Emerging role of regulatory T cells in gene transfer

Induction and maintenance of immune tolerance to therapeutic transgene products are key requirements for successful gene replacement therapies. Gene transfer may also be used to specifically induce immune tolerance and thereby augment other types of therapies. Similarly, gene therapies for treatment of autoimmune diseases are being developed in order to restore tolerance to self-antigens. Regulatory T cells have emerged as key players in many aspects of immune tolerance, and a rapidly increasing body of work documents induction and/or activation of regulatory T cells by gene transfer. Regulatory T cells may suppress antibody formation and cytotoxic T cell responses and may be critical for immune tolerance to therapeutic proteins. In this regard, CD4(+)CD25(+) regulatory T cells have been identified as important components of tolerance in several gene transfer protocols, including hepatic in vivo gene transfer. Augmentation of regulatory T cell responses should be a promising new tool to achieve tolerance and avoid immune-mediated rejection of gene therapy. During the past decade, it has become obvious that immune regulation is an important and integral component of tolerance to self-antigens and of many forms of induced tolerance. Gene therapy can only be successful if the immune system does not reject the therapeutic transgene product. Recent studies provide a rapidly growing body of evidence that regulatory T cells (T(reg)) are involved and often play a crucial role in tolerance to proteins expressed by means of gene transfer. This review seeks to provide an overview of these data and their implications for gene therapy.     

Immunological and anti-chaperone therapeutic approaches for Alzheimer disease

Alzheimer disease (AD) is the most common cause of dementia. Currently available therapies only provide symptomatic relief. A number of therapeutic approaches are under development that aim to increase the clearance of brain Abeta peptides. These include immune mediated clearance of Abeta and the inhibition of the interaction between Abeta and its pathological chaperones. Both active and passive immunization has been shown to have robust effects in transgenic mouse models of AD on amyloid reduction and behavioral improvements. However, a human trial of active immunization has been associated with significant toxicity in a minority of patients. New generation vaccines are being developed which likely will reduce the potential for cell-mediated toxicity. In addition, the recent development of anti-chaperone therapy opens a new therapeutic avenue which is unlikely to be associated with toxicity.     

A new era of antifungal therapy.

Invasive fungal infections pose major management problems for clinicians caring for hematopoietic cell transplant patients. Two major fungal genera, Candida and Aspergillus, account for most fungal infections. Rates of systemic Candida infection range from 15% to 25%, mostly in the pre-engraftment period. Prophylaxis by fluconazole has dramatically reduced the frequency of early Candida infections. Caspofungin has recently been shown to offer an excellent alternative to amphotericin B (with less toxicity) or fluconazole (with a broader spectrum) for therapy of systemic Candida infections. Aspergillus infections occur in 15% to 20% of allogeneic hematopoietic cell transplant patients, most frequently in the post-engraftment period; they are associated with a severe diminution of cell-mediated immune responses by graft-versus-host disease and prolonged corticosteroid use. Voriconazole, a recently introduced broad-spectrum azole, has excellent activity against Aspergillus and is generally well tolerated. Voriconazole currently offers the best prospect for success and tolerance as a first-line treatment for aspergillosis. Second-line therapies include lipid formulations of amphotericin B, caspofungin, or intravenous itraconazole. Unfortunately, early initiation of therapy for aspergillosis is frequently not possible because of inaccurate diagnostics. One new diagnostic, the galactomannan assay, has recently been approved, and others are in development; these offer promise for earlier diagnosis without the need for invasive procedures. It is hoped that these new therapies and new diagnostics will usher in a new era of antifungal therapy.     

Pediatric food allergy and mucosal tolerance

The gastrointestinal (GI) mucosal immune response is characterized by an intricate balance between host defense and immunoregulation. A principal element of this normal response is acquisition of oral tolerance. Aberrations in oral tolerance induction can lead to food allergy, an increasingly prevalent disorder that causes significant medical and psychosocial stressors for patients and families. At present there is no definitive therapy for food allergy and the mainstays of treatment are allergen avoidance, nutritional support, and ready access to emergency medications. Significant progress toward an active therapy for food allergy has been made with the advent of novel therapies such as oral immunotherapy (OIT) and sublingual immunotherapy (SLIT), which modulate the GI mucosal immune response with the goal of promoting oral tolerance. In this review, we will examine the mechanisms of oral tolerance induction and its relation to food allergy and explore novel immunotherapeutic strategies for treatment and prevention of food allergy.     

Tolerance in clinical liver transplantation

While advances in immunosuppressive therapy have lowered the rate of acute rejection following liver transplantation, the consequence has been an increase in morbidity and mortality related to the lifelong need for maintenance immunosuppression. These complications include an increased risk of malignancy, infection, metabolic disorders, and chronic kidney disease, as well as high health care costs associated with these therapies and the required drug monitoring. Given these issues, most clinicians attempt trial and error dose minimization with variable success rates, and there has been significant interest in full drug withdrawal in select patients through research protocols. These strategies would be more successful if immunomodulatory therapies early after transplantation could be developed and if immune activation biomarkers guiding drug tapering were available to personalize these approaches. This review will review the mechanisms of liver transplant tolerance and potential strategies to achieve immunosuppression withdrawal.     

99th Dahlem Conference on Infection,Inflammation and Chronic Inflammatory Disorders: Immune therapies of type 1 diabetes: new opportunities based on the hygiene hypothesis

Insulin‐dependent (type 1) diabetes is a prototypic organ‐specific autoimmune disease resulting from the selective destruction of insulin‐secreting β cells within pancreatic islets of Langerhans by an immune‐mediated inflammation involving autoreactive CD4⁺ and CD8⁺ T lymphocytes which infiltrate pancreatic islets. Current treatment is substitutive, i.e. chronic use of exogenous insulin which, in spite of significant advances, is still associated with major constraints (multiple daily injections, risks of hypoglycaemia) and lack of effectiveness over the long term in preventing severe degenerative complications. Finding a cure for autoimmune diabetes by establishing effective immune‐based therapies is a real medical health challenge, as the disease incidence increases steadily in industrialized countries. As the disease affects mainly children and young adults, any candidate immune therapy must therefore be safe and avoid a sustained depression of immune responses with the attendant problems of recurrent infection and drug toxicity. Thus, inducing or restoring immune tolerance to target autoantigens, controlling the pathogenic response while preserving the host reactivity to exogenous/unrelated antigens, appears to be the ideal approach. Our objective is to review the major progress accomplished over the last 20 years towards that aim. In addition, we would like to present another interesting possibility to access new preventive strategies based on the ‘hygiene hypothesis’, which proposes a causal link between the increasing incidence of autoimmune diseases, including diabetes, and the decrease of the infectious burden. The underlying rationale is to identify microbial‐derived compounds mediating the protective activity of infections which could be developed therapeutically.     

Combining targeted therapy with immunotherapy. Can 1 + 1 equal more than 2?

Targeted therapies have induced high response rates and improved survival in patients with cancer. However, the long-term effectiveness of targeted therapies has been limited by the development of acquired resistance in the majority of patients. On the other hand, the modern immunotherapy strategies have been associated with durable responses but in limited number of patients. Accordingly, research efforts have been focused on examining the effects of combinations of targeted therapy and immunotherapy in several different histological subtypes of cancer. There has been accumulated evidence to suggest that targeted therapy can induce immune effects in the tumor cells, the host immune system, and the tumor microenvironment. Subsequently, clinical trials have been designed to examine the efficacy of combining immune checkpoint blockade or adoptive cell transfer with tyrosine kinase inhibitors, HER family blockade, anti-angiogenic agents, histone deacetylase inhibitors, and cancer stem cell inhibitors. To date, the combination of immunotherapy with targeted therapy has demonstrated potential as a cancer treatment strategy, but further optimizations are required and caution must be taken to avoid toxicity. The current review summarizes existing evidence and provides rationale supporting the use of combined targeted and immune-therapy approaches in patients with different types of cancer.     

Regulatory T cells for tolerance

Regulatory T cells (Tregs) are critical mediators of immune homeostasis and hold significant promise in the quest for transplantation tolerance. Progress has now reached a critical threshold as techniques for production of clinical therapies are optimised and Phase I/II clinical trials are in full swing. Initial safety and efficacy data are being reported, with trials assessing a number of different strategies for the introduction of Treg therapy. It is now more crucial than ever to elucidate further the function and behaviour of Tregs in vivo and ensure safe delivery. This review will discuss the current state of the art and future directions in Treg therapy.     

CD4 T cells in hepatic immune tolerance

The liver features a unique immune microenvironment, which seems to favour immune tolerance, both locally and systemically. The hepatic microenvironment is formed by the unique anatomical structure of the liver sinusoids, a peculiar composition of antigen presenting cells and the relative abundance of anti-inflammatory cytokines. The outcome of T cell stimulation within the hepatic microenvironment is often tolerance. This is illustrated by the observations that antigen delivered to the portal vein, or allografts co-transplanted with allogeneic liver are not attacked by the immune system. Moreover, the tolerogenic properties of the liver seem to be part of the cause for the frequent persistence of hepatitis virus infections. This review summarizes some of the mechanisms of tolerance induction in the liver with a focus on CD4 T cells. Hepatic CD4 T cell tolerance seems to emerge from various tolerogenic mechanisms, including immune deviation from inflammatory to non-inflammatory effector function, a relative preponderance of negative co-stimulation notably through PD-1, generation and expansion of regulatory T cells, or the relative abundance of immunoinhibitory cytokines, such as inteleukin-10 and TGF-β. Understanding the mechanisms of hepatic tolerance induction may teach us how to develop or improve therapies for inflammatory diseases of the liver and other organs. Indeed, novel therapeutic options that utilize hepatic tolerance mechanisms are beginning to emerge, such as the generation of Treg in the liver for therapy of autoimmune disease or the blockade of PD-1 for the therapy of chronic viral hepatitis.     

Recent immunomodulatory strategies in transplantation

Despite preservation methods, surgical procedures, current immunosuppressive therapy regimens advances, organ transplantation is accompanied with a poor long-term survival and significant mortality. This has led to an increased interest to optimize outcomes while minimizing associated toxicity by using alternative methods for maintenance immunosuppression, organ rejection treatment, and monitoring of immunosuppression. Advance in long-standing allograft outcomes may depend on new drugs with novel mechanisms of action with minimal toxicity. Newer treatment techniques have been developed, including using novel stem cell-based therapies such as mesenchymal stem cells, phagosomes and exosomes. Immunoisolation techniques and salvage therapies, including photopheresis and total lymphoid irradiation have emerged as alternate therapeutic choices. The present review evaluates the recent clinical advances in immunosuppressive therapies for organ transplantation.     

Gene therapy in the transplantation of allogeneic organs and stem cells

Most of the current hematopoietic stem cell (HSC) -directed gene therapy applications have focused on the replacement of defective or deficient genes in an autologous setting. More recently HSC gene therapy applications have also included the enhancement or improvement of HSC features. Allogeneic HSCs have been used to facilitate and improve allogeneic transplantation and to achieve tolerance to transplanted cells, tissues or organs. Different gene transfer approaches addressing a variety of immunomodulatory mediators contributing to graft tolerance or immunological ignorance may have a critical role in improving long-term graft survival. Allogeneic tissues are frequently recognized by allospecific T cells as foreign and are rapidly rejected in the absence of immunosuppression. The higher susceptibility to cancer and infectious diseases of immunosuppressed patients led to investigation of new therapies to induce graft-specific tolerance. Peripheral tolerance to allogeneic grafts can be achieved by a variety of mechanisms including clonal deletion, suppression caused by regulatory T cells and anergy induction associated with microchimerism effect. In the last decades, potential candidates to confer allograft protection were identified. In this review, we summarize ongoing strategies and developments in genetic manipulation of cells, tissues and organs for allogeneic transplantation including modulating the effector arm of the immune response.     

Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis

Autoimmune diseases including multiple sclerosis (MS) are the result of an imbalanced immune tolerance network. Dendritic cells (DCs) are key players in both initiating immunity (immunogenic DCs) and regulating immune responses (tolerogenic DCs = tolDCs) and are potential targets for the treatment of MS. While the immunogenic potential of DCs in fighting infection and cancer has been well established, approaches that exploit their tolerogenic features to promote transplantation tolerance and autoimmunity have emerged only more recently. TolDCs usually maintain antigen‐specific T‐cell tolerance either directly by inducing anergy, apoptosis, or phenotype skewing or indirectly by induction of regulatory T (Treg) cells. The use of ex vivo‐generated tolDCs is an experimental approach to achieve tolerance towards myelin‐antigen‐specific CD4⁺ T cells. In the article by Ra?ch‐Regué and colleagues (Eur. J. Immunol. 2011. 42:772‐783) in this issue of the European Journal of Immunology, advances in human tolDC preparation and promise for autologous therapy are described. These findings raise hopes of achieving the "ideal" of a highly‐specific, causally‐oriented immune intervention for central nervous system (CNS) autoimmunity in MS. However, recent experience with antigen‐specific immune interventions in MS and some general caveats associated with cell‐based‐therapies highlight the challenges for clinical translation of the "immunologist's dream" of treating autoimmunity as discussed in this Commentary.     

The immune tolerance network: a new paradigm for developing tolerance-inducing therapies

Immune tolerance therapies are designed to reprogram immune cells in a highly specific fashion to eliminate pathogenic responses while preserving protective immunity. A concept that has tantalized immunologists for decades, the development of tolerance-inducing therapies, would revolutionize the management of a wide range of chronic and often debilitating diseases by obviating the need for lifelong immunosuppressive regimens. The advances of the past decade have provided a more detailed understanding of the molecular events associated with T-cell recognition and activation. Building on these advances, immunologists have demonstrated the feasibility of various tolerance-inducing approaches in small- and large-animal models of autoimmunity, allergy, and transplant graft rejection. Unprecedented opportunities to test these approaches in a variety of human diseases have now emerged. To capitalize on these advances, the National Institutes of Health recently established the Immune Tolerance Network (ITN), an international consortium of more than 70 basic and clinical immunologists dedicated to the evaluation of novel tolerance-inducing therapies and associated studies of immunologic mechanisms. By using a unique interactive approach to accelerate the development of clinical tolerance therapies, the ITN is partnering with the biotechnology and pharmaceutical industries to examine innovative tolerogenic approaches in a range of allergic and autoimmune diseases and to prevent graft rejection after transplantation. Two years since its inception, the ITN now has approximately 2 dozen clinical trials or tolerance assays studies ongoing or in later stages of protocol development. This report summarizes the rationale for emphasizing clinical research on immune tolerance and highlights the progress of the ITN.     

New Approaches to the Treatment of Pancreatic Cancer

The development of novel therapeutic strategies for pancreatic adenocarcinoma (PAC) has traditionally been considered particularly challenging for clinical and laboratory investigators due to its aggressive underlying biology and inherent resistance to currently available therapies. More recently, however, advances have been made in the identification of promising therapeutic targets for intervention, along with several key insights into the complex sequence of genetic alterations involved in the evolution of PAC from premalignant precursor lesion to malignant cells with metastatic potential. FOLFIRINOX (5-fluorouracil/leucovorin/irinotecan/oxaliplatin) has recently been identified as a combination cytotoxic therapy associated with a significant survival benefit over single-agent gemcitabine in good performance status patients with advanced disease; it is hoped that a similar benefit will be seen in planned trials of FOLFIRINOX as perioperative therapy. The success of immune therapy with the anti-cytotoxic T-lymphocyte antigen-4 antibody ipilimumab in advanced melanoma has spurred interest in the development of vaccines and immune therapies for other solid tumors. Certainly, the concept of harnessing the power of the immune system for cancer treatment is an attractive concept to patients and clinicians alike. Herein we discuss recent advances in the development of novel therapeutic approaches to PAC, focusing in particular on recent developments in immune and vaccine therapy.     

Autophagy inhibition in cancer therapy: metabolic considerations for antitumor immunity

Summary: Tumors and the immune system are intertwined in a competition where tilting the fine balance between tumor-specific immunity and tolerance can ultimately decide the fate of the host. Defensive and suppressive immunological responses to cancer are exquisitely sensitive to metabolic features of rapidly growing tumors, such as hypoxia, low nutrient availability, and aberrant growth factor signaling. As a result, clinical therapies impacting these properties change the in situ antitumor immune response by virtue of disrupting the tumor environment. To compensate for disruptions in cellular metabolism, cells activate autophagy to promote survival. On the basis of this notion, strategies designed to block autophagy in tumor cells are currently being tested in several human clinical trials. However, therapies that impair tumor metabolism must also take into account their effect on lymphocytes activated in the immune response to cancer. Given that a strong antitumor immune response is a positive prognostic factor in overall patient survival, identifying ways to block essential processes in tumor cells and suppressive immune cells while promoting those that are important for a robust immune response are of critical importance. Herein, we review the effects of anti-cancer agents that impact metabolism administered concurrently with autophagy inhibitors on immune cells and consider the implications for patient response to therapy.     

The struggle for iron: gastrointestinal microbes modulate the host immune response during infection

The gastrointestinal track is one source of potential bacterial entry into the host, and the local immune system at the mucosal border is paramount in establishing host immune tolerance and the immune response to invading organisms. Macrophages use iron for production of hydroxy-radical and superoxide reactions, which are necessary for microbial killing. Presumably, as a survival strategy, bacteria, which also require iron for survival, have adapted the ability to sequester iron from the host, thereby limiting the availability to macrophages. As current modes of antimicrobial therapy are evolving, examination of nontraditional therapies is emerging. One such potential therapy involves altering the bacterial micronutrient iron concentration. Necrotizing enterocolitis is a clinical condition where such a strategy makes intuitive sense. This review will describe the immune response to gastrointestinal infection, the mechanisms that the gastrointestinal system uses to absorb intraluminal iron, and the critical role iron plays in the infectious process.     

ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.     

Immune response to helper dependent adenoviral mediated liver gene therapy: challenges and prospects

Adenovirus-mediated gene therapy holds significant potential especially for applications requiring high levels of target tissue transduction. While significant advances in clinical adenoviral gene therapy applications have been made in cancer, the clinical translation of adenoviral gene replacement therapy for genetic disease has lagged. Encouragingly, advances in vector production have led to the development of Helper-Dependent ("gutted" or "high capacity") adenoviral vectors (HDV) deleted of all viral coding genes. HDV significantly reduces the chronic toxicity associated with early generation adenoviral vectors that has been most significant after systemic administration in both small and large animal models. However, the field remains confounded by innate immune responses inherent to adenovirus, and more generally, to the adaptive immune response to transgene. Together they decrease the effective therapeutic index for any particular treatment. This review summarizes the current advances toward understanding the decisive cell and molecular mechanisms underlying the acute toxicity to systemic HDV administration. We focus on the complex immune response and consequences of systemic vector delivery in the context of liver-directed monogenic disease therapy. Future development of interventions to avoid the innate immune response, including vector and pharmacologic manipulations, should further contribute to minimizing vector toxicity while maximizing the efficacy of systemic HDV gene transfer.     

To B or not to B cells‐mediate a healthy start to life

Maternal immune responses during pregnancy are critical in programming the future health of a newborn. The maternal immune system is required to accommodate fetal immune tolerance as well as to provide a protective defence against infections for the immunocompromised mother and her baby during gestation and lactation. Natural immunity and antibody production by maternal B cells play a significant role in providing such immunoprotection. However, aberrations in the B cell compartment as a consequence of maternal autoimmunity can pose serious risks to both the mother and her baby. Despite their potential implication in shaping pregnancy outcomes, the role of B cells in human pregnancy has been poorly studied. This review focuses on the role of B cells and the implications of B cell depletion therapy in pregnancy. It highlights the evidence of an association between aberrant B cell compartment and obstetric conditions. It also alludes to the potential mechanisms that amplify these B cell aberrances and thereby contribute to exacerbation of some maternal autoimmune conditions and poor neonatal outcomes. Clinical and experimental evidence suggests strongly that maternal autoantibodies contribute directly to the pathologies of obstetric and neonatal conditions that have significant implications for the lifelong health of a newborn. The evidence for clinical benefit and safety of B cell depletion therapies in pregnancy is reviewed, and an argument is mounted for further clinical evaluation of B cell‐targeted therapies in high‐risk pregnancy, with an emphasis on improving neonatal outcomes and prevention of neonatal conditions such as congenital heart block and fetal/neonatal alloimmune thrombocytopenia.     

Treatment of Graft-versus-Host Disease with Naturally Occurring T Regulatory Cells

A significant body of evidence suggests that treatment with naturally occurring CD4⁺CD25⁺ T regulatory cells (Tregs) is an appropriate therapy for graft-versus-host disease (GvHD). GvHD is a major complication of bone marrow transplantation in which the transplanted immune system recognizes recipient tissues as a non-self and destroys them. In many cases, this condition significantly deteriorates the quality of life of the affected patients. It is also one of the most important causes of death after bone marrow transplantation. Tregs constitute a population responsible for dominant tolerance to self-tissues in the immune system. These cells prevent autoimmune and allergic reactions and decrease the risk of rejection of allotransplants. For these reasons, Tregs are considered as a cellular drug in GvHD. The results of the first clinical trials with these cells are already available. In this review we present important experimental facts which led to the clinical use of Tregs. We then critically evaluate specific requirements for Treg therapy in GvHD and therapies with Tregs currently under clinical investigation, including our experience and future perspectives on this kind of cellular treatment.