in clinical practice, however not all patients respond, and treatment can have severe side-effects. Blood-based immunological biomarkers are an attractive method for predicting which patients will respond to therapy, however, reliable biomarkers for immune checkpoint blockade are lacking. This study aimed to identify patients before or early in treatment who would best respond to PD-1 inhibitors. We hypothesised that higher baseline PD-L1 and/or PD-1 on peripheral blood T cells could predict radiological response to PD-1 inhibitors. This pilot prospective cohort study assessed 26 patients with melanoma or non-small cell lung cancer, treated with pembrolizumab, nivolumab, or nivolumab/ipilimumab combined. Response was assessed by RECIST 1.1. Peripheral blood lymphocytes collected at baseline, after one cycle, 10 weeks and at discontinuation of therapy were analysed by flow cytometry. Patients with a higher proportion of PD-L1+ T cells at baseline had improved objective response to PD-1 inhibitor therapy, and patients with a lower proportion of regulatory T cells at baseline experienced more immune-related adverse events. These findings may prove useful to assist in clinical decision making. Further studies with larger cohorts are required to validate these findings.

Trained Innate Immunity in Hematopoietic Stem Cell and Solid Organ Transplantation.

Although significant progress has been made to improve short-term survival of transplant patients, long-term acceptance of allografts in solid organ and hematopoietic stem cell (HSC) transplantation is still a significant challenge. Current therapeutics for preventing or treating allograft rejection rely on potent immunosuppressive drugs that primarily target T cells of the adaptive immune response. Promising advances in transplant immunology have highlighted the importance of innate immune responses in allograft acceptance and rejection. Recent studies have demonstrated that innate immune cells are capable of mediating memory-like responses during inflammation, a term known as trained innate immunity. In this process, innate immune cells, such as macrophages and monocytes, undergo metabolic and epigenetic changes in response to a primary stimulus with a pathogen or their products that result in faster and more robust responses to a secondary stimulus. There is also some evidence to suggest that innate immune cells or their progenitors may be more anti-inflammatory after initial stimulation with appropriate agents, such as helminth products. Although this phenomenon has primarily been studied in the context of infection, there is emerging evidence to suggest that it could play a vital role in transplantation rejection and tolerance. Mechanisms of training innate immune cells and their progenitors in the bone marrow are therefore attractive targets for mediating long-term solid organ and HSC transplant tolerance. In this review, we highlight the potential role of proinflammatory and anti-inflammatory mechanisms of trained innate immunity in solid organ and HSC transplantation.

Application of natural killer cells in pancreatic cancer.

Pancreatic cancer, a highly malignant disease, is characterized by rapid progression and early metastasis. Although the integrative treatment of pancreatic cancer has made great progress, the prognosis of patients with advanced pancreatic cancer remains extremely poor. In recent years, with the advancements in tumor immunology, immunotherapy has become a promising remedy for pancreatic cancer. Natural killer (NK) cells are the key lymphocytes in the innate immune system. NK cell function does not require antigen pre-sensitization and is not major histocompatibility complex restricted. By targeting tumors or virus-infected cells, the cells play a key role in immune surveillance. Although several questions about NK cells in pancreatic cancer still need to be further studied, there are extensive theories supporting the clinical application prospects of NK cell immunotherapy in pancreatic cancer. Since very few studies have evaluated the role of NK cells in pancreatic cancer, this review provides a comprehensive update of the role of NK cells in pancreatic cancer immunotherapy.

Visual Genomics Analysis Studio as a Tool to Analyze Multiomic Data.

Type B adverse drug reactions (ADRs) are iatrogenic immune-mediated syndromes with mechanistic etiologies that remain incompletely understood. Some of the most severe ADRs, including delayed drug hypersensitivity reactions, are T-cell mediated, restricted by specific human leukocyte antigen risk alleles and sometimes by public or oligoclonal T-cell receptors (TCRs), central to the immunopathogenesis of tissue-damaging response. However, the specific cellular signatures of effector, regulatory, and accessory immune populations that mediate disease, define reaction phenotype, and determine severity have not been defined. Recent development of single-cell platforms bringing together advances in genomics and immunology provides the tools to simultaneously examine the full transcriptome, TCRs, and surface protein markers of highly heterogeneous immune cell populations at the site of the pathological response at a single-cell level. However, the requirement for advanced bioinformatics expertise and computational hardware and software has often limited the ability of investigators with the understanding of diseases and biological models to exploit these new approaches. Here we describe the features and use of a state-of-the-art, fully integrated application for analysis and visualization of multiomic single-cell data called Visual Genomics Analysis Studio (VGAS). This unique user-friendly, Windows-based graphical user interface is specifically designed to enable investigators to interrogate their own data. While VGAS also includes tools for sequence alignment and identification of associations with host or organism genetic polymorphisms, in this review we focus on its application for analysis of single-cell TCR–RNA–Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE)-seq, enabling holistic cellular characterization by unbiased transcriptome and select surface proteome. Critically, VGAS does not require user-directed coding or access to high-performance computers, instead incorporating performance-optimized hidden code to provide application-based fast and intuitive tools for data analyses and production of high-resolution publication-ready graphics on standard specification laptops. Specifically, it allows analyses of comprehensive single-cell TCR sequencing (scTCR-seq) data, detailing (i) functional pairings of α–β heterodimer TCRs, (ii) one-click histograms to display entropy and gene rearrangements, and (iii) Circos and Sankey plots to visualize clonality and dominance. For unbiased single-cell RNA sequencing (scRNA-seq) analyses, users extract cell transcriptome signatures according to global structure via principal component analysis, t-distributed stochastic neighborhood embedding, or uniform manifold approximation and projection plots, with overlay of scTCR-seq enabling identification and selection of the immunodominant TCR-expressing populations. Further integration with similar sequence-based detection of surface protein markers using oligo-labeled antibodies (CITE-seq) provides comparative understanding of surface protein expression, with differential gene or protein analyses visualized using volcano plot or heatmap functions. These data can be compared to reference cell atlases or suitable controls to reveal discrete disease-specific subsets, from epithelial to tissue-resident memory T-cells, and activation status, from senescence through exhaustion, with more finite transcript expression displayed as violin and box plots. Importantly, guided tutorial videos are available, as are regular application updates based on the latest advances in bioinformatics and user feedback.

Augmenting the Transplant Team With Artificial Intelligence: Toward Meaningful AI Use in Solid Organ Transplant.

Advances in systems immunology, such as new biomarkers, offer the potential for highly personalized immunosuppression regimens that could improve patient outcomes. In the future, integrating all of this information with other patient history data will likely have to rely on artificial intelligence (AI). AI agents can help augment transplant decision making by discovering patterns and making predictions for specific patients that are not covered in the literature or in ways that are impossible for humans to anticipate by integrating vast amounts of data (e.g. trending across numerous biomarkers). Similar to other clinical decision support systems, AI may help overcome human biases or judgment errors. However, AI is not widely utilized in transplant to date. In this rapid review, we survey the methods employed in recent research in transplant-related AI applications and identify concerns related to implementing these tools. We identify three key challenges (bias/accuracy, clinical decision process/AI explainability, AI acceptability criteria) holding back AI in transplant. We also identify steps that can be taken in the near term to help advance meaningful use of AI in transplant (forming a Transplant AI Team at each center, establishing clinical and ethical acceptability criteria, and incorporating AI into the Shared Decision Making Model).

The hidden history of hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is a relatively new construct, first reported in the early 20th century, despite major aetiological factors (farming, bird husbandry) having been part of human activities for millennia. Initial confirmed HP reports included exposure to farming and forestry (1932) and bird exposure (1965), much more recently than is often assumed. Later changes in occupational and living practices have led to HP associated with isocyanates, machine coolants, indoor mould, hot tubs and other exposures. Evolution of our pathological understanding of interstitial lung disease in general, wider computed tomography utilisation and advances in immunology and genomics have shaped our modern conceptualisation of HP. Examining historical accounts of HP and its causative factors not only considers when the first cases were recognised, but also explores why the disease emerged at specific times and places, and may provide further insights relevant to the mechanisms underlying HP and disease prevention.

Biomarkers for Early Complications of Endothelial Origin After Allogeneic Hematopoietic Stem Cell Transplantation: Do They Have a Potential Clinical Role?

Endothelial cell (EC) dysfunction causes a number of early and life-threatening post hematopoietic stem cell transplant (HCT) complications that result in a rapid clinical decline. The main early complications are graft-vs.-host disease (GVHD), transplant associated thrombotic microangiopathy (TA-TMA), and sinusoidal obstruction syndrome (SOS). Post-HCT endothelial dysfunction occurs as a result of chemotherapy, infections, and allogeneic reactivity. Despite major advances in transplant immunology and improvements in supportive care medicine, these complications represent a major obstacle for successful HCT. In recent years, different biomarkers have been investigated for early detection of post-transplant endothelial cell dysfunction, but few have been validated. In this review we will define GVHD, TA-TMA and SOS, summarize the current data available in HCT biomarker research and identify promising biomarkers for detection and diagnosis of early HCT complications.

Uveitis: Molecular Pathogenesis and Emerging Therapies.

The profound impact that vision loss has on human activities and quality of life necessitates understanding the etiology of potentially blinding diseases and their clinical management. The unique anatomic features of the eye and its sequestration from peripheral immune system also provides a framework for studying other diseases in immune privileged sites and validating basic immunological principles. Thus, early studies of intraocular inflammatory diseases (uveitis) were at the forefront of research on organ transplantation. These studies laid the groundwork for foundational discoveries on how immune system distinguishes self from non-self and established current concepts of acquired immune tolerance and autoimmunity. Our charge in this review is to examine how advances in molecular cell biology and immunology over the past 3 decades have contributed to the understanding of mechanisms that underlie immunopathogenesis of uveitis. Particular emphasis is on how advances in biotechnology have been leveraged in developing biologics and cell-based immunotherapies for uveitis and other neuroinflammatory diseases.

Immune-Mediated Drug-Induced Liver Injury: Immunogenetics and Experimental Models.

Drug-induced liver injury (DILI) is a challenging clinical event in medicine, particularly because of its ability to present with a variety of phenotypes including that of autoimmune hepatitis or other immune mediated liver injuries. Limited diagnostic and therapeutic tools are available, mostly because its pathogenesis has remained poorly understood for decades. The recent scientific and technological advancements in genomics and immunology are paving the way for a better understanding of the molecular aspects of DILI. This review provides an updated overview of the genetic predisposition and immunological mechanisms behind the pathogenesis of DILI and presents the state-of-the-art experimental models to study DILI at the pre-clinical level.

Overcoming Immunological Challenges Limiting Capsid-Mediated Gene Therapy With Machine Learning.

A key hurdle to making adeno-associated virus (AAV) capsid mediated gene therapy broadly beneficial to all patients is overcoming pre-existing and therapy-induced immune responses to these vectors. Recent advances in high-throughput DNA synthesis, multiplexing and sequencing technologies have accelerated engineering of improved capsid properties such as production yield, packaging efficiency, biodistribution and transduction efficiency. Here we outline how machine learning, advances in viral immunology, and high-throughput measurements can enable engineering of a new generation of de-immunized capsids beyond the antigenic landscape of natural AAVs, towards expanding the therapeutic reach of gene therapy.

Augmenting the Transplant Team With Artificial Intelligence: Toward Meaningful AI Use in Transplant

Advances in systems immunology, such as new biomarkers, offer the potential for highly personalized immunosuppression regimens that could improve patient outcomes. In the future, integrating all of this information with other patient history data will likely have to rely on artificial intelligence (AI). AI agents can help augment transplant decisionmaking by discovering patterns and making predictions for specific patients that are not covered in the literature or in ways that are impossible for humans to anticipate by integrating vast amounts of data (e.g. trending across numerous biomarkers). Similar to other clinical decision support systems, AI may help overcome human biases or judgment errors. However, AI is not widely utilized in transplant to date. In this rapid review, we survey the methods employed in recent research in transplant-related AI applications and identify concerns related to implementing these tools. We identify three key challenges (bias/accuracy, clinical decision process/AI explainability, AI acceptability criteria) holding back AI in transplant. We also identify steps that can be taken in the near term to help advance meaningful use of AI in transplant (forming a Transplant AI Team at each center, establishing clinical and ethical acceptability criteria, and incorporating AI into the Shared Decision Making Model).

Data silos are undermining drug development and failing rare disease patients

Data silos are proliferating while research and development activity explode following genetic and immunological advances for many clinically described disorders with previously unknown etiologies. The latter event has inspired optimism in the patient, clinical, and research communities that disease-specific treatments are on the way. However, we fear the tendency of various stakeholders to balkanize databases in proprietary formats, driven by current economic and academic incentives, will inevitably fragment the expanding knowledge base and undermine current and future research efforts to develop much-needed treatments. The proliferation of proprietary databases, compounded by a paucity of meaningful outcome measures and/or good natural history data, slows our ability to generate scalable solutions to benefit chronically underserved patient populations in ways that would translate to more common diseases. The current research and development landscape sets too many projects up for unnecessary failure, particularly in the rare disease sphere, and does a grave disservice to highly vulnerable patients. This system also encourages the collection of redundant data in uncoordinated parallel studies and registries to ultimately delay or deny potential treatments for ostensibly tractable diseases; it also promotes the waste of precious time, energy, and resources. Groups at the National Institutes of Health and Food and Drug Administration have started programs to address these issues. However, we and many others feel there should be significantly more discussion of how to coordinate and scale registry efforts. Such discourse aims to reduce needless complexity and duplication of efforts, as well as promote a pre-competitive knowledge ecosystem for rare disease drug development that cultivates and accelerates innovation.

T Cells as the Future of Cancer Therapy.

In the next 10 years, gene-engineered T-cell therapies have the potential to provide broad benefit for the treatment of patients with cancer. Advances in immunology, molecular biology, and bioengineering allow the design of gene-engineered T cells that actively target metastatic lesions, specifically recognize and kill cancer cells, and maintain long-term immunologic memory.

Antibody Therapy: From Diphtheria to Cancer, COVID-19, and Beyond

The dawn of the 20th century saw the formative years of developments in immunology. In particular, immunochemistry, specifically pertaining to antibodies, was extensively studied. These studies laid the foundations for employing antibodies in a variety of ways. Not surprisingly, antibodies have been used for applications ranging from biomedical research to disease diagnostics and therapeutics to evaluation of immune responses during natural infection and those elicited by vaccines. Despite recent advancements in cellular immunology and the excitement of T cell therapy, use of antibodies represents a large proportion of immunotherapeutic approaches as well as clinical interventions. Polyclonal antibodies in the form of plasma or sera continue to be used to treat a number of diseases, including autoimmune disorders, cancers, and infectious diseases. Historically, antisera to toxins have been the longest serving biotherapeutics. In addition, intravenous immunoglobulins (IVIg) have been extensively used to treat not only immunodeficiency conditions but also autoimmune disorders. Beyond the simplistic suppositions of their action, the IVIg have also unraveled the immune regulatory and homeostatic ramifications of their use. The advent of monoclonal antibodies (MAbs), on the other hand, has provided a clear pathway for their development as drug molecules. MAbs have found a clear place in the treatment of cancers and extending lives and have been used in a variety of other conditions. In this review, we capture the important developments in the therapeutic applications of antibodies to alleviate disease, with a focus on some of the recent developments.

MiRNAs and lncRNAs as Novel Therapeutic Targets to Improve Cancer Immunotherapy.

Simple SummaryCancer onset and progression are promoted by high deregulation of the immune system. Recently, major advances in molecular and clinical cancer immunology have been achieved, offering new agents for the treatment of common tumors, often with astonishing benefits in terms of prolonged survival and even cure. Unfortunately, most tumors are still resistant to current immune therapy approaches, and basic knowledge of the resistance mechanisms is eagerly awaited. We focused our attention on noncoding RNAs, a class of RNA that regulates many biological processes by targeting selectively crucial molecular pathways and that, recently, had their role in cancer cell immune escape and modulation of the tumor microenvironment identified, suggesting their function as promising immunotherapeutic targets. In this scenario, we point out that noncoding RNAs are progressively emerging as immunoregulators, and we depict the current information on the complex network involving the immune system and noncoding RNAs and the promising therapeutic options under investigation. Novel opportunities are emerging from noncoding-RNAs for the treatment of immune-refractory tumors.Immunotherapy is presently one of the most promising areas of investigation and development for the treatment of cancer. While immune checkpoint-blocking monoclonal antibodies and chimeric antigen receptor (CAR) T-cell-based therapy have recently provided in some cases valuable therapeutic options, the goal of cure has not yet been achieved for most malignancies and more efforts are urgently needed. Noncoding RNAs (ncRNA), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), regulate several biological processes via selective targeting of crucial molecular signaling pathways. Recently, the key roles of miRNA and lncRNAs as regulators of the immune-response in cancer have progressively emerged, since they may act (i) by shaping the intrinsic tumor cell and microenvironment (TME) properties; (ii) by regulating angiogenesis, immune-escape, epithelial-to-mesenchymal transition, invasion, and drug resistance; and (iii) by acting as potential biomarkers for prognostic assessment and prediction of response to immunotherapy. In this review, we provide an overview on the role of ncRNAs in modulating the immune response and the TME. We discuss the potential use of ncRNAs as potential biomarkers or as targets for development or clinical translation of new therapeutics. Finally, we discuss the potential combinatory approaches based on ncRNA targeting agents and tumor immune-checkpoint inhibitor antibodies or CAR-T for the experimental treatment of human cancer.

Interior Resistance

The interior frequently masquerades a resistance to being clean, often demonstrating different levels of hygiene, containment, and control. Yet, it is the–body–inside that simultaneously resists and distributes infection within the mineral contexts of the building. Ever since Van Leeuwenhoek's (1993) discovery of a strange microbial world of bacteria and protozoa, societal, bodily, and spatial interpretations of clean have shifted. Evolving levels of cleanliness continually reposition the interior to become progressively more visually hygienic and meticulously super–clean. While medical need often leads and intensifies infection control, it is personal fastidiousness, compulsion, and media image that shape human attitudes and cultures to grime and dirt. Historically, “homes–of–the–future” reinforce a technologically sanitized prototype, a strain of which persists in the sterility of the ordered “show–home.” Each avoids the pathogenic realities of the–body–inside revealing esthetic traces of the Modernist ideals of clean lines and clean living that recur in contemporary images of minimal occupation. As we move to develop new hyper–clean and locked–down pandemic–proof interiors capable of immunizing and shielding occupants, this paper re–evaluates what it means to be clean and how the interior helps to resist and mediate these efforts. As concerns over antimicrobial resistance and interior touching increases, our protection from allergy, disease, and contagion are changing. The interior is increasingly playing a critical role in arbitrating biological infection, either through intelligent cleaning systems, infrastructure, or material science. This paper sets out the existing resistance to, and the conditions for, a new clean interior and posits where and what the future might conceive, including the advancement of immunology by reintroducing “dirt” back into interiors (mirroring Edward Jenner's deliberate infection of humans to develop resistance to smallpox) enabling better biological resistant to the outside world.

Thromboembolic Adverse Drug Reactions in Janus Kinase (JAK) Inhibitors: Does the Inhibitor Specificity Play a Role?

Recent advances in immunology enabled the characterization of several signal transmitting pathways responsible for proper cytokine and chemokine signaling. Among them, Janus kinases (JAKs) are essential components of receptor activation systems. The discovery of JAK kinases enabled the synthesis of JAK kinase inhibitors (JAKi or Jakinibs), which have proven to be efficacious in the treatment of hematologic malignancies and several rheumatological disorders and continue to be investigated in many clinical indications. Blocking multiple cytokines belonging to several cytokine families with a single small molecule may, however, create a potential risk for the patients. Recently, a higher risk of thromboembolic complications, namely, deep vein thrombosis and pulmonary embolism, has been recognized as the main concern during treatment with Jakinibs. At present, it is not entirely clear whether this increased risk is related to direct cytokine blockade, the presence of concomitant diseases in treated patients or other unknown circumstances that work together to increase the risk of this side effect. In this review, we discuss data on the risk of thromboembolic side effects, with special emphasis on the mechanism that may be responsible for this increased risk. Many indirect data indicate that higher thromboembolic risk may be related to the specificity of JAK inhibitor action, such that preferentially blocking one signaling pathway upsets the balance between pro and anti-thrombotic activities.

Decision-Making in the Era of New Medical Technologies in Pediatric Hematology-Oncology: The Death of Palliative Care?

Recent advances in immunology, genomics, and cellular therapy have opened numerous therapeutic possibilities in pediatric hematology-oncology, generating new hope in poor prognosis situations. How decisions are made when it comes to treatments and aims needs to be explored in this new technologic context. In particular, their impact on the gold standard of early referral to palliative care must be assessed. Stemming from an ethnographic study combining semistructured interviews and observations carried out in a hematopoietic stem cell transplant unit in a Montréal Pediatric Hospital, we discuss the decision-making process when a patient faces poor prognosis. Although health care providers individually envisioned that palliative care may be the best course of action for patients receiving emergent therapy, they remained collectively in the curative mode. The intricate relationship between science, hope, caregiver, and care receiver sustains this perspective even when (near) death is the probable outcome. When proven treatment fails, emerging therapeutic possibilities offer new hope that can delay the referral to the palliative care team.

Cardiovascular Danger Disease in Patients with Microcirculation Factors in Multiple Sclerosis

Different sclerosis (MS) is a neurodegenerative issue that influences the focal sensory system (CNS), saving the fringe sensory system and uncovering its first signs in early adulthood, with a variable clinical course going from a harmless condition to a quickly developing debilitating infection. MS is the most widely recognized infection of the CNS and the most well-known reason for neurological handicap in youthful grown-ups, influencing around 2.5 million around the world, with variable movement and guess. The occurrence and commonness paces of MS shift significantly among locales and populaces, showing a run of the mill latitudinal slope most likely because of hereditary and social varieties. Europe is viewed as a high recurrence region for MS (predominance ≥ 30/100,000); other high commonness locales incorporate the northern USA, Israel, Canada, Southern Australia, New Zealand and Eastern Russia. Constant aggravation, perivenular binding, demyelization, gliosis and neuronal misfortune are signs of the pathology, creating plaque development and tissue annihilation in the white matter as well as in the cerebral cortex. In spite of significant advances in immunology and atomic science, MS is ineffectively perceived concerning etiology and its resistant trigger and causal pathways are generously obscure. Additionally, how etiopathological instruments impact the course of this illness stays indistinct. Studies with attractive reverberation imaging (MRI) have exhibited that white matter injuries correspond feebly with neurological handicap and longitudinal examinations including MS patients have shown sped up dark matter decay as result of dim matter sores. Dark matter (GM) decay corresponds with physical and psychological handicap more unequivocally than white matter decay. Numerous hypotheses have been created, and numerous potential causes have been distinguished: hereditary inclination, ecological components, contaminations, vascular danger factors, and horrible mind injury.