Radioimmunologic tests in children with pruritus and with a combination of pruritus and allergic respiratory disease

Radioimmunological tests were carried out in 180 children with pruritus and 167 children with pruritus and allergic respiratory diseases. Difference between these groups was statistically insignificant in case of food allergy. Results of RAST were more often positive in case of respiratory allergy in the patients with pruritus and coexisting allergic respiratory diseases than in patients with skin involvement only. Reaction was more intense and allergy polyvalence measured with RAST was higher. All differences were statistically significant (p less than 0.001 or 0.01). Mean IgE levels was higher in children of all age groups in case of pruritus coexisting with allergic respiratory diseases.     

The multitasking mast cell: positive and negative roles in the progression of autoimmunity

Among the potential outcomes of an aberrantly functioning immune system are allergic disease and autoimmunity. Although it has been assumed that the underlying mechanisms mediating these conditions are completely different, recent evidence shows that mast cells provide a common link. Mast cells reside in most tissues, are particularly prevalent at sites of Ag entry, and act as sentinel cells of the immune system. They express many inflammatory mediators that affect both innate and adaptive cellular function. They contribute to pathologic allergic inflammation but also serve an important protective role in bacterial and parasite infections. Given the proinflammatory nature of autoimmune responses, it is not surprising that studies using murine models of autoimmunity clearly implicate mast cells in the initiation and/or progression of autoimmune disease. In this review, we discuss the defined and hypothesized mechanisms of mast cell influence on autoimmune diseases, including their surprising and newly discovered role as anti-inflammatory cells.     

Itch in Liver Disease: Facts and Speculations

Pruritus in hepatobiliary disease is commonly believed to be caused by retention of bile acids with their sequestration in the skin. HOwever, we have recently demonstrated that skin levels of bile acids in patients with cholestasis correlate poorly with pruritus. In this report, we present additional data concerning the relationship of pruritus to bile acid retention: (1) the urinary excretion of sulfated and nonsulfated bile acids was not significantly different in patients with cholestasis who itched compared to those who did not; (2) one patient with itch associated with a liver abscess had normal levels of bile acids in serum, skin, and urine; (3) patients with primary biliary cirrhosis who itched had lower serum bile acid levels than patients with mechanical biliary obstruction who did not itch.These studies support our premise that pruritus in hepatobiliary diseases is not directly related to bile acid retention. They suggest that the type of cholestatic disorder, and not simply the magnitude of the cholestasis, as estimated by the elevation of serum bile acids, is important. We propose that the agent responsible for pruritus is produced in response to cholestasis, possibly through activation of the alternate pathway of bile acid synthesis. Properties of the hypothetical pruritogen are discussed.     

MEDICAL PROGRESS: Histamine and the Antihistaminic Drugs

The tissues affected by histamine and anaphylactic reactions are identical. Epinephrine antagonizes the action of histamine by acting on effector cells in a direction opposite to that of histamine. The so-called antihistaminic drugs block rather than antagonize the action of histamine. The injection into the human body of epinephrine or certain antihistaminic substances provokes the release of histamine and thereby produces a rise in the histamine blood level.There is a remarkable conformity of potency of antihistaminics as determined by Dale experiments and by histamine intoxication experiments in the intact guinea pig. Neoantergan, Pyribenzamine and Histadyl are usually superior to other compounds when potency is assayed by these methods.All antihistaminics provide similar protection again animal anaphylaxis. Larger doses are necessary to protect against anaphylaxis than against histamine intoxication.The differences in potency as determined by Dale experiments and histamine experiments in animals are not found in clinical use. One compound is not generally superior to all others in the treatment of any one or several allergic disorders.The antihistaminic drugs are beneficial in the symptomatic treatment of allergic rhinitis, acute urticaria and angioneurotic edema, and mild non-infective bronchial asthma. Their effectiveness in the management of moderately severe and severe non-infective bronchial bronchial asthma; infective bronchial asthma; migraine; atopic dermatitis (disseminated neurodermatitis), and pruritus of skin disorders other than acute urticaria and angioneurotic edema, is not worthy of particular commendation.The size of the dose of any antihistaminic substance influences the incidence of but not the type of side-effect that may accompany its usage. The quality of side effects varies according to the drug, although there is an individuality of response for each patient which must be reckoned with. In selecting an antihistaminic compound it is necessary to consider the percentage of cases in which side effects occur, as well as the percentage of good results. Optimal results are obtained by employing combinations of compounds and changing from one to the other as the case demands.     

Marine algae as a potential pharmaceutical source for anti-allergic therapeutics

The prevalence of allergic diseases such as asthma, atopic dermatitis, and allergic rhinitis has increased during the last two decades and contributed a great deal to morbidity and an appreciable mortality in the world. Until now, few novel efficacious drugs have been discovered to treat, control or even cure these diseases with a low adverse-effect profile. Meanwhile, glucocorticoids are still the mainstay for the treatment of allergic disease. Therefore, it is necessary to isolate novel anti-allergic agents from natural resources. Recently, marine algae have received much attention as they are a valuable source of chemically diverse bioactive compounds with numerous health benefit effects. This review focuses on anti-allergic agents derived from marine algae and presents an overview of their pharmaceutical potential in the treatment of allergic disorders.     

Histamine and the antihistaminic drugs

The tissues affected by histamine and anaphylactic reactions are identical. Epinephrine antagonizes the action of histamine by acting on effector cells in a direction opposite to that of histamine. The so-called antihistaminic drugs block rather than antagonize the action of histamine. The injection into the human body of epinephrine or certain antihistaminic substances provokes the release of histamine and thereby produces a rise in the histamine blood level. There is a remarkable conformity of potency of antihistaminics as determined by Dale experiments and by histamine intoxication experiments in the intact guinea pig. Neoantergan, Pyribenzamine and Histadyl are usually superior to other compounds when potency is assayed by these methods. All antihistaminics provide similar protection again animal anaphylaxis. Larger doses are necessary to protect against anaphylaxis than against histamine intoxication. The differences in potency as determined by Dale experiments and histamine experiments in animals are not found in clinical use. One compound is not generally superior to all others in the treatment of any one or several allergic disorders. The antihistaminic drugs are beneficial in the symptomatic treatment of allergic rhinitis, acute urticaria and angioneurotic edema, and mild non-infective bronchial asthma. Their effectiveness in the management of moderately severe and severe non-infective bronchial bronchial asthma; infective bronchial asthma; migraine; atopic dermatitis (disseminated neurodermatitis), and pruritus of skin disorders other than acute urticaria and angioneurotic edema, is not worthy of particular commendation. The size of the dose of any antihistaminic substance influences the incidence of but not the type of side-effect that may accompany its usage. The quality of side effects varies according to the drug, although there is an individuality of response for each patient which must be reckoned with. In selecting an antihistaminic compound it is necessary to consider the percentage of cases in which side effects occur, as well as the percentage of good results. Optimal results are obtained by employing combinations of compounds and changing from one to the other as the case demands.     

Prevalence of intestinal parasites among individuals with allergic skin diseases

The prevalence of intestinal protozoans and helminths in stool samples of individuals with allergic cutaneous symptoms was evaluated to study a possible link between parasites and allergy. Altogether, 218 patients who had chronic urticaria, atopic dermatitis, or pruritus of unknown origin were included in the study. Standard laboratory tests for the detection of allergic etiology were performed for all patients. The presence of intestinal parasites was investigated using microscopy, immunofluorescence, and immunoenzymatic assays. Overall, protozoans and helminths were recovered from the stools of 48 subjects (P = 0.004), 18 of whom were affected with intestinal symptoms (P = 0.023). The presence of Giardia lamblia in the stools was significantly associated with allergic cutaneous manifestations (P = 0.030). In addition, patients with allergy were significantly more likely to have > or = 5 Blastocystis hominis organisms per field (P = 0.046). There was a set of patients with allergic cutaneous diseases in whom the presence of intestinal parasites may not be incidental.     

The Role of Heparanase in Pulmonary Cell Recruitment in Response to an Allergic but Not Non-Allergic Stimulus

Heparanase is an endo-β-glucuronidase that specifically cleaves heparan sulfate proteoglycans in the extracellular matrix. Expression of this enzyme is increased in several pathological conditions including inflammation. We have investigated the role of heparanase in pulmonary inflammation in the context of allergic and non-allergic pulmonary cell recruitment using heparanase knockout (Hpa^-/-) mice as a model. Following local delivery of LPS or zymosan, no significant difference was found in the recruitment of neutrophils to the lung between Hpa^-/- and wild type (WT) control. Similarly neutrophil recruitment was not inhibited in WT mice treated with a heparanase inhibitor. However, in allergic inflammatory models, Hpa^-/- mice displayed a significantly reduced eosinophil (but not neutrophil) recruitment to the airways and this was also associated with a reduction in allergen-induced bronchial hyperresponsiveness, indicating that heparanase expression is associated with allergic reactions. This was further demonstrated by pharmacological treatment with a heparanase inhibitor in the WT allergic mice. Examination of lung specimens from patients with different severity of chronic obstructive pulmonary disease (COPD) found increased heparanase expression. Thus, it is established that heparanase contributes to allergen-induced eosinophil recruitment to the lung and could provide a novel therapeutic target for the development of anti-inflammatory drugs for the treatment of asthma and other allergic diseases.     

Mechanisms underlying eosinophil trafficking and their relevance in vivo

After their formation in the bone marrow, eosinophils circulate with a short half-life and are distributed throughout the body, especially in mucosal and sub-mucosal regions. Although a small amount of these cells are normally seen in healthy tissue, blood and tissue eosinophilia is a hallmark of helminthic and allergic diseases. The role of eosinophils in the normal physiology of mucosal tissues is not understood, but there is good evidence to demonstrate that these cells protect the host at least against some intestinal helminths, specially those with a lung cycle. In addition, there are now many data that support a role for eosinophils in the pathophysiology of allergic diseases, such as asthma. Because helminthic diseases have been largely controlled in developed countries, there has been much interest in the development of drugs which affect eosinophil migration and/or activation in the tissue and which may, thus, be useful in the treatment of allergic conditions. The understanding of the mechanisms controlling eosinophil trafficking and/or activation are essential in the development of anti-eosinophil-based therapeutic strategies. The present paper reviews aspects of eosinophil biology with emphasis on the role of eosinophils in parasitic infections and allergy, the basic mechanisms underlying the trafficking of eosinophils into tissue and how these can be modulated pharmacologically.     

The status of corticosteroid therapy in dermatology

Therapy with systemic corticosteroids, despite attendant serious risks, is mandatory in diseases such as pemphigus, acute disseminated lupus erythematosus and some cases of exfoliative dermatitis that are ordinarily fatal, for in such cases life may be prolonged and the patients made comfortable. If no contraindications exist, therapy with corticosteroids is desirable, for diseases of short duration-contact dermatitis, serum sickness reactions and drug eruptions of all kinds-provided the causative factors have been removed and the reactions are causing severe distress.On the basis of encouraging reports in the literature corticosteroid therapy may be instituted with justification for a group of unrelated, intractable and discomforting diseases such as maddening pruritus ani, sclerema neonatorum, dermatomyositis, certain cases of sarcoidosis, berylliosis, Behcet's syndrome, universal calcinosis, Reiter's disease and ulcers of sickle-cell anemia. One must always bear in mind the well-defined contraindications to corticosteroid therapy and the hazards of its use, particularly if therapy is to be prolonged. Results from topical hydrocortisone therapy are particularly pleasing in chronic eczematous otitis externa and especially when it is combined with an antibiotic drug. Results are excellent also in nuchal eczema, dermatitis of the eyelids and in pruritus ani. More often than not, hydrocortisone ointment and lotions benefit more than do other standard remedies such diseases as atopic eczema, contact dermatitis, lichen simplex-chronicus and eczematized phases of conditions such as psoriasis and superficial mycotic infections. Preparations containing a combination of hydrocortisone and an antibiotic are more useful than hydrocortisone alone. When used with discrimination, with full attention to the selection of cases and proper concentration in the correct vehicle, hydrocortisone preparations in combination with antibiotics are excellent antieczematous agents.     

Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.     

Treatment of allergic asthma: Modulation of Th2 cells and their responses

Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.     

Targeting toll-like receptors for drug development: a summary of commercial approaches

Toll-like receptors (TLRs) play a fundamental role in recognizing infectious and noxious agents as well as products of tissue damage. They are capable of initiating both protective and damaging inflammatory and immune responses. Several biotechnology and pharmaceutical companies have programmes to develop new drugs that are either: agonists of TLRs to enhance immune responses against tumours and infectious agents, or to correct allergic responses; or antagonists designed to reduce inflammation due to infection or autoimmune disease. This article reviews the commercial approaches being undertaken to develop new TLR drugs.     

Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans

Mast cells are immune cells critical in the pathogenesis of allergic, but also inflammatory and autoimmune diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Contact dermatitis and photosensitivity are skin conditions that involve non-immune triggers such as substance P (SP), and do not respond to conventional treatment. Inhibition of mast cell cytokine release could be effective therapy for such diseases. Unfortunately, disodium cromoglycate (cromolyn), the only compound marketed as a mast cell "stabilizer", is not particularly effective in blocking human mast cells. Instead, flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions. Here, we first compared the flavonoid quercetin (Que) and cromolyn on cultured human mast cells. Que and cromolyn (100 μM) can effectively inhibit secretion of histamine and PGD(2). Que and cromolyn also inhibit histamine, leukotrienes and PGD(2) from primary human cord blood-derived cultured mast cells (hCBMCs) stimulated by IgE/Anti-IgE. However, Que is more effective than cromolyn in inhibiting IL-8 and TNF release from LAD2 mast cells stimulated by SP. Moreover, Que reduces IL-6 release from hCBMCs in a dose-dependent manner. Que inhibits cytosolic calcium level increase and NF-kappa B activation. Interestingly, Que is effective prophylactically, while cromolyn must be added together with the trigger or it rapidly loses its effect. In two pilot, open-label, clinical trials, Que significantly decreased contact dermatitis and photosensitivity, skin conditions that do not respond to conventional treatment. In summary, Que is a promising candidate as an effective mast cell inhibitor for allergic and inflammatory diseases, especially in formulations that permit more sufficient oral absorption.     

Neurotrophins in inflammatory lung diseases: modulators of cell differentiation and neuroimmune interactions

Chronic inflammatory lung diseases represent a group of severe diseases with increasing prevalence as well as epidemiological importance. Inflammatory lung diseases could result from allergic or infectious genesis. There is growing evidence that the immune and nervous system are closely related not only in physiological but also in pathological reactions in the lung. Extensive communications between neurons and immune cells are responsible for the magnitude of airway inflammation and the development of airway hyperreactivity, a consequence of neuronal dysregulation. Neurotrophins are molecules regulating and controlling this crosstalk between the immune and peripheral nervous system (PNS) during inflammatory lung diseases. They are constitutively expressed by resident lung cells and produced in increasing quantities by immune cells invading the airways under inflammatory conditions. They act as activation, differentiation and survival factors for cells of both the immune and nervous system. This article will review the most recent data of neurotrophin signaling in the normal and inflamed lung and as yet unexplored, roles of neurotrophins in the complex communication within the neuroimmune network.     

Does IgE bind to and activate eosinophils from patients with allergy?

Human eosinophils have been reported to express both the mRNA and protein for the high affinity IgE receptor (FcepsilonRI); it is speculated that this receptor plays a role in eosinophil mediator release in allergic diseases. However, questions still remain. How much of the FcepsilonRI protein is actually expressed on the cell surface of the eosinophil? If they are present, are these IgE receptors associated with effector functions of eosinophils? To address these issues, we studied blood eosinophils from patients with ragweed hay fever. A high level of low affinity IgG receptor (FcgammaRII, CD32), but no expression of FcepsilonRI, was detectable on the eosinophil surface by standard FACS analysis. However, after in vitro sensitization with biotinylated chimeric IgE (cIgE), cell-bound cIgE was detected by PE-conjugated streptavidin. This cIgE binding was partially inhibited by anti-FcepsilonRI mAb, suggesting that eosinophils do express minimal amounts of FcepsilonRI detectable only by a sensitive method. Indeed, FACS analysis of whole blood showed that eosinophils express approximately 0.5% of the FcepsilonRI that basophils express. When stimulated with human IgE or anti-human IgE, these eosinophils did not exert effector functions; there was neither production of leukotriene C4 or superoxide anion nor any detectable degranulation response. In contrast, eosinophils possessed membrane-bound human IgG and showed functional responses when stimulated with human IgG or anti-human IgG. Thus, IgG and/or cytokines, such as IL-5, appear to be more important for eosinophil activation in allergic diseases than IgE.     

THE SIGNIFICANCE OF INFECTION IN ALLERGIC DISEASE—Its Influence on Diagnosis and Management

The presence of infection in allergic disease produces a confused picture in which two different causative factors must be clearly separated by the physician if he is to treat the patient successfully. The effects of infection are not consistent. There are situations, as seen in infectious diseases, where symptoms of allergic disease are temporarily relieved and others where the infection may intensify or precipitate the allergic condition. It is likewise important to recognize the complications superimposed upon allergic disease by infection. In such cases, control of the infection is as dependent upon control of the allergy as it is upon antibiotics.     

THE SIGNIFICANCE OF INFECTION IN ALLERGIC DISEASE-Its Influence on Diagnosis and Management

The presence of infection in allergic disease produces a confused picture in which two different causative factors must be clearly separated by the physician if he is to treat the patient successfully. The effects of infection are not consistent. There are situations, as seen in infectious diseases, where symptoms of allergic disease are temporarily relieved and others where the infection may intensify or precipitate the allergic condition. It is likewise important to recognize the complications superimposed upon allergic disease by infection. In such cases, control of the infection is as dependent upon control of the allergy as it is upon antibiotics.     

Sex-related differences in SLIGRL-induced pruritus in mice

Aims

Pruritus is a common symptom of skin diseases, and is associated with impaired sleep quality and a considerable reduction in the patient's quality of life. Recently, it was reported that there are sex-specific differences in scratching behavior in chronic pruritus patients. Namely, female chronic pruritus patients scratch more and have significantly more scratch lesions than male patients. However, few animal studies have examined sex-related differences in scratching behavior. Thus, the present work investigated sex-related differences in animal pruritus using pruritogens, which are often used to create experimental animal models of itching.

Main methods

Acute pruritus was induced in ICR mice by a single intradermal injection of histamine, 4-methylhistamine, serotonin, compound 48/80, substance P (SP), or the proteinase-activated receptor-2 (PAR-2)-activating peptide SLIGRL-NH₂. Chronic pruritus was induced by 5 weeks of the repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB) to BALB/c mice.

Key findings

Female mice showed significantly higher scratching counts in SLIGRL-NH₂-induced pruritus than male mice. Conversely, there was no obvious sex-related difference in scratching behavior for the other pruritogens examined.

Significance

These results indicate that sex-related differences may exist in the pruritogen-responsive neurons that transmit the itch signal induced by SLIGRL-NH₂, but not by histamine or 5-HT.     

Targeting the Neurokinin Receptor 1 with Aprepitant: A Novel Antipruritic Strategy

Background

Chronic pruritus is a global clinical problem with a high impact on the quality of life and lack of specific therapies. It is an excruciating and frequent symptom of e.g. uncurable renal, liver and skin diseases which often does not respond to conventional treatment with e.g. antihistamines. Therefore antipruritic therapies which target physiological mechanisms of pruritus need to be developed. Substance P (SP) is a major mediator of pruritus. As it binds to the neurokinin receptor 1 (NKR1), we evaluated if the application of a NKR1 antagonist would significantly decrease chronic pruritus.

Methods and Findings

Twenty hitherto untreatable patients with chronic pruritus (12 female, 8 male; mean age, 66.7 years) were treated with the NKR1 antagonist aprepitant 80 mg for one week. 16 of 20 patients (80%) experienced a considerable reduction of itch intensity, as assessed by the visual analog scale (VAS, range 0 to 10). Considering all patients, the mean value of pruritus intensity was significantly reduced from 8.4 VAS points (SD +/−1.7) before treatment to 4.9 VAS points (SD +/−3.2) (p<0.001, CI 1.913–5.187). Patients with dermatological diseases (e.g. atopic diathesis, prurigo nodularis) had the best profit from the treatment. Side-effects were mild (nausea, vertigo, and drowsiness) and only occurred in three patients.

Conclusions

The high response rate in patients with therapy refractory pruritus suggests that the NKR1 antagonist aprepitant may indeed exhibit antipruritic effects and may present a novel, effective treatment strategy based on pathophysiology of chronic pruritus. The results are promising enough to warrant confirming the efficacy of NKR1 antagonists in a randomized, controlled clinical trial.