New potential treatments for protection of pancreatic B‐cell function in Type 1 diabetes

Type 1 diabetes mellitus results from the progressive and specific autoimmune destruction of insulin‐secreting pancreatic B‐cells, which develops over a period of years and continues after the initial clinical presentation. The ultimate goal of therapeutic intervention is prevention or reversal of the disease by the arrest of autoimmunity and by preservation/restoration of B‐cell mass and function. Recent clinical trials of antigen‐specific or non‐specific immune therapies have proved that modulation of islet specific autoimmunity in humans and prevention of insulin secretion loss in the short term after the onset of disease is achievable. The identification of suitable candidates for therapy, appropriate dosage and timing, specificity of intervention and the side‐effect profile are crucial for the success of any approach. Considering the complexity of the disease, it is likely that a rationally designed approach of combined immune‐based therapies that target suppression of B‐cell specific autoreactivity and maintenance of immune tolerance, coupled with islet regeneration or replacement of the destroyed B‐cell mass, will prove to be most effective in causing remission/reversal of disease in a durable fashion.     

Current understanding of the role of gut dysbiosis in type 1 diabetes

Type 1 diabetes (T1D) is a chronic autoimmune disorder that results from destruction of the insulin‐producing pancreatic β‐cells. The disease mainly affects juveniles. Changes in the composition of the gut microbiota (dysbiosis) and changes in the properties of the gut barrier have been documented in T1D subjects. Because these factors affect immune system functions, they are likely to play a role in disease pathogenesis. However, their exact role is currently not fully understood and is under intensive investigation. In this article we discuss recent advancements depicting the role of intestinal dysbiosis on immunity and autoimmunity in T1D. We also discuss therapies aimed at maintaining a healthy gut barrier as prevention strategies for T1D.     

Immune checkpoint blockade immunotherapy to activate anti‐tumour T‐cell immunity

The tumour microenvironment plays a dual role in cancer: it can promote tumour progression by establishing pro‐tumour survival conditions but can also suppress tumour progression by killing cancer cells or inhibiting their outgrowth. These dynamically interconnected processes are under intense investigation to better understand cancer pathophysiology and allow identification of new therapeutic approaches. The ability of cancer cells to evade anti‐tumour T‐cell activity in the microenvironment has recently been accepted as a hallmark of cancer progression. This review will highlight the most promising therapeutic approach aimed at activating anti‐tumour T‐cell immunity in the cancer microenvironment: blocking inhibitory immune regulatory proteins (immune checkpoint ligands and receptors). There is emerging evidence that haematological tumours co‐opt immune checkpoints as a major immune resistance mechanism. Pre‐clinical findings indicate that targeted therapies and blockade of immune checkpoints could be combined to promote therapeutic synergy and long‐term anti‐tumour immunity to improve clinical outcomes for cancer patients.     

Immune Monitoring of Islet and Pancreas Transplant Recipients

Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing beta-cells are destroyed. Islet or pancreas transplantation can restore insulin secretion and are established therapies for subgroups of T1D patients. Long-term insulin-independence is, however, hampered by recurrent autoimmunity and rejection. Accurate monitoring of these immune events is therefore of critical relevance for the timely detection of deleterious immune responses. The identification of relevant immune biomarkers of allo- and autoreactivity has allowed a more accurate monitoring of disease progression and responses to therapy at early stages, allowing proper therapeutic intervention, and possibly improvements in the success rate of islet and pancreas transplantation. This review describes the tools established and validated to monitor immune correlates of auto- and alloreactivity that associate with clinical outcome and identifies challenges that current immunosuppression strategies trying to preserve islet graft function face.     

Zonulin as a potential putative biomarker of risk for shared type 1 diabetes and celiac disease autoimmunity

The incidence of type 1 diabetes (T1D) is increasing annually, in addition to other childhood‐onset autoimmune diseases. This review is inspired by recent strides in research defining the pathophysiology of autoimmunity in celiac disease, a disease that has significant genetic overlap with T1D. Population genetic studies have demonstrated an increased proportion of newly diagnosed young children with T1D also have a higher genetic risk of celiac disease, suggesting that shared environmental risk factors are driving the incidence of both diseases. The small intestine barrier forms a tightly regulated interface of the immune system with the outside world and largely controls the mucosal immune response to non‐self‐antigens, dictating the balance between tolerance and immune response. Zonulin is the only known physiological modulator of the intercellular tight junctions, important in antigen trafficking, and therefore, is a key player in regulation of the mucosal immune response. While usually tightly controlled, when the zonulin pathway is dysregulated by changes in microbiome composition and function, antigen trafficking control is lost, leading to loss of mucosal tolerance in genetically susceptible individuals. The tenant of this hypothesis is that loss of tolerance would not occur if the zonulin‐dependent intestinal barrier function is restored, thereby preventing the influence of environmental triggers in individuals genetically susceptible to autoimmunity. This review outlines the current research and a structured hypothesis on how a dysregulated small intestinal epithelial barrier, a “leaky gut,” may be important in the pathogenesis of autoimmunity in certain individuals at risk of both T1D and celiac disease.     

Aetiology of type 1 diabetes: Physiological growth in children affects disease progression

The prevailing view is that type 1 diabetes (T1D) develops as a consequence of a severe decline in β‐cell mass resulting from T‐cell‐mediated autoimmunity; however, progression from islet autoantibody seroconversion to overt diabetes and finally to total loss of C‐peptide production occurs in most affected individuals only slowly over many years or even decades. This slow disease progression should be viewed in relation to the total β‐cell mass of only 0.2 to 1.5 g in adults without diabetes. Focal lesions of acute pancreatitis with accumulation of leukocytes, often located around the ducts, are frequently observed in people with recent‐onset T1D, and most patients display extensive periductal fibrosis, the end stage of inflammation. An injurious inflammatory adverse event, occurring within the periductal area, may have negative implications for islet neogenesis, dependent on stem cells residing within or adjacent to the ductal epithelium. This could in part prevent the 30‐fold increase in β‐cell mass that would normally occur during the first 20 years of life. This increase occurs in order to maintain glucose metabolism during the physiological increases in insulin production that are required to balance the 20‐fold increase in body weight during childhood and increased insulin resistance during puberty. Failure to expand β‐cell mass during childhood would lead to clinically overt T1D and could help to explain the apparently more aggressive form of T1D occurring in growing children when compared with that observed in affected adults.     

Vaccines modulating lipoprotein autoimmunity as a possible future therapy for cardiovascular disease

Current strategies for prevention of cardiovascular disease focus on risk factor intervention. Although these have been proven both safe and effective results from randomized clinical trials suggest that it is difficult to achieve relative risk reductions exceeding 40% with this approach. To further improve efficacy future therapies must aim at targeting the actual disease process in the arterial wall. Emerging evidence have identified an important role of the immune system in atherosclerosis and suggest that modulation of autoimmune responses against oxidized LDL and other antigens in the atherosclerotic plaque represent one possible new approach to disease prevention. Oxidized LDL is targeted by both antibody‐mediated and cellular immune responses and as much as 10% of the T cells in atherosclerotic plaques are oxidized LDL‐specific. Immune activation in the atherosclerotic plaque is primarily of the pro‐inflammatory Th1‐type and inhibition Th1 immunity reduces atherosclerosis in experimental animals. Atherosclerosis vaccines based on antigens derived from LDL have been developed to modulate these processes. Their mechanisms of action remain to be full characterized but may involve expression of protective antibodies that facilitate the removal of oxidized LDL and antigen‐specific regulatory T cells that counteract Th1 autoimmunity against oxidized LDL. In this review we will discuss the possibilities and challenges encountering the translation of immune‐modulatory therapy for atherosclerosis from the experimental stage into the clinic.     

Inverse vaccination,the opposite of Jenner’s concept,for therapy of autoimmunity

Abstract. Steinman L (Stanford University, Stanford, CA, USA). Inverse vaccination, the opposite of Jenner’s concept, for therapy of autoimmunity (foresight). J Intern Med 2010: 267 : 441–451. DNA‐based vaccines to induce antigen‐specific inhibition of immune responses in human autoimmune diseases represent the inverse of what Jenner intended when he invented vaccination. Jenner’s vaccine induced antigen‐specific immunity to small pox. DNA vaccines for autoimmunity have been developed in preclinical settings, and now tested in human trials. The first two clinical trials, one in relapsing remitting multiple sclerosis, and the other in type 1 diabetes indicate that specific inhibition of antigen‐specific antibody and T‐cell responses is attainable in humans. Further development of this approach is ongoing. This new version of immunization termed ‘inverse vaccination’ when applied to autoimmune diseases, may allow targeted reduction of unwanted antibody and T‐cell responses to autoantigens, while leaving the remainder of the immune system intact. The method of specifically reducing a pathological adaptive autoimmune response is termed inverse vaccination.     

Progress and prospects for engineered T cell therapies

Proof‐of‐concept studies have demonstrated the therapeutic potential of engineered T cells. Transfer of recombinant antigen‐specific T cell receptors (TCR) and chimaeric antigen receptors (CARs) against tumour and viral antigens are under investigation by multiple approaches, including viral‐ and nonviral‐mediated gene transfer into both autologous and allogeneic T cell populations. There have been notable successes recently using viral vector‐mediated transfer of CARs specific for B cell antigens, but also reports of anticipated and unanticipated complications in these and other studies. We review progress in this promising area of cellular therapy, and consider developments in antigen receptor therapies including the application of emerging gene‐editing technologies.     

Therapeutic potential of umbilical cord blood cells for type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) is a chronic disorder that results from autoimmune‐mediated destruction of pancreatic islet β‐cells. However, to date, no conventional intervention has successfully treated the disease. The optimal therapeutic method for T1DM should effectively control the autoimmunity, restore immune homeostasis, preserve residual β‐cells, reverse β‐cell destruction, and protect the regenerated insulin‐producing cells against re‐attack. Umbilical cord blood is rich in regulatory T (T_reg) cells and multiple types of stem cells that exhibit immunomodulating potential and hold promise in their ability to restore peripheral tolerance towards pancreatic islet β‐cells through remodeling of immune responses and suppression of autoreactive T cells. Recently, reinfusion of autologous umbilical cord blood or immune cells from cord blood has been proposed as a novel therapy for T1DM, with the advantages of no risk to the donors, minimal ethical concerns, a low incidence of graft‐versus‐host disease and easy accessibility. In this review, we revisit the role of autologous umbilical cord blood or immune cells from cord blood‐based applications for the treatment of T1DM.     

2017 Clinical trials update in new treatments of β‐thalassemia

The underlying basis of β‐thalassemia pathology is the diminished β‐globin synthesis leading to α‐globin accumulation and premature apoptotic destruction of erythroblasts, causing oxidative stress‐induced ineffective erythropoiesis, bone marrow hyperplasia, splenomegaly, and increased intestinal iron absorption with progressive iron overload. Better understanding of the molecular mechanisms underlying this disease led to the recognition of new targets with potential therapeutic utility. Agents such as JAK2 inhibitors and TGF‐β ligand traps that reduce the ineffective erythropoiesis process are already being tested in clinical trials with promising results. Other agents that aim to reduce oxidative stress (activators of Foxo3, HRI‐eIF2aP, Prx2, Hsp70, and PK anti‐oxidant systems and inhibitors of HO‐1) and to decrease iron overload (hepcidin agonists, erythroferrone inhibitors and exogenous transferrin) are also under experimental investigation. Significant progress has also been made in the area of allogeneic hematopoietic stem cell transplantation with several ongoing clinical trials examining new condition regimens as well as different donor selection and stem cell source options. Gene therapy has reached a critical point and phase 1 clinical trials have recently been launched to examine the effectiveness and especially long term safety. Epigenetic manipulation and genomic editing of the γ‐ or β‐globin gene are novel and promising experimental gene therapy approaches for β‐thalassemia giving hope for cure for this chronic disease. This review outlines the key points of the molecular mechanisms underlying β‐thalassemia in relation to the development of new therapies and an update is given both at the pre‐clinical and clinical level. Am. J. Hematol. 91:1135–1145, 2016. © 2016 Wiley Periodicals, Inc.     

Immunobiology of hepatitis B virus infection

The adaptive immune response, particularly the virus‐specific CD8⁺ T‐cell response, is largely responsible for viral clearance and disease pathogenesis during hepatitis B virus (HBV) infection. The HBV‐specific CD8⁺ T‐cell response is vigorous, polyclonal and multispecific in acutely infected patients who successfully clear the virus and relatively weak and narrowly focused in chronically infected patients. The immunological basis for this dichotomy is unclear. A recent study using HBV transgenic mice and HBV‐specific T‐cell receptor transgenic mice suggests that intrahepatic antigen presentation by HBV positive hepatocytes suppresses HBV‐specific CD8⁺ T‐cell responses through a co‐inhibitory molecule, programmed cell death 1 (PD‐1). In contrast, antigen presentation by activated professional antigen‐presenting cells induces functional differentiation of HBV‐specific CD8⁺ T cells. These findings suggest that the outcome of T‐cell priming is largely dependent on the nature of antigen‐presenting cells. Another study suggests that the timing of HBV‐specific CD4⁺ T‐cell priming regulates the magnitude of the HBV‐specific CD8⁺ T‐cell response. Other factors that could regulate HBV‐specific cellular immune responses are high viral loads, mutational epitope inactivation, T‐cell receptor antagonism and infection of immunologically privileged tissues. However, these pathways become apparent only in the setting of an ineffective cellular immune response, which is therefore the fundamental underlying cause. Understanding the cellular and molecular mechanisms by which HBV evades host immune responses will eventually help develop new immunotherapeutic strategies designed to terminate chronic HBV infection.     

The New insights from DPP‐4 inhibitors: their potential immune modulatory function in autoimmune diabetes

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are a new class of anti‐diabetic agents that are widely used in clinical practice to improve glycemic control and protect β‐cell function in patients with type 2 diabetes. DPP‐4 is also known as lymphocyte cell surface protein CD26 and plays an important role in T‐cell immunity. Autoimmune diabetes, a T‐cell mediated organ‐specific disease, is initiated by the imbalance between pathogenic and regulatory T‐lymphocytes. DPP‐4 inhibitors can suppress pathogenic effects of Th1 and Th17 cells and up‐regulate Th2 cells and regulatory T cells, which play a critical role in ameliorating autoimmune diabetes. This provides a basis for the potential use of DPP‐4 inhibitors in the treatment of autoimmune diabetes. Recent studies suggest that DPP‐4 inhibitors improve β‐cell function and attenuate autoimmunity in type 1 diabetic mouse models. However, there are few clinical studies on the treatment of autoimmune diabetes with DPP‐4 inhibitors. Further studies are warranted to confirm the therapeutic effects of DPP‐4 inhibitors on autoimmune diabetes in humans. Copyright © 2014 John Wiley & Sons, Ltd.     

The immune system and cancer evasion strategies: therapeutic concepts

The complicated interplay between cancer and the host immune system has been studied for decades. New insights into the human immune system as well as the mechanisms by which tumours evade immune control have led to the new and innovative therapeutic strategies that are considered amongst the medical breakthroughs of the last few years. Here, we will review the current understanding of cancer immunology in general, including immune surveillance and immunoediting, with a detailed look at immune cells (T cells, B cells, natural killer cells, macrophages and dendritic cells), immune checkpoints and regulators, sialic acid‐binding immunoglobulin‐like lectins (Siglecs) and other mechanisms. We will also present examples of new immune therapies able to reverse immune evasion strategies of tumour cells. Finally, we will focus on therapies that are already used in daily oncological practice such as the blockade of immune checkpoints cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) and programmed death‐1 (PD‐1) in patients with metastatic melanoma or advanced lung cancer, or therapies currently being tested in clinical trials such as adoptive T‐cell transfer.     

Targeting T‐cell migration in inflammatory bowel disease

Crohn's disease and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract and are collectively referred to as inflammatory bowel disease (IBD). IBD is a major cause of lifetime morbidity, has a severe impact on quality of life of patients (equivalent to that of rheumatoid arthritis, asthma, migraine or diabetes) and constitutes a substantial economic burden to the healthcare system. The introduction of anti‐tumour necrosis factor (TNF) antibodies has dramatically improved the treatment of IBD, but approximately one‐third of patients are nonresponders and another 30–50% will eventually lose the therapeutic effect or become intolerant to these antibodies. Thus, there is an urgent and unmet need for new therapies. The aetiologies of the different forms of IBD have not been fully elucidated but there is strong evidence implicating T cells and T‐cell migration to the gut in initiating and perpetuating the intestinal inflammatory process and tissue destruction. In recent years, progress in basic science has shed light on the mechanisms regulating T‐cell migration to the gut and new therapeutics targeting these pathways have been developed. It is interesting that some of the factors directing the localization of T cells to the gut have been shown to be relatively organ specific, potentially enabling new T‐cell‐targeted treatments to demonstrate improved safety whilst preserving therapeutic efficacy. Here, fundamental aspects of the gut immune system, the generation of tissue‐tropic effector T cells and the mechanisms of T‐cell trafficking to the gut mucosa will be reviewed. In addition, the role of these processes in IBD and how they have been exploited for the development of novel therapies for IBD will be discussed.     

Therapeutic vaccination using CD4+CD25+ antigen-specific regulatory T cells

Autoimmune disease results from the dysregulation of basic tolerogenic processes designed to control self/non-self-discrimination. Approaches to treat autoimmunity have focused historically on potent immunosuppressives that block the activation and expansion of antigen-specific T cells before they differentiate into pathogenic T cell responses. These therapies are very efficient in reducing clonal expansion and altering early signaling pathways. However, once the pathogenic responses are established (i.e., autoimmunity), the interventions are less effective on activated and differentiated T cell subsets (including memory T cells) or acting in the presence of an inflammatory milieu to abort immune responses at the target tissue and systemically. Moreover, the current immunotherapies require continuous use because they do not redirect the immune system to a state of tolerance. The continuous treatment leads to long-term toxicities and can profoundly suppress protective immune responses targeted at viruses, bacteria, and other pathogens. Over the past decade, there have been tremendous advances in our understanding of the basic processes that control immune tolerance. Among the most exciting has been the identification of a professional regulatory T cell subset that has shown enormous potential in suppressing pathologic immune responses in autoimmune diseases, transplantation, and graft vs. host disease. In this review, we summarize current efforts to induce and maintain tolerance in the autoimmune diabetes setting by using therapeutic vaccination with CD4(+)CD25(+) regulatory T cells. Emphasis will be placed on approaches to exploit regulatory T cells either directly or through the use of anti-CD3 immunotherapy.     

Promoting Immune Regulation in Type 1 Diabetes Using Low-Dose Interleukin-2

Dysregulation of the immune system contributes to the breakdown of immune regulation, leading to autoimmune diseases, such as type 1 diabetes (T1D). Current therapies for T1D include daily insulin, due to pancreatic β-cell destruction to maintain blood glucose levels, suppressive immunotherapy to decrease the symptoms associated with autoimmunity, and islet transplantation. Genetic risks for T1D have been linked to IL-2 and IL-2R signaling pathways that lead to the breakdown of self-tolerance mechanisms, primarily through altered regulatory T cell (Treg) function and homeostasis. In attempt to correct such deficits, therapeutic administration of IL-2 at low doses has gained attention due to the capacity to boost Tregs without the unwanted stimulation of effector T cells. Preclinical and clinical studies utilizing low-dose IL-2 have shown promising results to expand Tregs due to their high selective sensitivity to respond to IL-2. These results suggest that low-dose IL-2 therapy represents a new class of immunotherapy for T1D by promoting immune regulation rather than broadly suppressing unwanted and beneficial immune responses.     

Comparison of intravenous immune globulin and high dose anti‐D immune globulin as initial therapy for childhood immune thrombocytopenic purpura

This report documents our experience with intravenous immune globulin (IVIG) (1 g/kg, iv) and high‐dose, anti‐D immune globulin (anti‐D) (75 μg/kg) as initial treatment for childhood immune thrombocytopenic purpura (ITP). The medical records of children diagnosed with ITP at a single institution between January 2003 and May 2008 were retrospectively reviewed. Participants received either IVIG or high‐dose anti‐D immune globulin as their initial treatment for ITP. For the 53 patients included for analysis, there was no statistical difference in efficacy between each group; however, patients who received anti‐D experienced a higher rate of adverse drug reactions (ADRs), particularly chills and rigours, and 2 of 24 patients in the anti‐D group developed severe anaemia requiring medical intervention. Patients who presented with mucosal bleeding had higher rates of treatment failure (32%) compared to those who presented with dry purpura (6%), regardless of treatment. Both IVIG and high‐dose anti‐D are effective first‐line therapies for childhood ITP. However, we observed increased ADRs in the high‐dose anti‐D group in contrast to previously published reports. Further studies are needed to evaluate safety and premedications for high‐dose anti‐D and to determine the utility of using the presence of mucosal bleeding to predict treatment failure.     

Fulminant type 1 diabetes: A comprehensive review of an autoimmune condition

Fulminant type 1 diabetes (FT1D) is a subset of type 1 diabetes characterized by extremely rapid pancreatic β‐cell destruction with aggressive progression of hyperglycaemia and ketoacidosis. It was initially classified as idiopathic type 1 diabetes due to the absence of autoimmune markers. However, subsequent studies provide evidences supporting the involvement of autoimmunity in rapid β‐cell loss in FT1D pathogenesis, which are crucial for FT1D being an autoimmune disease. This article highlights the role of immunological aspects in FT1D according to the autoimmune‐associated genetic background, viral infection, innate immunity, adaptive immunity, and pancreas histology.     

The environment and the origins of islet autoimmunity and Type 1 diabetes

Type 1 diabetes involves the specific destruction of the pancreatic islet β‐cells, eventually resulting in a complete dependency of exogenous insulin. The clinical onset of diabetes is preceded by the appearance of autoantibodies against β‐cell antigens. The human leukocyte antigen (HLA) region is the single most important genetic determinant of Type 1 diabetes susceptibility, yet variability in the HLA region has been estimated to explain only approximately 60% of the genetic influence of the disease. Over 50 identified non‐HLA genetic polymorphisms support the notion that genetics alone cannot explain Type 1 diabetes. Several lines of evidence indicate that environmental triggers may be integral in inducing the onset of islet autoimmunity in genetically susceptible individuals. The association between environmental factors and the clinical onset is complicated by observation that the rate of progression to clinical onset may be affected by environmental determinants. Hence, the environment may be aetiological as well as pathogenic. Putative inductive mechanisms include viral, microbial, diet‐related, anthropometric and psychosocial factors. Ongoing observational cohort studies such as The Environmental Determinants of Diabetes in the Young (TEDDY) study aim to ascertain environmental determinants that may trigger islet autoimmunity and either speed up or slow down the progression to clinical onset in subjects with persistent islet autoimmunity.