Galcanezumab: First Global Approval.

Galcanezumab-gnlm (Emgality™; Eli Lilly and Company), hereafter galcanezumab, is a humanized monoclonal antibody against the calcitonin gene-related peptide (CGRP) ligand. A potent vasodilator, CGRP is implicated in nociceptive transmission and migraine pathogenesis. In September 2018, the US FDA approved galcanezumab as a once-monthly subcutaneous injection for the preventive treatment of migraine in adults. In the same month, the EMA issued a positive opinion for galcanezumab for the prophylaxis of migraine in adults who have at least 4 migraine days per month. Galcanezumab is also undergoing phase III evaluation for the preventive treatment of cluster headache in North America and Europe. This article summarizes the milestones in the development of galcanezumab leading to its first approval for the preventive treatment of migraine in adults.

Implications of a vasodilatory human monoclonal autoantibody in postural hypotension.

Functional autoantibodies to the autonomic receptors are increasingly recognized in the pathophysiology of cardiovascular diseases. To date, no human activating monoclonal autoantibodies to these receptors have been available. In this study, we describe for the first time a ß2-adrenergic receptor (ß2AR)-activating monoclonal autoantibody (C5F2) produced from the lymphocytes of a patient with idiopathic postural hypotension. C5F2, an IgG3 isotype, recognizes an epitope in the N terminus of the second extracellular loop (ECL2) of ß2AR. Surface plasmon resonance analysis revealed high binding affinity for the ß2AR ECL2 peptide. Immunoblotting and immunofluorescence demonstrated specific binding to ß2AR in H9c2 cardiomyocytes, CHO cells expressing human ß2AR, and rat aorta. C5F2 stimulated cyclic AMP production in ß2AR-transfected CHO cells and induced potent dilation of isolated rat cremaster arterioles, both of which were specifically blocked by the ß2AR-selective antagonist ICI-118551 and by the ß2AR ECL2 peptide. This monoclonal antibody demonstrated sufficient activity to produce postural hypotension in its host. Its availability provides a unique opportunity to identify previously unrecognized causes and new pharmacological management of postural hypotension and other cardiovascular diseases.

Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis.

RATIONALE: Previous studies suggest an important immunoregulatory role of vasoactive intestinal peptide (VIP) in experimental models of chronic noninfectious inflammation. Sarcoidosis is characterized by noncaseating epitheloid cell granulomas, where excessive tumor necrosis factor-alpha production by pulmonary macrophages plays a critical role in granuloma formation and disease progression, which may lead to fatal organ dysfunction. OBJECTIVES: To test whether inhaled VIP has an immunoregulatory role. Sarcoid alveolitis was used as a prototype of immune-mediated chronic lung inflammation. METHODS: In an open clinical phase II study, we treated 20 patients with histologically proved sarcoidosis and active disease with nebulized VIP for 4 weeks. MEASUREMENTS AND MAIN RESULTS: VIP inhalation was safe, well-tolerated, and significantly reduced the production of tumor necrosis factor-alpha by cells isolated from bronchoalveolar lavage fluids of these patients. VIP treatment significantly increased the numbers of bronchoalveolar lavage CD4(+)CD127(-)CD25(+) T cells, which showed regulatory activities on conventional effector T cells. In vitro experiments demonstrated the capacity of VIP to convert naive CD4(+)CD25(-) T cells into CD4(+)CD25(+)FoxP3(+) regulatory T cells, suggesting the generation of peripheral regulatory T cells by VIP treatment. CONCLUSIONS: This study is the first to show the immunoregulatory effect of VIP in humans, and supports the notion of inhaled VIP as an attractive future therapy to dampen exaggerated immune responses in lung disorders. Thus, the inhalation of neuropeptides may be developed into a new therapeutic principle for chronic inflammatory lung disorders in humans.

Effects of pentoxifylline during Schistosoma mansoni infection in Swiss mice: an analysis of worm burden, fecundity and liver histopathology.

The short-term effects of pentoxifylline (PTX) on granulomatous lesions during Schistosoma mansoni infection in Swiss mice were evaluated. Drug administration was initiated 42 and 140 days post-infection (DPI) for the acute and chronic infection groups, respectively. Treatment was carried out daily with 200 mg/kg (subcutaneous route) of the drug for five consecutive days. Recovery of parasites and tissues was performed at 49 DPI and 147 DPI, respectively. Liver histological analysis showed a decrease in the inflammatory reaction and fibrous content of the granulomas studied, and a significant reduction (P < 0.001) in their mean diameter was observed in the groups of rodents treated with PTX in acute and chronic infection, when compared to their respective control groups. However, no alteration in the number of S. mansoni recovered from the portal system was observed, and egg-laying kinetics was not notably modified by PTX treatment, and the immature stage distribution of S. mansoni eggs showed minor intrinsic variations with no statistical differences in the parameter second-stage/female/g among untreated mice and treated mice in acute and chronic infections, respectively, when evaluated by intestinal oograms. Data obtained indicate probable immunomodulatory effects of PTX in murine schistosomiasis both in acute and chronic infection.

Na-Tosyl-Phe chloromethyl ketone prevents granule movement and mast cell synergistic degranulation elicited by costimulation of antigen and adenosine.

Adenosine has been shown to enhance mast cell degranulation when added together with an antigen. Such augmentation of mast cell activation is relevant to exacerbation of allergic asthma symptoms. Na-Tosyl-Phe chloromethyl ketone (TPCK) is a chymotrypsine-like chymase inhibitor, which has anti-inflammatory properties. In this study, we investigated the effects of TPCK on mast cell synergistic degranulation induced by antigen and adenosine. Here, we report that TPCK almost completely suppressed enhanced degranulation by inhibiting granule movement. Consistent with this, intraperitoneal administration of TPCK resulted in significant amelioration of passive cutaneous anaphylaxis in mice. Furthermore, we demonstrated that TPCK completely inhibited Thr308 phosphorylation of protein kinase B in mast cells stimulated with antigen and adenosine. These results provide a novel action of TPCK for the prevention of mast cell degranulation induced by antigen and adenosine.

Pediatric angioedema.

Angioedema is a self-limited nonpitting edema generally affecting the deeper layers of the skin and mucous membranes. It is the result of increased vascular permeability causing the leakage of fluid into the skin in response to potent vasodilators released by immunologic mediators. Two main pathways are thought to be implicated in angioedema. The mast cell pathway in which preformed mediators, such as histamine, rapidly formed mediators, leukotrienes and prostaglandins, are released from mast cells through IgE or direct activation. This is the most common pathway among children, with food, medications, and infections commonly implicated. The second pathway is the kinin pathway, most notably affected by angiotensin-converting enzyme (ACE) inhibitors and hereditary forms of angioedema, which ultimately results in the formation of bradykinin, a potent vasodilator. Angioedema is being encountered with increasing frequency, particularly among children and is important to recognize and treat for its life-threatening associated manifestations such as anaphylaxis and airway obstruction. Although angioedema is still not fully understood, we have broadened our understanding of the possible causes and clinical course of angioedema. An understanding of these potential causes and mechanisms by which angioedema can occur may guide the clinician in determining the need for diagnostic testing and the extent of treatment.

Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry?

Chronic fatigue syndrome is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory. Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, nitric oxide, endogenous opioids and insulin, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault, promotion of neural development and the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection, significant physical exercise or de novo. It is proposed that release of these substances is accompanied by a loss of tolerance either to them or their receptor binding sites in CFS. Such an occurrence would have predictably serious consequences resulting from compromised function of the key roles these substances perform. All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation. Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition. The novel status of these substances together with their extremely small concentrations in blood and tissues means that clinical research into them is still in its infancy. A biologically plausible theory of CFS causation associated with vasoactive neuropeptide dysfunction would promote a coherent and systematic approach to research into this and other possibly associated disabling conditions.

Is sudden infant death syndrome (SIDS) an autoimmune disorder of endogenous vasoactive neuropeptides?

Sudden infant death syndrome (SIDS) remains a perplexing diagnosis with conflicting laboratory investigation and lack of a biologically plausible aetiology. Investigations into the endogenous vasoactive neuropeptides, including pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are revealing the critical role these substances have in homeostasis including thermo- and cardiovascular regulation. For example, studies in PACAP receptor-deficient mice have revealed sudden neonatal death attributed to respiratory control defects, possibly due to mutations in genes encoding components of PACAP signalling pathways. PACAP and VIP belong to the secretin/glucagon superfamily of hormones and function as vasoactive neuropeptides. They act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to small peptide fragments. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Vasoactive neuropeptides have a known role in thermoregulation and deficiency states are associated with higher neonatal death rates in rats. PACAP plays a significant role in carbohydrate and lipid metabolism and impairment of functioning has potentially serious consequences. It is postulated PACAP and VIP receptors in brain may become compromised through autoimmune phenomena resulting in cardio-respiratory dysfunction and death. This paper discusses the potential role of certain vasoactive neuropeptides in causing autoimmune responses in susceptible infants predisposing them to SIDS.

Is Gulf War Syndrome an autoimmune disorder of endogenous neuropeptides, exogenous sandfly maxadilan and molecular mimicry?

Gulf War Syndrome (GWS) remains a contentious diagnosis with conflicting laboratory investigation and lack of a biologically plausible aetiology. This paper discusses the potential role of maxadilan, a potent sandfly vasoactive peptide, in causing autoimmune responses in susceptible individuals through possible molecular mimicry with pituitary adenylate cyclase activating polypeptide (PACAP) and the PAC1R receptor. Gulf War Syndrome may share some causative pathology with Chronic Fatigue Syndrome (CFS), a disorder characterised by prolonged fatigue and debility mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory has been recently raised as possible cause of CFS. Vasoactive neuropeptides act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to small peptide fragments. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. Maxadilan, while not sharing substantial sequence homology with PACAP is a known agonist of the PACAP specific receptor (PAC1R) and therefore emulates these functions. Moreover a specific amino acid sequence peptide deletion within maxadilan converts it to a PACAP receptor antagonist raising the possibility of this substance provoking a CFS like response in humans exposed to it. This paper describes a biologically plausible mechanism for the development of a GWS-like chronic fatigue state based on loss of immunological tolerance to the vasoactive neuropeptide PACAP or its receptor following bites of the sandfly Phlebotomus papatasi and injection of the vasodilator peptide maxadilan. Exacerbation of this autoimmune response as a consequence of recent or simultaneous multiple vaccination exposures deserves further investigation. While the possible association between the relatively recently discovered vasoactive neuropeptides and chronic fatigue conditions has only recently been reported in the literature, this paper explores links for further research into GWS and CFS.

Is fibromyalgia an autoimmune disorder of endogenous vasoactive neuropeptides?

Fibromyalgia (FM) is a disorder characterised by soft tissue pain, disturbance of function an often prolonged course and variable fatigue and debility. A clearly defined aetiology has not been described. This paper proposes that immunological aberration is likely and this may prove to be associated with an expanding group of novel vasoactive neuropeptides. Vasoactive neuropeptides act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to small peptide fragments. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault and the maintenance of homeostasis. Failure of these substances has adverse consequences for homeostasis. This paper describes a biologically plausible mechanism for the development of FM based on loss of immunological tolerance to the vasoactive neuropeptides. The proposed mechanism of action is that inflammatory cytokines are provoked by tissue injury from unaccustomed exercise or physical injury. This may trigger a response by certain vasoactive neuropeptides which then undergo autoimmune dysfunction as well as affecting their receptor binding sites. The condition may potentially arise de novo perhaps in genetically susceptible individuals. FM is postulated to be an autoimmune disorder and may include dysfunction of purine nucleotide metabolism and nociception.

Is osteoporosis linked to vaccinations and Gulf War Syndrome?

Gulf War Syndrome (GWS) remains a contentious diagnosis with conflicting laboratory investigations and lack of a biologically plausible aetiology. Assertions have been made that GWS may be the result of vaccinations given to serving military personnel in the Persian Gulf and may be associated with osteoporosis. Calcitonin gene related protein (CGRP) is a vasoactive neuropeptide that is synthesised in conjunction with calcitonin gene expression. Vasoactive neuropeptides act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to small peptide fragments. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions. This paper describes a biologically plausible mechanism for the development of osteoporosis in the context of GWS based on loss of immunological tolerance to the vasoactive neuropeptide CGRP or its receptors following a variety of antigenic events.

Interleukin-1 beta rapidly inhibits aortic endothelium-dependent relaxation by a DNA transcription-dependent mechanism.

OBJECTIVES: This study examined the effects of interleukin-1 beta on isometric tension development and relaxation in isolated rat aortic rings in response to the alpha-1 adrenergic agonist phenylephrine, the endothelium-dependent vasodilator acetylcholine, and the endothelium-independent vasodilator sodium nitroprusside. DESIGN: Randomized, controlled, paired design. SETTING: Animal laboratory within a university department of physiology. SUBJECTS Paired aortic thoracic aortic rings from specific pathogen-free Sprague-Dawley rats. INTERVENTIONS: Series I examined the potential for interleukin-1 beta to cause early arterial endothelial dysfunction. Paired aortic rings were incubated for 2 hrs with interleukin-1 beta or vehicle. Series II examined the potential for inhibition of DNA transcription to attenuate interleukin-1 beta-mediated endothelial dysfunction. Paired rings received either dactinomycin or vehicle before interleukin-1 beta incubation. Series III quantified the degree to which inhibition of DNA transcription inhibited early interleukin-1 beta-mediated endothelial dysfunction. Paired rings received either dactinomycin pretreatment followed by interleukin-1 beta incubation, or pretreatment and incubation with inert vehicles. Series IV assessed the effects of interleukin-1 beta on responsiveness to an exogenous nitric oxide donor, sodium nitroprusside, in the presence of the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester. MEASUREMENTS AND MAIN RESULTS: Incubation with interleukin-1 beta for 2 hrs had no effect on contractile response but attenuated endothelium-dependent relaxation significantly relative to control. Dactinomycin pretreatment inhibited early interleukin-1 beta-mediated endothelial dysfunction. The combination of interleukin-1 beta and dactinomycin produced effects on endothelium-dependent relaxation that were not different from that seen in rings not exposed to interleukin-1 beta. Interleukin-1 beta attenuated responsiveness to sodium nitroprusside relative to control. CONCLUSIONS: Interleukin-1 beta causes an early impairment of endothelium-dependent vasorelaxation with an onset that precedes its effects on systemic contractility. This impairment occurs via a mechanism that is wholly or predominantly dependent on DNA transcription. The altered vasorelaxation induced by interleukin-1 beta is at least partly mediated by a reduction in nitric oxide responsiveness.

[Intradermal tests with vasomotor agents in chronic noninfectious rhinitis]. / Intradermalni testovi vazomotornim agensima kod hronicnog, neinfektivnog rinitisa.

The aim of this prospective study was to examine the skin reactivity to four vasomotor agents in chronic, non-infectious rhinitis patients, and to determine whether non-allergic rhinitis (NAR) patients differ from allergic rhinitis (AR) patients. Seventy four patients with NAR and 44 with AR were subjected to intradermal testing with papaverine (5 mg/ml), metacholine (0.02, 0.2 and 2.0 mg/ml), histamine (0.01, 0.1, 1.0 and 10.0 micrograms/ml), compound 48/80 (0.01, 0.1, 1.0 and 10.0 micrograms/ml) and saline. It was found that the frequency of pathological skin reactivity to papaverine in the patients with NAR (25/74) was significantly greater (p = 5.0 x 10(-3)) then in the patients with AR (4/44). No significant inter-group difference in skin reactivity to metacholine, histamine, compound 48/80 and saline was observed. The frequency of the total pathological skin reactivity to vasomotor agents, singly and in combinations, in patients with NAR (80%) was significantly greater (p = 0.03) than in patients with AR (61%). These findings suggested that the pathological skin reactivity to papaverine, metacholine, histamine and compound 48/80 was a feature of chronic, non-infectious rhinitis patients and it was more frequently associated with non-allergic than with the allergic etiology of rhinitis.

A multi-centre, double-blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome.

OBJECTIVE: To evaluate the safety of liposomal PGE1 (TLC C-53) in patients with acute respiratory distress syndrome (ARDS), and determine its efficacy in improving oxygenation and reducing ventilator dependency. DESIGN: A multi-centre, randomized, double-blind, placebo-controlled clinical study. SETTING: Thirty-one hospitals in six European countries. PATIENTS: One hundred two patients with ARDS. INTERVENTIONS: Patients were randomized in a 2:1 ratio to receive infusions of either the study drug TLC C-53 or placebo. Infusions were given over 60 min every 6 h for 7 days. The dose of study drug started at 0.6 microg/kg per h, rising over 24 h to a maximum dose of 1.8 microg/kg per h. MEASUREMENTS AND MAIN RESULTS: Seventy patients received the study drug and 32 placebo. Sixty-nine patients (47 treatment, 22 placebo) completed the study protocol. Patients were monitored for changes in the PaO2/FIO2 ratio, changes in lung compliance, time to off-ventilator and 28-day mortality, in addition to basic haematological and haemodynamic parameters. There were no significant differences in demographics and baseline characteristics between the two groups. There were no differences in the time to off-ventilation (16 days with treatment, 16.6 days with placebo, p=0.94) or in 28-day mortality (30% with treatment, 28% with placebo, p=0.78). There was a difference in the time to achieve a PaO2/FIO2 ratio above 300 in favour of TLC C-53 (10.3 versus 26.5 days) but this was not statistically significant (p=0.23). CONCLUSIONS: TLC C-53 was generally well-tolerated but failed to reduce mortality or duration of mechanical ventilation.

[Intradermal tests using vasomotor agents in allergic rhinitis]. / Intradermisni testovi vazomotornim agensima u alergijskom rinitisu.

INTRODUCTION: Allergic rhinitis is characterised by nasal hyperactivity to specific and non-specific agents. For research purposes, non-specific nasal hyperactivity can be estimated by histamine and metacholine nasal challenge tests. At present, nasal challenge tests are not used for routine diagnosis of rhinitis. Wayoff and colleagues proposed the examination of the skin reactivity to papaverine, acetylcholine, histamine and compound 48/80 in rhinitis patients. Our previous study of skin reactivity to vasomotor agents, using modified skin tests of Wayoff and colleagues showed their clinical validation and usefulness for subclassification of patients with non-allergic rhinitis. To the present, there are only a few studies of skin reactivity to vasomotor agents in patients with allergic rhinitis. The aim of this study was to examine the skin reactivity to vasomotor agents of allergic rhinitis patients and determine whether the patients with allergic rhinitis differ from healthy subjects. METHODS: A prospective, controlled, in vivo study was carried out in 86 subjects: 44 patients with allergic rhinitis and 42 healthy subjects. Skin reactivity was examined by intradermal tests with different concentrations of papaverine, metacholine, histamine and compound 48/48. The non-specific skin reactivity to saline was also measured. Skin reactivity to intradermal test with different concentrations of papaverine, metacholine, histamine and compound 48/48 was measured, as well as specific skin reactivity to control saline solution. Pathological skin reactivity to vasomotor agents was defined as follows: hyporeactivity to papaverine (5 mg/mL), when wheal-and-flare skin reaction diameter was less than 15 mm; hyper-reactivity to metacholine (0.02, 0.2 and 2.0 mg/mL), when two of three wheal-and-flare skin reaction diameters were greater than 15, 25 and 31 mm, respectively; hyper-reactivity to histamine (0.01, 0.1, 1.0 and 10.0 mg/mL), when three of four wheal-and-flare skin reaction diameters were greater than 7, 13, 25 and 40 mm, respectively; and hyper-reactivity to compound 48/80 (0.01, 0.1, 1.0 and 10.0 mg/mL), when three of four wheal-and-flare skin reaction diameters were greater than 9, 16, 26 and 38 mm, respectively. RESULTS: The study included 86 subjects: 44 patients with allergic rhinitis and 42 healthy subjects. The control group of healthy subjects consisted of 22 females, aged from 18 to 35 yrs (mean 28 yrs), and 20 males, aged from 18 to 40 yrs (mean 28 yrs). The difference between the number [p(= 0.758) > 0.05] and age [p(= 0.990) > 0.05] of females and males was not significant. In the allergic rhinitis patients group, there were 23 females, aged from 18 to 54 yrs (mean 33 yrs) and 21 males, aged from 18 to 50 yrs (mean 36 yrs). The difference between the number [p(= 0.763) > 0.05] and age [p(= 0.558) > 0.05] of females and males was not significant. Frequencies of pathological skin reactivity to single vasomotor agents and saline in the control group of healthy subjects and in the allergic rhinitis patients group are shown in Table 1. In the control group, frequencies of normal skin reactivity to papaverine [p(= 1.8 x 10(-7)) < 0.01], metacholine [p(= 4.3 x 10(-6)) < 0.01], histamine [p(= 4.3 x 10(-6)) < 0.01], compound 48/80 [p(= 1.8 x 10(-7) < 0.01] and saline [p(= 6.9 x 10(-4)) < 0.01] were significantly greater than frequencies of pathological skin reactivity. In the patients group, frequencies of normal skin reactivity to papaverine [p(= 6.0 x 10(-8)) < 0.01] and saline [p(= 2.6 x 10(-3) < 0.01] were significantly greater, and to metacholine [p(= 0.016) < 0.05] were significantly greater than frequencies of pathological skin reactivity. In this group, the difference between frequencies of pathological skin reactivity to histamine [p(= 0.366) > 0.05] and compound 48/80 [p(= 0.070) > 0.05] were not significant. There was no significant intergroup difference for pathological skin reactivity to papaverine, metacholine and saline (Table 1). In the patients group frequencies of pathological skin reactivity to histamine and compound 48/80 were significantly higher than in the control group of healthy subjects. Frequencies of pathological skin reactivity to single vasomotor agents and in combinations in the control group of healthy subjects and in the allergic rhinitis patients group are shown in Table 2. The difference of pathological skin reactivity to single vasomotor agents and in combinations between the control group (14/42) and the allergic rhinitis patients group (27/44) was significant [p(= 0.017) < 0.05]. CONCLUSION: In routine evaluation of the rhinitis patients, skin tests with vasomotor agents have some advantages: these tests do not require special equipment, they are not time-consuming, they are easy to perform and simple for the interpretation of results. (ABSTRACT TRUNCATED)

Effect of CD8+ T-cell depletion on bronchial hyper-responsiveness and inflammation in sensitized and allergen-exposed Brown-Norway rats.

We examined the role of CD8+ T cells in a Brown-Norway rat model of asthma, using a monoclonal antibody to deplete CD8+ T cells. Ovalbumin (OA)-sensitized animals were given anti-CD8 antibody (0.5 mg/rat) intravenously 1 week prior to exposure to 1% OA aerosol and were studied 18-24 hr after aerosol exposure. Following administration of anti-CD8 antibody, CD8+ cells were reduced to <1% of total lymphocytes in whole blood and in spleen. In sensitized animals, OA exposure induced bronchial hyper-responsiveness (BHR), accumulation of eosinophils, lymphocytes and neutrophils in bronchoalveolar lavage (BAL) fluid, and also an increase in tissue eosinophils and CD2+, CD4+ and CD8+ T cells in airways. Anti-CD8 antibody caused a further increase in allergen-induced BHR (P<0.03, compared with sham-treated animals), together with a significant increase in eosinophil number in BAL fluid (P<0.05). While CD2+ and CD4+ T cells in airways were not affected by anti-CD8 treatment, the level of CD8+ T cells was significantly reduced in sensitized, saline-exposed animals (P<0.04, compared with sham-treated rats), and sensitized and OA-challenged rats (P<0.002, compared with sham-treated rats). Using reverse transcription-polymerase chain reaction, an increase of T helper (Th)2 cytokine [interleukin (IL)-4 and IL-5], and also of Th1 cytokine [interferon-gamma (IFN-gamma) and IL-2], mRNA in the lung of sensitized and OA-exposed animals was found; after CD8+ T-cell depletion, Th1 cytokine expression was significantly reduced (P<0.02), while Th2 cytokine expression was unchanged. CD8+ T cells have a protective role in allergen-induced BHR and eosinophilic inflammation, probably through activation of the Th1 cytokine response.