Pioglitazone restores mitochondrial oxidant production in CGD phagocytes and enhances their bactericidal capacity

In addition to having a nonfunctional NADPH oxidase, activated phagocytes from patients with chronic granulomatous disease (CGD) and gp91phox-/- mice (modeling X-linked CGD) lack oxidant production from mitochondria, as reported by authors Fernandez-Boyanapalli et al (http://www.jacionline.org/article/S0091-6749%2814%2901576-0/abstract) . Specifically, neutrophils and monocytes from blood, as well as recruited neutrophils and macrophages from inflamed tissues of CGD mice, failed to produce mitochondrial oxidants when activated. Deficient mitochondrial oxidant production was shown to contribute to impaired bactericidal activity against Staphylococcus aureus and Burkholderia cepacia in vitro. Importantly, the researchers demonstrated that mitochondrial oxidant production was restored (see Figure) following short-term treatment of CGD mice with pioglitazone, a PPAR? agonist approved for treatment of type 2 diabetes. Pioglitazone is known to induce metabolic changes that mimic “starvation signaling,” including altering mitochondrial functions. Treatment of CGD mice with pioglitazone restored the bactericidal activity of their phagocytes to approximately 30% of normal murine phagocytes and enhanced early bacterial clearance of S aureus in a peritonitis model. Treatment of monocytes from X-linked CGD patients with pioglitazone ex vivo similarly restored mitochondrial oxidant production supporting the hypothesis that pioglitazone may be useful therapeutically in the treatment of CGD.

Anti-IL-23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, pharmacokinetics, and biomarker results of a single-rising-dose, randomized, double-blind, placebo-controlled trial

Psoriasis, a chronic immune-mediated inflammatory skin disease, affects approximately 2% of the global population. Eighty to ninety percent of patients have plaque psoriasis, and the extent of the affected surface areas of the body and the degree of redness, hardening, and scaling of the skin define its severity. In addition to its negative effect on well-being and quality of life, moderate-to-severe psoriasis has comorbidities including increased risk of heart disease and stroke. Approximately 25% of psoriasis patients have moderate-to-severe disease.

Genome-wide association studies have previously linked a variant in the genes for the IL-23 receptor and the p19 subunit of IL-23, or IL-23A, to psoriasis susceptibility. BI 655066 is a fully-human IgG₁ mAb selective for IL-23A. In this phase I proof-of-concept study, Krueger et al evaluated the results of administering a single-rising-dose of BI 655066 to patients with moderate-to-severe plaque psoriasis (J Allergy Clin Immunol 2015, in press). The primary objective was to assess the safety and tolerability of BI 65066, which was done via physical examinations, vital signs, electrocardiogram, clinical laboratory tests, and occurrence of adverse events.  However, mechanistic effects of IL-23 blockade were explored by histologic methods, deep RNA sequencing, and quantitative RT-PCR methods.

The study, the first of its kind, found that the majority of patients well-tolerated single-dose BI 655066. The patients who received the antibody showed clinical improvement after 2 weeks that was maintained for up to 66 weeks after treatment. After 12 weeks, 87% of treated patients experienced a decrease in  the Psoriasis Area and Severity Index of  at least 75% (PASI75). The treatment and placebo groups reported a similar frequency of adverse events. Strong inhibition of IL-17 and disease-related genes related to the IL-23/Th17 axis was measured in antibody-treated patients.  Treatment responses were maintained in most patients until 24 weeks and a smaller subset of patients followed without additional treatment maintained clearing of psoriasis for 10 months or more.  The results support a new model for treating psoriasis and raise the possibility of attaining long-term remission from a single drug intervention.

Allergy to furry animals: New insights, diagnostic approaches, and challenges

The prevalence of allergy to furry animals has been increasing, and allergy to cats, dogs, or both is considered a major risk factor for the development of asthma and rhinitis. A workshop on furry animals was convened to provide an up-to-date assessment of our understanding of (1) the exposure and immune response to the major mammalian allergens, (2) the relationship of these responses (particularly those to specific proteins or components) to symptoms, and (3) the relevance of these specific antibody responses to current or future investigation of patients presenting with allergic diseases. In this review by Konradsen et al, research results discussed at the workshop are presented, including the effect of concomitant exposures from other allergens or microorganisms, the significance of the community prevalence of furry animals, molecular-based allergy diagnostics, and a detailed discussion of cat and dog components (J Allergy Clin Immunol 2015; 135: 616-625).

Exposure to allergens from these furry animals is ubiquitous, and the clinician should evaluate all patients with allergic airway disease for sensitization to animal dander. In fact, allergic sensitization to several mammalian animals is prevalent, which might reflect co-sensitization or cross-reactivity. In some countries sensitization to furry animals is associated with more severe allergic disease, which poses extended diagnostic and therapeutic challenges. An important step forward in the diagnosis of allergy to furry animals has been made with the introduction of molecular-based allergy diagnostics, which offer new opportunities for improved characterization. For example, it has been shown that IgE responses to different cat components can be induced through different routes of exposure and are associated with either inhalant symptoms or  food allergy. Cat IgA and other cat proteins carrying alpha-gal are present as minor constituents of cat dander extracts but are better represented in epithelial extracts.  Interestingly, the cross-reactivity between cat and pork albumin is the most consistent.

Although there is clear evidence for the clinical importance of analyzing cat components in relation to both alpha-gal and pork-cat syndrome, the authors believe that future studies will clarify the clinical utility of molecular-based allergy diagnostics in the management of patients sensitized to furry animals. The workshop identified 6 areas for future research related to the specific allergens derived from furry animals that could contribute to our understanding and management of relevant allergic diseases.

Question for the authors:

Based on what is already known about cat allergy, it seems that once an allergy to cat is established, immunotherapy may significantly improve outcomes for patients that suffer from asthma and rhinitis. What is known about cat immunotherapy as it relates to asthma and rhinitis outcomes, regardless of other allergies the patient may have?

Fel d 1 is the most important allergen in cat dander and up to 95% of cat-allergic patients are sensitized to this protein. Subcutaneous immunotherapy (SIT) with cat dander extract has been shown to improve symptom/medication scores for both asthma and rhinoconjunctivitis. In addition, SIT has been shown to decrease skin, conjunctival and bronchial allergen sensitivity and to induce production of IgG and IgG₄ antibodies towards Fel d 1. Accordingly, subcutaneous immunotherapy with cat dander extract is considered to be an effective treatment for both allergic asthma and rhinitis. ^[1-5]

1. Hedlin G, Graff-Lonnevig V, Heilborn H, et al. Immunotherapy with cat- and dog-dander extracts. V. Effects of 3 years of treatment. The Journal of allergy and clinical immunology 1991;87(5):955-64

2. Alvarez-Cuesta E, Cuesta-Herranz J, Puyana-Ruiz J, et al. Monoclonal antibody-standardized cat extract immunotherapy: risk-benefit effects from a double-blind placebo study. The Journal of allergy and clinical immunology 1994;93(3):556-66

3. Van Metre TE, Jr., Marsh DG, Adkinson NF, Jr., et al. Immunotherapy for cat asthma. The Journal of allergy and clinical immunology 1988;82(6):1055-68

4. Varney VA, Edwards J, Tabbah K, et al. Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 1997;27(8):860-7

5. Hedlin G, Wille S, Browaldh L, et al. Immunotherapy in children with allergic asthma: effect on bronchial hyperreactivity and pharmacotherapy. The Journal of allergy and clinical immunology 1999;103(4):609-14

Role of siglecs and related glycan-binding proteins in immune responses and immunoregulation

Recent years have seen a tremendous acceleration of knowledge in the field of glycobiology, revealing many intricacies and functional contributions that were previously poorly appreciated or even unrecognized. This review by Bochner and Zimmermann highlights several topics relevant to glycoimmunology in which mammalian and pathogen-derived glycans displayed on glycoproteins and other scaffolds are recognized by specific glycan-binding proteins (GBPs), leading to a variety of proinflammatory and anti-inflammatory cellular responses (J Allergy Clin Immunol 2015; 135: 598-608). Their main focus is on 2 families of GBPs, sialic acid–binding immunoglobulin-like lectins (siglecs) and selectins, which are involved in multiple steps of the immune response, including distinguishing pathogens from self, cell trafficking to sites of inflammation, fine-tuning of immune responses leading to activation or tolerance, and regulation of cell survival. Importantly for the clinician, accelerated rates of discovery in the field of glycoimmunology are being translated into innovative medical approaches that harness the interaction of glycans and GBPs to the benefit of the host and might soon lead to novel diagnostics and therapeutics.

Lectins are members of families with carbohydrate recognition domains, and glycosaminoglycan-binding proteins, which bind mostly sulfated glycosaminoglycans. The authors focus mainly on sialic acid–binding immunoglobulin-like lectins (siglecs), which are I-type (immunoglobulin superfamily–type) lectins, and selectins, a subset of the C-type (calcium-dependent) lectin family, which collectively function in the immune system in processes such as pathogen recognition and cell adhesion, activation, signaling, and death. The inhibitory function of siglecs is being exploited for suppressing unwanted immune responses, such as autoimmunity, transplantation, allergic diseases, and others. Current therapeutic approaches mainly involve the use of immunosuppressive drugs; however, this compromises normal immunity and thus carries risks. Novel methods are being explored that would induce antigen-specific tolerance while preserving protective immunity.

Although there is great complexity in glycobiology and glycoimmunology, clear patterns for the role of glycans and GBPs in immune responses are emerging. Glycans are one part of the immune system’s ability to distinguish self from danger; however, pathogens can sometimes use their glycocalyx to evade immune recognition. Similarly, cancer cells can adapt their glycome as part of an evolutionary advantage to evade immune reactivity. Glycans and GBPs are part of the regulation of recruitment of immune cells to sites of inflammation, and defects in GPBs or their ligands can lead to immunodeficiencies. The level of immune response or tolerance is regulated in part by glycans and GBPs, and knowledge of this balance is guiding targeted therapy by using novel approaches involving glycans, including vaccination. Several tactics exploiting glycoimmunology have already or will soon make their way to the clinic, and it is anticipated that additional therapeutic approaches will emerge as our understanding of the glycome and its function in immune responses expands.

Question for the authors:

Preserving protective immunity while suppressing unwanted immune responses would have momentous outcomes. Based on current research, when can clinicians expect to see novel therapeutics utilizing glycobiology in clinical trials?

A company called Glycomimetics, Inc. is already in advanced stages of clinical trials with a pan-selectin antagonist (full disclosure:  Dr. Bochner has received shares of stock from them as a result of my consulting efforts with them a few years ago).  Another company, Sialix, is focusing on therapies targeting specific glycans on cancers and other inflammation-related glycans.  We should soon know whether glycan-based vaccines will prove useful, and glycan-based targeting via liposomal delivery of drug payloads shows exciting beneficial effects in pre-clinical testing in various disease models.  So several glycan and glycan-binding protein based therapies are, or will soon be, in clinical trials.

The alpha gal story: Lessons learned from connecting the dots

Anaphylaxis is a severe allergic reaction that can be rapidly progressing and fatal; thus, establishing the etiology of anaphylaxis is pivotal to long-term risk management. Recently, Steinke and colleagues have identified a novel IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal) (J Allergy Clin Immunol 2015; 135: 589-596). IgE to alpha-gal has been associated with two distinct forms of anaphylaxis: i) immediate onset anaphylaxis during first exposure to intravenous cetuximab which is a monoclonal antibody specific for the epidermal growth factor receptor (EGFR), and ii) delayed onset anaphylaxis 3-6 hours after ingestion of mammalian food products (e.g., beef and pork). Results from their studies and those of others strongly suggest that tick bites are a cause, if not the only significant cause, of IgE antibody responses to alpha-gal in the southern, eastern and central United States, Europe, Australia and parts of Asia.

In 2004, cetuximab was in clinical trials for the treatment of metastatic colorectal cancer and was causing hypersensitivity reactions, but they were occurring primarily in a group of southern US states. Patients who had reactions to cetuximab also had IgE antibodies specific for this molecule before they started treatment. It was later determined that the antigen was alpha-gal which represents a major transplantation barrier between primates and other mammals. Humans and higher primates cannot produce alpha-gal which makes it possible for these animals to make IgG antibodies directed towards this oligosaccharide. The antibodies causing reactions to cetuximab overlapped the same geographical area where allergic reactions to red meat were occurring. It was later discovered that tick bites represent the most important cause of alpha-gal sensitization and that epidemiological evidence in the USA would suggest that the rise in the deer population has played an important role.

The results described in this review provide evidence that: IgE responses to an oligosaccharide can induce significant or severe allergic symptoms, demonstration of sensitization to this epitope by skin test often requires intradermal as well as prick test, ticks can induce high titer food specific IgE responses in adult life, and also that eating mammalian products carrying this epitope does not give rise to any symptoms during the first hour or more. The delay in onset of symptoms following eating red meat is best explained by delayed arrival of the relevant form of antigen in the circulation, but the question remains as to what form of glycoprotein or more likely glycolipid takes 3 hours or more to appear in the circulation. Finally, the often-rapid production of IgE antibodies to alpha-gal after tick bites provides a striking model of a parasite induced IgE response; however, it remains a challenge to identify why the response is so strong and why it is directed so consistently against the alpha-gal carbohydrate residue. 

Current biologics to treat inflammatory skin diseases

Psoriasis and atopic dermatitis (AD) are the most common inflammatory skin conditions that share similarities, including epidermal hyperplasia, marked T-cell and dendritic cell infiltration, and a relatively increased Th1 axis. However, T cell polarization differs and therapeutic targeting has confirmed that TNF-α, IL-17, and IL-23 are the main cytokine drivers of psoriasis while AD has been recently characterized as Th2/Th22 polarized, with some Th17 involvement. Noda et al detail the different therapeutic approaches that have been approved or being tested for these diseases (J Allergy Clin Immunol 2015; 135: 324-336).

Up to 3% of adults have psoriasis, which is associated with red scaly lesions, a shorter life span, and a high risk for cardiovascular diseases, obesity, and diabetes. Up to 20% of these patients have severe disease which requires systemic therapies. Conventional treatments for psoriasis such as phototherapy, methotrexate, cyclosporine, and aceitretin are associated with loss of efficacy, side effects and toxicity. This led to the introduction of biologics, selective immune antagonists, such as TNF-α and IL-12/IL-23p40, and IL-17A which have demonstrated higher efficacy and a better safety profile. Various biologics are FDA approved and have revolutionized the treatment of psoriasis and psoriatic arthritis. Despite the rapid improvements associated with biologics, high cost has driven the development of small-molecule, orally available treatments which provide alternatives to injection therapies.

AD is the most common inflammatory skin disorder affecting up to 25% of children and up to 7% of adults characterized by highly pruritic erythematous plaques that are prone to infections, which is rarely seen in patients with psoriasis.  Severe AD resistant to topical medications is treated with oral steroids, phototherapy and other immunosuppressants that are associated with inconvenience or toxicity, much like the conventional treatments for psoriasis. The inflammatory AD profile has only recently been established, characterized by overexpression of the Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL17, CCL18, and CCL26), as well as the Th22 cytokine IL-22. The Th17 axis is also activated in patients with AD and might have a role in promoting Th2 differentiation.  Studies on the effects of biologics in patients with AD are lagging behind psoriasis by about a decade, and selective antagonists are only recently being examined for the treatment of AD in clinical trials.  The drug dupilumab is currently in phase III trials for AD, which binds to IL-4 receptor alpha (IL-4Rα) and blocks IL-4 and IL-13 activity. The drug significantly reduced levels of the Th2 chemokines and reversed epidermal hyperplasia in phase I and II studies. Other phase I or II trials are underway that target various antagonists such as IL-12/23p40, IL-22, IL-31, IgE and TSLP.

The authors summarize that while psoriasis develops through well-understood mechanisms and has many targeted biologics with proved efficacy, clinical trials and subsequent molecular analyses using human samples will be able to clarify the relative roles of polar cytokines in patients with AD.

Are there any known side effects of immune suppression from the long term use of biologics? For example, is there data from the long term use of biologics that have been successful in other diseases such as arthritis or Crohn’s disease?

Reactivation of tuberculosis is the concern with the use of TNF blockers. No cumulative toxicity has been reported with up to 5-year exposure to ustekinumab in psoriasis patients (Papp KA et al. Br J Dermatol 2013).

Asthma phenotypes and the use of biologic medications in asthma and allergic disease

Asthma has traditionally been defined using non-specific clinical and physiologic variables which encompass multiple different phenotypes and is treated with non-specific anti-inflammatory therapies. However, it is increasingly recognized that human asthma is a heterogeneous disease. In their review, Fajt and Wenzel analyzed randomized double blind placebo controlled trials of molecularly targeted therapies in defined allergic disease and asthma phenotypes (J Allergy Clin Immunol 2015; 135: 299-310).

There is an increasing appreciation of heterogeneity within asthma and allergic diseases, based primarily on recent cluster analyses, molecular phenotyping, biomarkers and differential responses to targeted and non-targeted therapies. These pioneering studies have led to successful therapeutic trials of molecularly targeted therapies in defined phenotypes. Pathobiologic studies combined with therapeutic trials of type-2 targeted therapies either approved or in clinical trials include those targeted to IgE, IL-5, IL-13, the IL-4 receptor alpha (IL-4Rα) and thymic stromal lymphopoietin (TSLP). IgE was the first successful biological target used in allergic disease and asthma with the overall success of the drug omalizumab (humanized monoclonal anti-IgE antibody) by reducing the allergic asthmatic response. Omalizumab has been shown to be effective in treating allergic rhinitis and peanut allergy although it is not FDA approved for these indications. The authors review other therapies targeting the canonical type-2 cytokines IL-4, IL-5, and IL-13 that have shown consistent efficacy especially in asthma with evidence for a Th2/type-2 inflammation (“type-2 high asthma”).

Recent clustering, molecular studies and treatment trials have begun to suggest that type-2 asthma itself represents several different molecular phenotypes. Data are emerging that late onset, less allergic but highly eosinophilic asthma may respond better to IL-5 targeted therapies than earlier onset (allergic) asthma, while in allergic models of asthma, anti-IL-4/13 approaches appear superior. However, approximately half of all asthmatics do not have evidence for type-2 inflammation, called “type-2 low asthma” which is defined by the absence of type-2 cytokines and their downstream signatures. This group is poorly defined, clinically heterogeneous and without specific biomarkers making molecular phenotyping and targeted therapy approaches difficult.  Non-type-2 patients generally have adult onset disease, often in association with obesity, post-infectious, neutrophilic and smoking related factors and are less likely to be atopic/allergic.

As the results of these studies summarized in this manuscript are varied even for antibodies directed towards the same biologic pathway, it is appreciated that the response to a biologic medication can be confounded by multiple factors including treatment duration, dose, phenotype and differing outcome measures assessed. Moving forward, it will be critical to determine the optimal biomarkers necessary to determine which patients will derive the best therapeutic benefit from each specific targeted medication. 



Question for the authors:
Considering many who suffer from allergic asthma can have multiple allergic diseases such as atopic dermatitis, allergic rhinitis and food allergy, are there studies that resulted in improvement of multiple atopic diseases in the same patient?


There are a few studies which come to mind:

In the Corren et al. (JACI, 2011), in patients with a history of cat allergen–induced asthma, treatment with omalizumab reduced the severity of acute airway reactions and symptoms (including  allergic rhinoconjunctivitis)  caused by controlled cat room exposure to allergens.

In the SOLAR study (Vignola, Allergy, 2004), asthmatic patients with allergic rhinitis treated with omalizumab not only experienced fewer asthma exacerbations but also had clinically significant improvement in both Asthma Quality of Life Questionnaire and Rhinitis Quality of Life Questionnaire scores.

In terms of the monoclonal antibody to IL4R, dupilumab, 2 separate studies showed strong efficacy in atopic dermatitis and in asthma. In adults with moderate-to-severe atopic dermatitis despite treatment with topical corticosteroids and calcineurin inhibitors, Beck et al. (NEJM, 2014) showed that dupilumab treatment resulted in marked clinical efficacy and medication reduction.  In moderate-severe asthma on mid-high dose ICS/LABA with Type-2 High Phenotype, Wenzel et al. (NEJM, 2013) showed that dupilimab therapy resulted in a ↓ in asthma exacerbation, rescue beta agonist use, upper airway symptoms and exhaled nitric oxide.

These studies suggest that the same biologic target may be efficacious in more than 1 allergic disease, but further studies are needed to specifically address this question.