Inflammation & Allergy-Drug Targets (Discontinued) - Volume 9, Issue 4, 2010

Mast cells are bone marrow derived cells capable of secreting many active molecules: mediators stored in specific granules, such as histamine and heparin; small molecules produced immediately upon stimulation, such as lipid derivatives and nitric oxide; and many constitutively secreted, pleiotropic cytokines. Thanks to these secretion products and perhaps direct cell-cell interactions, mast cells play roles in inflammation and tissue repair, angiogenesis and fibrosis. Mast cells themselves respond to many mediators of their own, giving rise to autocrine loops. Successful anti-allergic therapies have typically targeted the receptors for mast cell secretory products, particularly those for histamine. Among agents directly affecting mast cells, disodium chromoglycate and glucocorticoids are known since some time, while new pharmacological approaches may stem from the recognition of an interference with mast cell growth and differentiation by cyclosporine A, monoclonal antibodies, interferons, and JAK3 inhibitors. The action of agents that affect mast cell differentiation and function is considered here from a cell and tissue biological perspective as a premise to the application of these agents to the clinics, therefore special attention has been paid to references pertaining to humans.

ABX-IL8 is a fully human IgG2 monoclonal antibody generated using transgenic mouse technology (Xenomouse®) that binds to human Interleukin-8 with high affinity and specificity. The objective of this study was to evaluate the pharmacokinetic (PK) properties of ABX-IL8 in patients with active inflammatory diseases. Patients with psoriasis and rheumatoid arthritis received single or multiple short intravenous infusions of ABX-IL8 or placebo. Serum concentrations of ABX-IL8, baseline serum IgG and IgG2 concentrations and Anti-Drug Antibody (ADA) response to ABX-IL8 were determined using relevant immunoassays. Pharmacokinetic analyses of the serum ABX-IL8 concentration-time data were performed. Following single-dose administration of ABX-IL8, dose proportional increases in drug exposure were observed. Consistent with the disposition properties of the endogenous IgG antibodies, ABX-IL8 appeared to be primarily distributed into the plasma compartment and the extra-vascular fluid and the steady-sate volume of distribution (61 ± 14 to 71 ± 14 mL/kg) was comparable to that for the endogenous antibodies. Following the multipledose administration, PK properties of the antibody were linear with dose and time. Steady-state clearance (2.6 ± 1.1 to 2.7 ± 1.4 mL/day/kg) was similar to that observed following the single dose administration and no ADA response was detected throughout the study. PK variability and serum exposure to ABX-IL8 following administration of the fixed doses were comparable to those observed following administration of the weight-adjusted doses; the impact of body weight on clearance was minimal and this correlation did not translate into requirements for body weight-adjusted dosing. Additionally, age and disease type (psoriasis or RA) had no impact on ABX-IL8 pharmacokinetics.

There is evidence that many pathogens co-evolve with their hosts. This is often reflected in species specific virulence factors that can selectively interfere with host defense mechanisms, innate and acquired as well as a range of interactions with host homeostatic pathways that contribute to the course and severity of an infection. In this review, we highlight a number of select examples of these interactions and suggest that understanding of molecular pathogenesis requires a broad systems approach that can evaluate the multiple and dynamic interactions that are occurring during infection.

Osteopontin (OPN) is an extracellular matrix protein with chemokine, cytokine and integrin properties. It has multiple immunological functions and is secreted by activated macrophages, leukocytes and activated T lymphocytes. It is present in extracellular fluids and is up-regulated at sites of inflammation. OPN has intracellular and secreted isoforms. It has been shown to be involved in inflammation and autoimmune disorders, including multiple sclerosis. Multiple sclerosis (MS) is an immune mediated inflammatory disease of the central nervous system (CNS) in which autoreactive T cells attack the myelin-oligodendrocyte complex. Experimental autoimmune encephalomyelitis (EAE) is a widely used experimental model for MS. This review presents updated evidence for the role of OPN in MS and EAE, starting with the data provided by microarray analysis showing elevated levels of OPN transcripts in MS brain lesions and spinal cords of rats with EAE. This plausible target has since been validated in EAE, by showing that OPN knockout mice are protected from severe EAE. Increased levels of OPN were reported in plasma and CSF of MS patients in comparison to healthy controls. Potential mechanisms of OPN involvement in inflammatory demyelination are discussed. The involvement of OPN, in part via non-immune effects, in remyelination and its neuroprotective potential need to be balanced against its pro-inflammatory properties.

The aim of this study was to establish the clinical types of food reactions and the food sensitization profile in an adult cohort of patients with Eosinophilic esophagitis (EoE). We have prospectively analyzed the food allergen sensitization profile using skin prick test (SPT) and atopy patch test (APT) to 22 plant and animal-derived foods in 19 adult patients with biopsy-proven EoE. For each patient the following data was collected: age, sex, atopic disease status, and clinical characteristics of the EoE. A total of 123 food sensitizations were detected by SPT and 45 food sensitizations by patch testing in 18 patients (94.8%). Thirty-five double- positive (SPT+, APT+) responses against the same food were detected in 15 patients (78.9%). We have also identified 11 clinical episodes clearly suggestive of oral allergy syndrome, urticaria and/or anaphylaxis after intake of some specific foods. All cases showed positive SPT to the offending food (Type 1 food reactors). 68 clinically apparent episodes of EoE related with specific foods were detected in our patients. In 40 instances (58.8%) the foods involved in developing EoE symptoms showed a positive SPT and/or APT results (Type 2). 155 food sensitizations were identified in 18 patients (94.7%) using SPT and/or APT neither related with clinically apparent episodes of EoE nor with clinical episodes suggestive of oral allergy syndrome, urticaria and/or anaphylaxis after food intake (Type 3). In conclusion, the patients with EoE can be allocated into 3 different groups of food reactors, with well-defined clinical and biological characteristics.

Flavonoids are polyphenolic substances derived from plants that play several pharmacological activities. They possess anti-viral, anti-microbial, anti-inflammatory and anti-allergic potential that can be expressed on different cell types, both in animal and human models. Many of these properties prove inhibitory to a huge panoply of molecular targets in the micromolar concentration range, either by down-regulating or suppressing many inflammatory pathways and functions. Flavonoids exert their properties both as purified aglycone molecules and as plant extracts. Depending on little changes in the flavone-backbone and on subtle mechanisms of cell behavior and responsiveness, flavonoids can play a modulating, biphasic and regulatory action on immunity and inflammation; in this context only few flavones and flavonols have been assayed, mainly because of their chemical similarity with quercetin, so evidence reported in the literature about the action of flavonoids is limited to a restricted group of molecules. Many of the effects reported about flavonoids regard quercetin, as probably the most diffused and known nature-derived flavonol. Quercetin has shown a biphasic behavior in basophils at nanomolar doses and hence its action on cells involved in allergic inflammation is here described. Like many other molecules sharing a flavone ring, quercetin affects immunity and inflammation by acting mainly on leukocytes and targeting many intracellular signaling kinases and phosphatases, enzymes and membrane proteins often crucial for a cellular specific function. This overview collects and discusses the role of flavonoids as antiinfectious and anti-inflammatory compounds, trying to focus on the complex and modulating interaction of these polyphenolic substances with cell function. However, the wide group of intracellular targets and the elevated number of natural compounds potentially effective as anti-inflammatory therapeutical agents, asks for further insights and evidence to comprehend the role of these substances in animal cell biology.

Cytomegalovirus (CMV) is a significant health problem among immunosuppressed individuals. In particular, transplant and AIDS patients and the developing fetus in utero are highly susceptible to CMV. In these vulnerable populations, infection leads to life threatening end organ viral disease or in surviving newborn babies to deafness or to mental retardation. Currently, the most effective way to control CMV infection, given the lack of an effective vaccine, is by antiviral therapy. However, available antivirals suffer from complications associated with prolonged use, such as drug toxicity as well as the emergence of resistant strains of virus. Additionally, since CMV has multiple complex immune evasion strategies, to avoid innate and adaptive immune responses, there is a need for new antiviral development. Any antiviral should be tested in a controlled animal model but species specificity of HCMV precludes the direct study of the virus in an animal model. Consequently, animal CMV in their respective animal host are used to study intervention strategies. In this review, both current and new antiviral strategies are discussed as are the various animal models and strategies to improve existing antiviral animal models by humanizing animal CMV.

Epidemiological studies have shown that particulate air pollutants, such as diesel exhaust particles (DEPs) are implicated in the increased incidence of allergic airway disorders. DEPs induce and exaggerate allergic airway inflammation in vitro and in vivo. Studies of molecular mechanisms have focused on the role of reactive oxygen species (ROS) generated directly and indirectly by exposure to DEPs. The ROS play an important role in proinflammatory reaction in airways. Nuclear erythroid 2 P45-related factor 2 (Nrf2) is a key transcription factor that regulates host antioxidant and contributes to regulate airway inflammation and exacerbation of allergic inflammation induced by DEPs. The authors demonstrated that DEPs-induced oxidants stress and resultant inflammatory changes were blocked by antioxidants such as N-acetyl cysteine (NAC). Therefore, chemoprevention against DEPs health effects in susceptible individuals may become a choice for future environmental protection policy.

Intractable and untreatable pain from cancer remains a challenge for both patients and clinicians. The pain may be related to the disease itself or the consequences of treatment, such as surgery, chemotherapy or radiation therapy. Cancer pain is intense and has a major impact on patient's quality of life and survival. A significant number of patients receiving analgesic therapy with opioids report persisting pain of a higher intensity than the pain in those who were not on this class of drugs. The pathophysiology of pain in cancer patients is complex and remains poorly understood. Several research groups have studied and demonstrated that cancer and cancer-related symptoms may have an underlying problem of membrane hyper-excitability due to over-presentation of sodium channels and glutamate build-up or over-stimulation of glutamate/N-methyl-D-aspartate (NMDA)/α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) system in cancer cells and the body. Dimethyl sulfoxide (DMSO) is a naturally derived, inexpensive, non-toxic solvent and pharmaceutical agent that has been demonstrated to have numerous health enhancing and therapeutic benefits. In the present article, we provide the scientific evidence and substantiate possible application of DMSO as a well-tolerated excitatory modulator in the management of cancer pain.

Systemic Sclerosis (SSc) is a multisystem connective tissue disease characterized by fibrosis of the skin and internal organs and extensive vasculopathy. We report a case of a 41 year-old white woman with a 10 year-history of limited scleroderma, who developed the rare combination of Scleroderma Renal Crisis (SRC) and Systemic Sclerosis related Pulmonary Arterial Hypertension (SScPAH) in the same time. Although the patient received the proposed antihypertensive treatment, the renal function did not recover, and she initiated on renal replacement therapy. SRC and SScPAH are two aspects of SSc vasculopathy characterized by endothelial dysfunction mediated by endothelin-1 and other vasoactive hormones. Further new studies with therapies directed towards the underlying mechanisms of SRC (i.e. endothelin-receptor antagonists), which are proven helpful in SScPAH, should take place to establish new therapeutic options and improve prognosis of these patients, for which our therapeutic armamentarium is currently poor.