Malignancy-associated immune responses: Lessons from human inborn errors of immunity

It is widely understood that cancer is a significant cause of morbidity and mortality worldwide. Despite numerous available treatments, prognosis for many remains poor, thus, the development of novel therapies remains essential. Given the incredible success of many immunotherapies in this field, the important contribution of the immune system to the control, and elimination, of malignancy is clear. While many immunotherapies target higher-order pathways, for example, through promoting T-cell activation via immune checkpoint blockade, the potential to target specific immunological pathways is largely not well researched. Precisely understanding how immunity can be tailored to respond to specific challenges is an exciting idea with great potential, and may trigger the development of new therapies for cancer. Inborn Errors of Immunity (IEI) are a group of rare congenital disorders caused by gene mutations that result in immune dysregulation. This heterogeneous group, spanning widespread, multisystem immunopathology to specific immune cell defects, primarily manifest in immunodeficiency symptoms. Thus, these patients are particularly susceptible to life-threatening infection, autoimmunity and malignancy, making IEI an especially complex group of diseases. While precise mechanisms of IEI-induced malignancy have not yet been fully elucidated, analysis of these conditions can highlight the importance of particular genes, and downstream immune responses, in carcinogenesis and may help inform mechanisms which can be utilised in novel immunotherapies. In this review, we examine the links between IEIs and cancer, establishing potential connections between immune dysfunction and malignancy and suggesting roles for specific immunological mechanisms involved in preventing carcinogenesis, thus, guiding essential future research focused on cancer immunotherapy and providing valuable insight into the workings of the immune system in both health and disease.     

Desmin-Related Myopathy: Ultrastructural Findings

While murine models of autoimmune (lupus-like) glomerulonephritis have been available for sometime, it is only recently that immune and inflammatory mechanisms and molecular genetics have been extensively investigated. Genes involved in murine and human lupus nephritis have been discovered and provide insight into this disease process and provide avenues for molecular-targeted therapy. Immune modulation of murine nephritis has provided insight into novel therapy that may attenuate this disease or halt disease progression. With the advances in understanding the pathogenesis of lupus nephritis using translational research modalities, including electron microscopy, and molecular genetics, many “designer” therapies have become available for clinical use and for clinical investigational trials. This paper reviews autoimmune (lupus-like) glomerulonephritis in murine models, candidate genes involved in lupus nephritis, adhesion molecules implicated in murine lupus-like nephritis, immune modulation of murine lupus-like nephritis, and novel and potential therapy for immune complex glomerulonephritis.     

The Basic Science/Clinical Science Interface and Treatment Development

Psychological constructs often are incorporated into treatments before they are investigated systematically from a basic-science perspective. We discuss the potential costs of such a sequence of events and the potential benefits of closer working ties between basic and clinical scientists, and we consider how applying basic knowledge of cognitive processes could enhance our understanding of psychotherapy outcome and mechanisms of action. We call upon clinical and basic scientists to engage in a more "mindful" enterprise of translational research.     

Immunological mechanisms underpinning faecal microbiota transplantation for the treatment of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease that results from a dysregulated immune response against specific environmental triggers in a genetically predisposed individual. Increasing evidence has indicated a causal role for changes in gut microbiota (dysbiosis) contributing to this immune-mediated intestinal inflammation. These mechanisms involve dysregulation of multiple facets of the host immune pathways that are potentially reversible. Faecal microbiota transplantation (FMT) is the transfer of processed stool from a healthy donor into an individual with an illness. FMT has shown promising results in both animal model experiments and clinical studies in IBD in the resolution of intestinal inflammation. The underlying mechanisms, however, are unclear. Insights from these studies have shown interactions between modulation of dysbiosis via changes in abundances of specific members of the gut microbial community and changes in host immunological pathways. Unravelling these causal relationships has promising potential for a translational therapy role to develop targeted microbial therapies and understand the mechanisms that underpin IBD aetiopathogenesis. In this review, we discuss current evidence for the contribution of gut microbiota in the disruption of intestinal immune homeostasis and immunoregulatory mechanisms that are associated with the resolution of inflammation through FMT in IBD.     

Review of autoimmune (lupus-like) glomerulonephritis in murine models

While murine models of autoimmune (lupus-like) glomerulonephritis have been available for sometime, it is only recently that immune and inflammatory mechanisms and molecular genetics have been extensively investigated. Genes involved in murine and human lupus nephritis have been discovered and provide insight into this disease process and provide avenues for molecular-targeted therapy. Immune modulation of murine nephritis has provided insight into novel therapy that may attenuate this disease or halt disease progression. With the advances in understanding the pathogenesis of lupus nephritis using translational research modalities, including electron microscopy, and molecular genetics, many “designer” therapies have become available for clinical use and for clinical investigational trials. This paper reviews autoimmune (lupus-like) glomerulonephritis in murine models, candidate genes involved in lupus nephritis, adhesion molecules implicated in murine lupus-like nephritis, immune modulation of murine lupus-like nephritis, and novel and potential therapy for immune complex glomerulonephritis.     

Toward clinically applicable biomarkers for asthma: An EAACI position paper

Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best‐defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non‐type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point‐of‐care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers.     

A fresh look at the hygiene hypothesis: How intestinal microbial exposure drives immune effector responses in atopic disease

There currently is no consensus on which immunological mechanisms can best explain the rise in atopic disease post industrialization. The hygiene hypothesis lays groundwork for our understanding of how altered microbial exposures can drive atopy; yet since its introduction increasing evidence suggests the exposure of our immune system to the intestinal microbiota plays a key role in development of atopic disease. As societal change shifts our microbial exposure, concordant shifts in the tolerant and effector functions of our immune systems give rise to more hypersensitive responses to external antigens. This is contrasted with the greater immune tolerant capabilities of individuals still living in regions with lifestyles more representative of our evolutionary history. Recent findings, buoyed by technological advances in the field, suggest a direct role for the intestinal microbiota-immune system interplay in the development of atopic disease mechanisms. Overall, harnessing current mechanistic studies for translational research into microbiota composition and function in relation to atopy have potential for the design of therapeutics that could moderate these diseases.     

Therapy for Alzheimer’s disease: Missing targets and functional markers?

The development of the next generation therapy for Alzheimer’s disease (AD) presents a huge challenge given the number of promising treatment candidates that failed in trials, despite recent advancements in understanding of genetic, pathophysiologic and clinical characteristics of the disease. This review reflects some of the most current concepts and controversies in developing disease-modifying and new symptomatic treatments. It elaborates on recent changes in the AD research strategy for broadening drug targets, and potentials of emerging non-pharmacological treatment interventions. Established and novel biomarkers are discussed, including emerging cerebrospinal fluid and plasma biomarkers reflecting tau pathology, neuroinflammation and neurodegeneration. These fluid biomarkers together with neuroimaging findings can provide innovative objective assessments of subtle changes in brain reflecting disease progression. A particular emphasis is given to neurophysiological biomarkers which are well-suited for evaluating the brain overall neural network integrity and function. Combination of multiple biomarkers, including target engagement and outcome biomarkers will empower translational studies and facilitate successful development of effective therapies.     

Role of microRNA in the pathogenesis of systemic sclerosis tissue fibrosis and vasculopathy

Systemic Sclerosis (SSc) pathogenesis involves multiple immunological, vascular and fibroproliferative abnormalities that contribute to a severe and complex clinical picture. Vasculopathy and fibroproliferative alterations are two hallmark pathological processes in SSc that are responsible for the most severe clinical manifestations of the disease and determine its clinical outcome and mortality. However, the pathogenesis of SSc vasculopathy and of the uncontrolled SSc fibrotic process remain incompletely understood. Recent investigations into the molecular pathways involved in these processes have identified an important role for epigenetic processes that contribute to overall disease progression and have emphasized microRNAs (miRNAs) as crucial epigenetic regulators. MiRNAs hold unique potential for elucidating SSc pathogenesis, improving diagnosis and developing effective targeted therapies for the disease. This review examines the important role that miRNAs play in the development and regulation of vascular and fibroproliferative alterations associated with SSc pathogenesis and their possible participation in the establishment of pathogenetic connections between these two processes. This review also emphasizes that further understanding of the involvement of miRNA in SSc fibrosis and vasculopathy will very likely provide novel future research directions and allow for the identification of groundbreaking therapeutic interventions within these processes. MiR-21, miR- 31, and miR-155 are of particular interest owing to their important involvement in both SSc vasculopathy and fibroproliferative alterations.     

Time for a paradigm shift in asthma treatment: from relieving bronchospasm to controlling systemic inflammation

Inflammation is a key pathology in asthma. In the central airways local inflammation leads to irreversible remodeling and airway dysfunction. Complex inflammatory changes also occur in the nose, sinuses, and small airways. In particular, rhinitis and asthma are linked by a common pathogenic process with common inflammatory cells, mediators, and cytokines. Cross-communication between the airways and bone marrow through inflammatory mediators in the circulation leads to systemic propagation of airway inflammation. Treatment of asthma has traditionally focused on relieving bronchospasm with beta(2)-agonists, which do not affect inflammation. Treatment of eosinophilic inflammation in the central airways with inhaled corticosteroids reduces local inflammation and improves pulmonary function but does not improve the systemic manifestations of asthma. If asthma is a systemic disease, the underlying systemic pathology should be targeted by identifying common disease mediators, mechanisms, or both that are triggered only during active disease. Of currently available therapies, leukotriene receptor antagonists block the action of cysteinyl leukotrienes and thus improve both asthma and rhinitis and other conditions systemically linked with asthma. Other potential treatments include receptor-blocking molecules and synthesis inhibitors related to eicosanoid inflammation. Treatment of asthma as a systemic disease requires clinical trials that evaluate the effects of new treatments on both lung function and the wider systemic pathology.     

Asthma therapy in the new millennium

Bronchial asthma is one of the most common chronic diseases in modern society and yet, despite the availability of highly effective drugs, there is increasing evidence to suggest that its incidence is increasing. It is a general health problem in several industrialised countries and will remain one for the next decades. With regard to asthma pathogenesis, our understanding has increased tremendously over the last two decades. Therefore, the potential for specific targeted and constructed therapies has become evident. Monoclonal antibodies to IgE, soluble receptors or antibodies to certain cytokines such as IL-4 and IL-5 are being investigated as possible treatments for asthma. Besides the already known receptor antagonists, new compounds directed to novel receptor types (e.g. cytokine, adenosine, adhesion molecules, etc.) are now under development. New targets in the cytosol will come into focus. Preliminary studies of selective phosphodiesterase (PDE) inhibitors in asthmatic patients have been encouraging. It is also very likely that the use of glucocorticoids cannot be excluded from therapy. However, we should generate new glucocorticoids with less side-effects, probably by using the so-called retrometabolic drug design. The first representative of this new steroid class, loteprednol is already approved for the therapy of certain allergic disorders. Because asthma is a disease of many different gene polymorphisms, gene therapy seems to be of low success at present. Alternatively, antisense oligonucleotides could be used. Future developments may also include strategies targeting the remodeling of structural elements of the airways. Today's intensive search for new treatments should ensure a greater diversity of therapeutic possibilities for the management of asthma in the next millennium.     

New directions in MS therapeutics: vehicles of hope

Basic immunological research has greatly expanded our understanding of the suspected immunopathology of multiple sclerosis (MS) and, more importantly, spawned a new generation of clinical trials evaluating dozens of immune-based therapies. Adhesion molecules are the furthest into development, although patient acceptance and neutralizing antibodies both support the development of small, orally available molecules. Progressive MS probably has a significant neurodegenerative component, so progress with neuroprotective strategies will require appropriate animal models, as well as more advanced clinical imaging techniques, such as brain atrophy and diffusion tensor. Dozens of therapies are in various stages of clinical development and results from these clinical studies will provide important tests of immune and inflammatory mechanisms of MS disease.     

Unmet Needs in the Field of Psoriasis: Pathogenesis and Treatment

In times of targeted therapies, innovative therapeutics become tools to further unravel the pathogenesis of the treated disease, thus influencing current pathogenetic concepts. Based on such paradigm shifts, the next generation of novel therapeutic targets might be identified. Psoriasis is a good example for the resulting most fruitful dialog between clinical and fundamental research. As a result of this, the key role of Th17 lymphocytes, some of their effector molecules, as well as mediators contributing to their maturation have been identified, many of these being targeted by some of the most effective drugs currently available to treat psoriasis. During this process, it became obvious that major parts of the puzzle remain yet to be uncovered or understood in much more detail. This review will therefore address the search for additional important effector cells other than Th17 lymphocytes, such as neutrophils, monocytes, and mast cells, mediators other than IL-17A, including some other IL-17 isoforms, and trigger factors such as potential autoantigens. This will lead to discussing the next generation of targeted therapies for psoriasis as well as treatment goals. These goals need to comprise both psoriasis as well as its comorbidities, as a comprehensive approach to manage the whole patient with all his health issues is urgently needed. Finally, given the substantial differences in resources available in different parts of the world, the global burden of psoriasis and options on how to care for patients outside developed countries will be assessed.     

Tacrolimus treatment for infertility related to maternal‐fetal immune interactions

Many approaches have been used to achieve successful pregnancies in patients with infertility, though existing treatments remain unsatisfactory in patients with infertility caused by abnormal maternal‐fetal immunity. However, our understanding of the immunological aspects of infertility has steadily progressed, aided by recent research into organ transplantation and cancer. The results of these recent analyses have led to the development and evaluation of several candidate immunological treatments, but the use of immunological treatments remains a novel approach. The current paper presents the hypothesis that tacrolimus may have potential as a candidate agent for the treatment of maternal‐fetal immunity‐related infertility.     

Liquid and surfactant delivery into pulmonary airways

We describe the mechanisms by which liquids and surfactants can be delivered into the pulmonary airways. These are instilled and transported throughout the lung in clinical therapies such as surfactant replacement therapy, partial liquid ventilation and drug delivery. The success of these treatments is contingent on the liquid distribution and the delivery to targeted regions of the lung. The targeting of a liquid plug can be influenced by a variety of factors such as the physical properties of the liquid, the interfacial activity, the gravitational orientation, instillation method and propagation speed. We provide a review of experimental and theoretical studies that examine these effects in single tubes or channels, in tubes with single bifurcations and in the whole lung.     

Induced pluripotent stem cells as a next-generation biomedical interface

Recent advances in DNA sequencing technologies and subsequent progress in genome-wide association study (GWAS) are rapidly changing the landscape of human diseases. Our knowledge on disease-gene linkage has been exponentially growing, and soon we will obtain complete maps of SNPs and mutations linked to nearly all major disease conditions. These studies will undoubtedly lead us to a more comprehensive understanding of how multiple genetic modifications link to human pathobiology. But what comes next after we discover these genetic linkages? To truly understand the mechanisms of how polygenic modifications identified through GWAS lead to disease conditions, we need an experimental interface to study their pathobiological effects. In this study, induced pluripotent stem cells (iPSCs), retaining all the genetic information from patients, will likely serve as a powerful resource. Indeed, pioneering studies have demonstrated that disease-specific iPSCs are useful for understanding disease mechanisms. Moreover, iPSC-derived cells, when recapitulating some disease phenotypes in vitro, can be a fast track screening tool for drug discovery. Further, with GWAS information, iPSCs will become a valuable tool to predict drug efficacy and toxicity for individuals, thus promoting personalized medicine. In this review, we will discuss how patient-specific iPSCs will become a powerful biomedical interface in clinical translational research.     

Beyond Depression Commentary: Wherefore Art Thou,Depression Clinic of Tomorrow?

[Clin Psychol Sci Prac 18: 305–310, 2011] An exciting review in this issue ( Forgeard et al., 2011 ) highlights a number of emerging themes in contemporary translational research. A primary challenge for the next generation of researchers reading this work will be how to carry out the grand charges levied by Forgeard et al. on the ground, that is, to lay the foundations for moving the emerging basic science of depression into the Depression Clinic of Tomorrow. Addressing these challenges could suggest changes in the nature of the basic science, and the questions that are being asked, and employed approaches in contemporary depression research. Preconditions for clinical adoption discussed in the review include (a) beginning to hold neuroscience‐based measures of features of depression to the same standards held for other depression measures in the clinic, (b) attending to how the proposed methods might actually end up being feasibly imported into the clinic, and (c) what interventions targeted at mechanisms of depression might look like in the next decade.     

Novel immunotherapies for psoriasis.

New insights into the pathophysiology of psoriasis have suggested possibilities for targeted therapeutic intervention. Several novel, systemic immunomodulatory therapies are currently in clinical development and results of recent clinical trials are remarkable. These include approaches targeting antigen presentation and costimulation, T-cell activation and leukocyte adhesion, the action of proinflammatory mediators and the administration of anti-inflammatory cytokines. These trials contribute to our further understanding of the disease, indicating which mechanisms play a greater or lesser part in its development. Moreover, they will lead to new therapeutic options. If psoriasis is considered as a visible model disease for T-cell-mediated disorders characterized by a type-1 cytokine pattern these recent findings might have a more general impact on the treatment of autoimmune disorders.     

MR evaluation of response to targeted treatment in cancer cells

The development of molecular technologies, together with progressive sophistication of molecular imaging methods, has allowed the further elucidation of the multiple mutations and dysregulatory effects of pathways leading to oncogenesis. Acting against these pathways by specifically targeted agents represents a major challenge for current research efforts in oncology. As conventional anatomically based pharmacological endpoints may be inadequate to monitor the tumor response to these targeted treatments, the identification and use of more appropriate, noninvasive pharmacodynamic biomarkers appear to be crucial to optimize the design, dosage and schedule of these novel therapeutic approaches. An aberrant choline phospholipid metabolism and enhanced flux of glucose derivatives through glycolysis, which sustain the redirection of mitochondrial ATP to glucose phosphorylation, are two major hallmarks of cancer cells. This review focuses on the changes detected in these pathways by MRS in response to targeted treatments. The progress and limitations of our present understanding of the mechanisms underlying MRS-detected phosphocholine accumulation in cancer cells are discussed in the light of gene and protein expression and the activation of different enzymes involved in phosphatidylcholine biosynthesis and catabolism. Examples of alterations induced in the MRS choline profile of cells exposed to different agents or to tumor environmental factors are presented. Current studies aimed at the identification in cancer cells of MRS-detected pharmacodynamic markers of therapies targeted against specific conditional or constitutive cell receptor stimulation are then reviewed. Finally, the perspectives of present efforts addressed to identify enzymes of the phosphatidylcholine cycle as possible novel targets for anticancer therapy are summarized.     

Immunosenescence of ageing

Ageing is a complex process that negatively impacts the development of the immune system and its ability to function. The mechanisms that underlie these age-related defects are broad and range from defects in the haematopoietic bone marrow to defects in peripheral lymphocyte migration, maturation and function. The thymus is a central lymphoid organ responsible for production of na?ve T cells, which play a vital role in mediating both cellular and humoral immunity. Chronic involution of the thymus gland is thought to be one of the major contributing factors to loss of immune function with increasing age. It has recently been demonstrated that thymic atrophy is mediated by a shift from a stimulatory to a suppressive cytokine microenvironment. In this review we present an overview of the morphological, cellular and biochemical changes that have been implicated in the decline of thymic and peripheral immune function with ageing. We conclude with the clinical implications of age-associated immunosenescence to vaccine development for tumours and infectious disease. A fundamental understanding of the complex mechanisms by which ageing attenuates immune function will enable translational research teams to develop new therapies and vaccines specifically aimed at overcoming these defects in immunological function in the aged.