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Glioblastomas (GBM) are the most frequent and aggressive malignant primary brain tumor and remains a therapeutic challenge: even after multimodal therapy, median survival of patients is only 15 months. Dendritic cell vaccination (DCV) is an active immunotherapy that aims at inducing an antitumoral immune response. Numerous DCV trials have been performed, vaccinating hundreds of GBM patients and confirming feasibility and safety. Many of these studies reported induction of an antitumoral immune response and indicated improved survival after DCV. However, two controlled randomized trials failed to detect a survival benefit. This raises the question of whether the promising concept of DCV may not hold true or whether we are not yet realizing the full potential of this therapeutic approach. Here, we discuss the results of recent vaccination trials, relevant parameters of the vaccines themselves and of their application, and possible synergies between DCV and other therapeutic approaches targeting the immunosuppressive microenvironment of GBM.

The innate immune system represents the first line of defense against influenza viruses, which cause severe inflammation of the respiratory tract and are responsible for more than 650,000 deaths annually worldwide. mRNA vaccines are promising alternatives to traditional vaccine approaches due to their safe dosing, low-cost manufacturing, rapid development capability, and high efficacy. In this review, we provide our current understanding of the innate immune response that uses pattern recognition receptors to detect and respond to mRNA vaccination. We also provide an overview of mRNA vaccines, and discuss the future directions and challenges in advancing this promising therapeutic approach.

Graftversushost disease (GVHD) is a common complication and the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Pharmacological immunosuppression used in GVHD prophylaxis and treatment lacks specificity and can increase the likelihood of infection and relapse. Regulatory T lymphocytes (Tregs) play a vital role in restraining excessive immune responses and inducing peripheral immune tolerance. In particular, clinical trials have demonstrated that Tregs can prevent and treat GVHD, without increasing the risk of relapse and infection. Hence, adoptive transfer of Tregs to control GVHD using their immunosuppressive properties represents a promising therapeutic approach. To optimally apply Tregs for control of GVHD, a thorough understanding of their biology is necessary. In this review, we describe the biological characteristics of Tregs, including how the stability of FOXP3 expression can be maintained. We will also discuss the mechanisms underlying Tregs-mediated modulation of GVHD and approaches to effectively increase Tregs’ numbers. Finally, we will examine the developing trends in the use of Tregs for clinical therapy.

© 2021 Jaén, Sánchez-García, Fernández-Velasco, Boscá and Prieto., Inflammation is an a physiological response instead an essential response of the organism to injury and its adequate resolution is essential to restore homeostasis. However, defective resolution can be the precursor of severe forms of chronic inflammation and fibrosis. Nowadays, it is known that an excessive inflammatory response underlies the most prevalent human pathologies worldwide. Therefore, great biomedical research efforts have been driven toward discovering new strategies to promote the resolution of inflammation with fewer side-effects and more specificity than the available anti-inflammatory treatments. In this line, the use of endogenous specialized pro-resolving mediators (SPMs) has gained a prominent interest. Among the different SPMs described, lipoxins stand out as one of the most studied and their deficiency has been widely associated with a wide range of pathologies. In this review, we examined the current knowledge on the therapeutic potential of lipoxins to treat diseases characterized by a severe inflammatory background affecting main physiological systems, paying special attention to the signaling pathways involved. Altogether, we provide an updated overview of the evidence suggesting that increasing endogenously generated lipoxins may emerge as a new therapeutic approach to prevent and treat many of the most prevalent diseases underpinned by an increased inflammatory response., This work was supported by Ministerio de Economıa, Industria y ́ Competitividad, Ministerio de Ciencia, Investigación y Universidades, and Agencia Estatal de Investigación (SAF2017-82436R), Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CB16/11/00222), Consorcio de Investigación en Red de la Comunidad de Madrid, S2017/BMD-3686 and Fondo Europeo de Desarrollo Regional. RI holds a FPU PhD fellowship of the Ministerio de Ciencia, Investigación y Universidades (FPU16/00827).

Vitiligo is a disease of the skin characterized by the appearance of white spots. Significant progress has been made in understanding vitiligo pathogenesis over the past 30 years, but only through perseverance, collaboration, and open-minded discussion. Early hypotheses considered roles for innervation, microvascular anomalies, oxidative stress, defects in melanocyte adhesion, autoimmunity, somatic mosaicism, and genetics. Because theories about pathogenesis drive experimental design, focus, and even therapeutic approach, it is important to consider their impact on our current understanding about vitiligo. Animal models allow researchers to perform mechanistic studies, and the development of improved patient sample collection methods provides a platform for translational studies in vitiligo that can also be applied to understand other autoimmune diseases that are more difficult to study in human samples. Here we discuss the history of vitiligo translational research, recent advances, and their implications for new treatment approaches.

Patients infected with SARS-CoV-2 show a wide spectrum of clinical manifestations ranging from mild febrile illness and cough up to acute respiratory distress syndrome, multiple organ failure, and death. Data from patients with severe clinical manifestations compared to patients with mild symptoms indicate that highly dysregulated exuberant inflammatory responses correlate with severity of disease and lethality. Epithelial-immune cell interactions and elevated cytokine and chemokine levels, i.e. cytokine storm, seem to play a central role in severity and lethality in COVID-19. The present perspective places a central cellular pro-inflammatory signal pathway, NF-κB, in the context of recently published data for COVID-19 and provides a hypothesis for a therapeutic approach aiming at the simultaneous inhibition of whole cascades of pro-inflammatory cytokines and chemokines. The simultaneous inhibition of multiple cytokines/chemokines is expected to have much higher therapeutic potential as compared to single target approaches to prevent cascade (i.e. redundant, triggering, amplifying, and synergistic) effects of multiple induced cytokines and chemokines in critical stage COVID-19 patients.

COVID-19 is a global pandemic currently in an acute phase of rapid expansion. While public health measures remain the most effective protection strategy at this stage, when the peak passes, it will leave in its wake important health problems. Historically, very few viruses have ever been eradicated. Instead, the virus may persist in communities causing recurrent local outbreaks of the acute infection as well as several chronic diseases that may arise from the presence of a "suppressed" virus or as a consequence of the initial exposure. An ideal solution would be an anti-viral medication that (i) targets multiple stages of the viral lifecycle, (ii) is insensitive to frequent changes of viral phenotype due to mutagenesis, (iii) has broad spectrum, (iv) is safe and (v) also targets co-morbidities of the infection. In this Perspective we discuss a therapeutic approach that owns these attributes, namely "lipid raft therapy." Lipid raft therapy is an approach aimed at reducing the abundance and structural modifications of host lipid rafts or at targeted delivery of therapeutics to the rafts. Lipid rafts are the sites of the initial binding, activation, internalization and cell-to-cell transmission of SARS-CoV-2. They also are key regulators of immune and inflammatory responses, dysregulation of which is characteristic to COVID-19 infection. Lipid raft therapy was successful in targeting many viral infections and inflammatory disorders, and can potentially be highly effective for treatment of COVID-19.

Food allergy is rising at an alarming rate and is a major public health concern. Globally, food allergy affects over 500 million people, often starting in early childhood and increasingly reported in adults. Commercially, only one approved oral immunotherapy-based treatment is currently available and other allergen-based immunotherapeutic are being investigated in clinical studies. As an alternative approach, a substantial amount of research has been conducted on natural compounds and probiotics, focusing on the immune modes of action, and therapeutic uses of such sources to tackle various immune-related diseases. Food allergy is primarily mediated by IgE antibodies and the suppression of allergic symptoms seems to be mostly modulated through a reduction of allergen-specific IgE antibodies, upregulation of blocking IgG, and downregulation of effector cell activation (e.g., mast cells) or expression of T-helper 2 (Th-2) cytokines. A wide variety of investigations conducted in small animal models or cell-based systems have reported on the efficacy of natural bioactive compounds and probiotics as potential anti-allergic therapeutics. However, very few lead compounds, unlike anti-cancer and anti-microbial applications, have been selected for clinical trials in the treatment of food allergies. Natural products or probiotic-based approaches appear to reduce the symptoms and/or target specific pathways independent of the implicated food allergen. This broad range therapeutic approach essentially provides a major advantage as several different types of food allergens can be targeted with one approach and potentially associated with a lower cost of development. This review provides a brief overview of the immune mechanisms underlying food allergy and allergen-specific immunotherapy, followed by a comprehensive collection of current studies conducted to investigate the therapeutic applications of natural compounds and probiotics, including discussions of their mode of action and immunological aspects of their disease-modifying capabilities.

Conditions in which abnormal or excessive immune responses exist, such as autoimmune diseases (ADs), graft-versus-host disease, transplant rejection, and hypersensitivity reactions, are serious hazards to human health and well-being. The traditional immunosuppressive drugs used to treat these conditions can lead to decreased immune function, a higher risk of infection, and increased tumor susceptibility. As an alternative therapeutic approach, cell therapy, in which generally intact and living cells are injected, grafted, or implanted into a patient, has the potential to overcome the limitations of traditional drug treatment and to alleviate the symptoms of many refractory diseases. Cell therapy could be a powerful approach to induce immune tolerance and restore immune homeostasis with a deeper understanding of immune tolerance mechanisms and the development of new techniques. The purpose of this review is to describe the current panoramic scope of cell therapy for immune-mediated disorders, discuss the advantages and disadvantages of different types of cell therapy, and explore novel directions and future prospects for these tolerogenic therapies.

Behcet's syndrome (BS) is a multisystemic vasculitis, characterized by different clinical involvements, including mucocutaneous, ocular, vascular, neurological, and gastrointestinal manifestations. Based on this heterogeneity, BS can be hardly considered as a single clinical entity. Growing evidence supports that, within BS, different phenotypes, characterized by clusters of co-existing involvements, can be distinguished. Namely, three major BS phenotypes have been reported: (a) the mucocutaneous and articular phenotype, (b) the extra-parenchymal neurological and peripheral vascular phenotype, and (c) the parenchymal neurological and ocular phenotype. To date, guidelines for the management of BS have been focused on the pharmacological treatment of each specific BS manifestation. However, tailoring the treatments on patient's specific phenotype, rather than on single disease manifestation, could represent a valid strategy for a personalized therapeutic approach to BS. In the present literature review, we summarize current evidence on the pharmacological treatments for the first-, second-, and third-line treatment of the major BS phenotypes.

For more than 25 years, dendritic cell (DC) based vaccination has flashily held promises to represent a therapeutic approach for cancer treatment. While the vast majority of studies has focused on the use of antigen loaded DC, the intratumoral delivery of unloaded DC aiming at in situ vaccination has gained much less attention. Such approach grounds on the ability of inoculated DC to internalize and process antigens directly released by tumor (usually in combination with cell-death-inducing agents) to activate broad patient-specific antitumor T cell response. In this review, we highlight the recent studies in both solid and hematological tumors showing promising clinical results and discuss the main pitfalls and advantages of this approach for endogenous cancer vaccination. Lastly, we discuss how in situ vaccination by DC inoculation may fit with current immunotherapy approaches to expand and prolong patient response.

The wound repair program is tightly regulated and coordinated among different cell constituents including epithelial cells, fibroblasts, immune cells and endothelial cells following consecutive steps to ensure timely, and proper wound closure. Specifically, innate and adaptive immune cells are pivotal participants that also closely interact with the vasculature. Tumors are portrayed as wounds that do not heal because they undergo continuous stromal remodeling and vascular growth with immunosuppressive features to ensure tumor propagation; a stage that is reminiscent of the proliferative resolution phase in wound repair. There is increasing evidence from mouse model systems and clinical trials that targeting both the immune and vascular compartments is an attractive therapeutic approach to reawaken the inflammatory status in the "tumor wound" with the final goal to abrogate tumor cells and invigorate tissue homeostasis. In this review, we compare the implication of immune cells and the vasculature in chronic wounds and tumor wounds to underscore the conceptual idea of transitioning tumors into an inflammatory wound-like state with antiangiogenic immunotherapies to improve beneficial effects in cancer patients. ispartof: FRONTIERS IN IMMUNOLOGY vol:10 ispartof: location:Switzerland status: published

Atherosclerosis is a chronic low-grade inflammatory disease that affects large and medium-sized arteries and is considered to be a major underlying cause of cardiovascular disease (CVD). The high risk of mortality by atherosclerosis has led to the development of new strategies for disease prevention and management, including immunonutrition. Plant-based dietary patterns, functional foods, dietary supplements, and bioactive compounds such as the Mediterranean Diet, berries, polyunsaturated fatty acids, ω-3 and ω-6, vitamins E, A, C, and D, coenzyme Q10, as well as phytochemicals including isoflavones, stilbenes, and sterols have been associated with improvement in atheroma plaque at an inflammatory level. However, many of these correlations have been obtained in vitro and in experimental animals' models. On one hand, the present review focuses on the evidence obtained from epidemiological, dietary intervention and supplementation studies in humans supporting the role of immunonutrient supplementation and its effect on anti-inflammatory response in atherosclerotic disease. On the other hand, this review also analyzes the possible molecular mechanisms underlying the protective action of these supplements, which may lead a novel therapeutic approach to prevent or attenuate diet-related disease, such as atherosclerosis.

Human immunodeficiency virus (HIV) establishes life-long latency in infected individuals. Although highly active antiretroviral therapy (HAART) has had a significant impact on the course of HIV infection leading to a better long-term outcome, the pool of latent reservoir remains substantial even under HAART. Numerous approaches have been under development with the goal of eradicating the latent HIV reservoir though with limited success. Approaches that combine immune-mediated control of HIV to activate both the innate and the adaptive immune system under suppressive therapy along with “shock and kill” drugs may lead to a better control of the reactivated virus. Interferon-α (IFN-α) is an innate cytokine that has been shown to activate intracellular defenses capable of restricting and controlling HIV. IFN-α, however, harbors numerous functional subtypes that have been reported to display different binding affinities and potency. Recent studies have suggested that certain subtypes such as IFN-α8 and IFN-α14 have potent anti-HIV activity with little or no immune activation, whereas other subtypes such as IFN-α4, IFN-α5, and IFN-α14 activate NK cells. Could these subtypes be used in combination with other strategies to reduce the latent viral reservoir? Here, we review the role of IFN-α subtypes in HIV infection and discuss the possibility that certain subtypes could be potential adjuncts to a “shock and kill” or therapeutic vaccination strategy leading to better control of the latent reservoir and subsequent functional cure.

Altres ajuts: BM1305 (COST action A FACTT). Polish Ministry of Science and Higher Education (grant no. IP2011 033771) and National Centre of Science, Poland (funding decision no. DEC-2011/01/D/NZ3/00262); National Centre for Research and Development (grants LIDER/160/L-6/14/NCBR/2015); grants G0801537/ID: 88245 and MR/J006742/1MR/J006742/1; grant from the Italian Telethon Foundation "Comitato Telethon Fondazione Onlus," Core grant TIGET TGT16G01 and the Italian Association for Cancer Research project IG 2013 N 14105 Adoptive therapy with regulatory T cells or tolerance-inducing antigen (Ag)- presenting cells is innovative and promising therapeutic approach to control undesired and harmful activation of the immune system, as observed in autoimmune diseases, solid organ and bone marrow transplantation. One of the critical issues to elucidate the mechanisms responsible for success or failure of these therapies and define the specificity of the therapy is the evaluation of the Ag-specific T-cell responses. Several efforts have been made to develop suitable and reproducible assays. Here, we focus on dye-based proliferation assays. We highlight with practical examples the fundamental issues to take into consideration for implementation of an effective and sensitive dye-based proliferation assay to monitor Ag-specific responses in patients. The most critical points were used to design a road map to set up and analyze the optimal assay to assess Ag-specific T-cell responses in patients undergoing different treatments. This is the first step to optimize monitoring of tolerance induction, allowing comparison of outcomes of different clinical studies. The road map can also be applied to other therapeutic interventions, not limited to tolerance induction therapies, in which Ag-specific T-cell responses are relevant such as vaccination approaches and cancer immunotherapy.

Leprosy remains a health problem in several countries. Current management of patients with leprosy is complex and requires multidrug therapy. Nonetheless, antibiotic treatment is insufficient to prevent nerve disabilities and control Mycobacterium leprae. Successful infectious disease treatment demands an understanding of the host immune response against a pathogen. Immune-based therapy is an effective treatment option for malignancies and infectious diseases. A promising therapeutic approach to improve the clinical outcome of malignancies is the blockade of immune checkpoints. Immune checkpoints refer to a wide range of inhibitory or regulatory pathways that are critical for maintaining self-tolerance and modulating the immune response. Programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4, and lymphocyte-activation gene-3 are the most important immune checkpoint molecules. Several pathogens, including M. leprae, are supposed to utilize these mechanisms to evade the host immune response. Regulatory T cells and expression of co-inhibitory molecules on lymphocytes induce specific T-cell anergy/exhaustion, leading to disseminated and progressive disease. From this perspective, we outline how the co-inhibitory molecules PD-1, PD-L1, and Th1/Th17 versus Th2/Treg cells are balanced, how antigen-presenting cell maturation acts at different levels to inhibit T cells and modulate the development of leprosy, and how new interventions interfere with leprosy development.

Chronic pain is a debilitating condition that still is challenging both clinicians and researchers. Despite intense research, it is still not clear why some individuals develop chronic pain while others do not or how to heal this disease. In this review, we argue for a multisystem approach to understand chronic pain. Pain is not only to be viewed simply as a result of aberrant neuronal activity but also as a result of adverse early-life experiences that impact an individual’s endocrine, immune, and nervous systems and changes which in turn program the pain system. First, we give an overview of the ontogeny of the central nervous system, endocrine, and immune systems and their windows of vulnerability. Thereafter, we summarize human and animal findings from our laboratories and others that point to an important role of the endocrine and immune systems in modulating pain sensitivity. Taking “early-life history” into account, together with the past and current immunological and endocrine status of chronic pain patients, is a necessary step to understand chronic pain pathophysiology and assist clinicians in tailoring the best therapeutic approach.

Regulatory T cells (Tregs) play an important role in preventing effector T-cell (Teff) targeting of self-antigens that can lead to tissue destruction in autoimmune settings, including type 1 diabetes (T1D). Autoimmunity is caused in part by an imbalance between Teff and Tregs. Early attempts to treat with immunosuppressive agents have led to serious side effects, thus requiring a more targeted approach. Low-dose IL-2 (LD IL-2) can provide immuno-regulation with few side effects by preferentially acting on Tregs to drive tolerance. The concept of LD IL-2 as a therapeutic approach is supported by data in mouse models where autoimmunity is cured and further strengthened by success in human clinical studies in Hepatitis C Virus (HCV) induced vasculitis, chronic graft vs host disease (GVHD) and Alopecia areata (AA). Treatment will require identification of a safe therapeutic window, which is a difficult task given that patients are reported to have deficient or defective IL-2 production or signalling and have experienced mild activation of NK cells and eosinophils with LD IL-2 therapy. In T1D, a LD IL-2 clinical trial concluded that Tregs can be safely expanded in humans; however, the study was not designed to address efficacy. Antigen-specific therapies have also aimed at regulation of the autoimmune response, but have been filled with disappointment despite an extensive list of diverse islet antigens tested in humans. This approach could be enhanced through the addition of LD IL-2 to the antigenic treatment regimen to improve the frequency and function of antigen-specific Tregs, without global immunosuppression. Here we will discuss the use of LD IL-2 and islet antigen to enhance antigen-specific Tregs in T1D and focus on what is known about their immunological impact, their safety and potential efficacy, and need for better methods to identify therapeutic effectiveness.

Since its widespread introduction in the early 1980s, immunoglobulin therapy (IG) has been extensively investigated to understand its mechanism of action and clinical benefits. Research has also continued to improve its production. The survival benefits of IG for patients with primary immunodeficiency (PID) are accepted (1). The basic principle of replacing the missing protein has led to proposals for progressive increases in dosage, delivered intravenously (2), or subcutaneously (3). It is suggested that continuously increasing IG trough levels decreases pulmonary infections and damage. In contrast, other studies on large patient cohorts found no correlation between IG trough level and the incidence of pneumonia and serious infections when trough levels were raised above 400 mg/dl (4, 5). Dosage and other aspects of the therapeutic regimen remain open questions even in the mainstream indication of substitution therapy in PID. These issues have influenced the development of product modifications such as highly concentrated solutions and fast infusion rates. They have also contributed to the increased usage of 16–20% IG infused subcutaneously. Simple replacement of the antibody defect in PID is now known to be an incomplete explanation of the mechanism of IG. A range of immunomodulatory and anti-inflammatory mechanisms are involved (6). These mechanisms are important in the role of IG in autoimmune disorders, particularly neuropathies including chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barre syndrome (GBS), and multifocal motor neuropathy (MMN). These indications represent the largest area of IG use in the established economies. They contribute greatly to the steady increase in demand for immunoglobulins experienced in the past 20 years, despite uncertainty in mechanisms of action. The increase in adverse events, such as thrombogenicity (7) and haemolysis (8), experienced in recent years makes a better understanding of mechanism and dosage even more important. The substantial increase in the usage of expensive IG products has also influenced developments in formulation and infusion practices. Faster infusion of more concentrated solutions will decrease hospital stay and costs. The subcutaneous route is supposedly easier and more convenient to deliver in home therapy settings (9), also potentially decreasing hospital stay. Although approved by regulatory agencies, these developments have yet to be validated through the long period of clinical practice experienced with the previous range of IG products. The increased demand for IG has also seen the rapid development of new manufacturing methods replacing the traditional Cohn fractionation system (10). This system has demonstrated decades of safety and efficacy and caution is warranted as new methods are introduced into production and clinical use. This Research Topic of Frontiers in Immunology has been assembled by an editorial team which have experienced sufficient “dark forebodings” (11) regarding the uncertainties outlined above. They have called upon a group of international experts to assess some of these issues from their perspective. The mechanism of IG on the immune system is explored by Nagelkerke and Kuijpers (12) who describe the different Fcγ receptors variants on immune cells and the direct IG effects at the level of the activating Fcγ receptors, including the more recently described FcgRIIc. Mitrevski et al. (13) assess analogous mechanisms in the action of IG in PID, showing that IG at replacement dosages could prime B cells to an anergic, apoptotic state through the generation of an increase in CD21low B cells. Matucci et al. (14) discuss the role of benefits additional to the direct substitution of deficient IG, such as the immunomodulatory and anti-inflammatory effects of IG preparations, while Paquin-Proulx and Sandberg (15) discuss the role of immune activation in the pathology of commonest PID – common variable immunodeficiency (CVID) – and its alleviation by IG therapies. Taken together, this body of work mitigates our “dark forebodings” regarding the lack of clarity on the mechanism of action of IG. More work is also needed to optimize therapeutic practice. Kerr et al. (16) note the desirability of progressing beyond simple, mandated, weight-based dosages in PID, and the need to approach more individualized therapeutic regimens for different PID patients. Their approach is augmented by the review of Wolf et al. (17) demonstrating how the identification of impaired IG formation may differentiate patients requiring IG from those who do not. Patient data collected through long term monitoring led Lucas et al. (18) to conclude that “The goal of replacement therapy should be to improve clinical outcome and not to reach a particular IgG trough level” supporting previous work tailoring optimal IG prophylaxis regimens to clinical and immunological markers (19). Studies such as those cited should influence treatment protocols and a negate a “one size fits all” therapeutic approach as reflected in many current guidelines. Kerr et al. (16) also note how little evidence underpins the dosage regimens used in autoimmune indications. It is to be wondered that empirically driven doses developed for the treatment of idiopathic thrombocytopenic purpura have been extended into the treatment of the various autoimmune neuropathies. The importance of individualizing treatment is also discussed by Compagno et al. (20) in their review of the use of IG in the various acquired hypogammaglobulinemic diseases. We are aware of large discrepancies between and within countries in this area, leading to the need for better evidence based on individualized treatment. Overall, these particular contributions support the need to improve outcomes in PID as shown by the study of Tabolli et al. (21) who conclude that Health-Related Quality of Life in PID patients is not related to IG therapy but to more sophisticated personal and clinical preferences. The final component of this Research Topic of Frontiers in Immunology examines the manufacture of IG therapies and its effect on the efficacy and safety of the products. Goldacker et al. (22) show that, despite the mandatory large plasma donation pool size for IG products, the content of specific, therapeutically important antibodies is still subject to geographical influence. This is very important in the context of continuing to ensure that IG therapies are relevant in the protection of PID patients in different countries. We suggest that this requires the attention of regulatory authorities. Finally, Farrugia and Quinti (23) and Spath et al. (24) discuss the history of the manufacture of IG therapies. They suggest ways whereby changes introduced by companies to optimize yield and minimize hospital related costs might alter the repertoire of specificities and the efficacy of IG. These changes may also have played a role in recently observed surges in adverse events. These observations suggest that a more cautionary approach in the usage IG therapies is warranted. Overall, the therapeutics of diseases caused by a deficiency or an inappropriate type of antibodies continues to be an exciting and fruitful area of clinical research, and well suited to contribute to the ongoing evolution in medicine toward more individualized and patient centric paradigms. We hope that this Research Topic of Frontiers in Immunology contributes to this debate. Such a wide debate between experts is necessary to enable the new challenges in immunoglobulin usage.

Immunooncology is still a growing area in cancer therapy. Drugs within this therapeutic approach do not directly target/attack the tumor but interfere with immune checkpoints and target or reprogram key metabolic pathways critical for anti-cancer immune defense. Indolamine 2,3-dioxygenase 1 (IDO1) and the tryptophan (TRP)-kynurenine pathway were identified as critical mechanisms in cancer immune escape and their inhibition as an approach with promising therapeutic potential. Particularly, a multitude of IDO1 inhibiting tryptophan analogs are widely applied in several clinical trials. However, this therapy results in a variety of implications for the patient's physiology. This is not only due to the inhibition of an enzyme important in almost every organ and tissue in the body but also because of the general nature of the inhibitor as an analog of a proteinogenic amino acid as well as the initiation of cellular detoxification known to affect inflammatory pathways. In this review we provide a deeper insight into the physiological consequences of an IDO1 inhibiting therapy based on TRP related molecules. We discuss potential side and off-target effects that contribute to the interpretation of unexpected positive as well as negative results of ongoing or discontinued clinical studies while we also highlight the potential of these inhibitors independent of the IDO1 signaling pathway.

Physical trauma can be considered an unrecognized "pandemic" because it can occur anywhere and affect anyone and represents a global burden. Following severe tissue trauma, patients frequently develop acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) despite modern surgical and intensive care concepts. The underlying complex pathophysiology of life-threatening ALI/ARDS has been intensively studied in experimental and clinical settings. However, currently, the coronavirus family has become the focus of ALI/ARDS research because it represents an emerging global public health threat. The clinical presentation of the infection is highly heterogeneous, varying from a lack of symptoms to multiple organ dysfunction and mortality. In a particular subset of patients, the primary infection progresses rapidly to ALI and ARDS. The pathophysiological mechanisms triggering and driving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced ALI/ARDS are still poorly understood. Although it is also generally unknown whether insights from trauma-induced ARDS may be readily translated to SARS-CoV-2-associated ARDS, it was still recommended to treat coronavirus-positive patients with ALI/ARDS with standard protocols for ALI/ARDS. However, this strategy was questioned by clinical scientists, because it was documented that some severely hypoxic SARS-CoV-2-infected patients exhibited a normal respiratory system compliance, a phenomenon rarely observed in ARDS patients with another underlying etiology. Therefore, coronavirus-induced ARDS was defined as a specific ARDS phenotype, which accordingly requires an adjusted therapeutic approach. These suggestions reflect previous attempts of classifying ARDS into different phenotypes that might overall facilitate ARDS diagnosis and treatment. Based on the clinical data from ARDS patients, two major phenotypes have been proposed: hyper- and hypo-inflammatory. Here, we provide a comparative review of the pathophysiological pathway of trauma-/hemorrhagic shock-induced ARDS and coronavirus-induced ARDS, with an emphasis on the crucial key points in the pathogenesis of both these ARDS forms. Therefore, the manifold available data on trauma-/hemorrhagic shock-induced ARDS may help to better understand coronavirus-induced ARDS.