Inflammation & Allergy-Drug Targets (Discontinued) - Volume 6, Issue 4, 2007

In opposite to the classic view of the systemic inflammatory response, there is increasing evidence that, during critical illness, there is a systemic antiinflammatory state intended to avoid the spread of the local proinflammatory response. The resulting immunosupression increases the risk of nosocomial infections, and has been related to an increase in morbidity and mortality in critically ill patients. Monocytes play a key role in orchestrating the inflammatory response, and a functional impairment of this population is the responsible for these phenomena. The decreased surface expression of class II molecules of the Main Histocompatibility Complex is both a marker of this state and a pathogenetic mechanism, as it decreases the antigen presentation capabilities of the mononuclear phagocytes. There are some therapeutic strategies to overcome this situation. Cytokines like IFNγ or GM-CSF have been tested in animal models and patients, but there are no conclusive data. Other drugs like Flt3, AS101 or antibodies against IL-10 have been tested only in experimental models. The development of a new framework on the inflammatory response, the need for a consensus in immune monitoring and the development of experimental and clinical trials are required to improve the outcome of severe patients with systemic injuries.

Bombesin-like peptides (BLP) and its receptors are widely distributed in mammalian peripheral tissues and in the central nervous system. Recently, effects of these peptides on the production and release of cytokines were described both in animal models and humans with inflammatory diseases. Some pathological conditions such as exposure to tobacco smoke, chronic obstructive pulmonary diseases and eosinophilic granuloma have recently been found to be associated with an increase of pulmonary BLP-producing cells. Proinflammatory neuropeptides have a key role in the pathogenesis and maintenance of rheumatoid arthritis and sepsis. Together, these findings support the view that the GRPR should be considered a therapeutic target for a subset of inflammatory diseases.

Understanding mechanisms that underlie lung disorders is crucial to achieving optimum care and improved outcomes in pulmonary medicine. Extensive investigations have revealed that inflammation displays an active role in the pathogenesis of these diseases. The byproduct of these inflammatory reactions has been shown to propagate pulmonary disease in consonance with alteration in haemostatic balance. It is now apparent that the two phenomena constitute an interwoven relationship with protective but damaging effects, when dysregulated. However, the precise role of coagulation abnormalities in pulmonary pathology is still evolving. A large body of evidence suggests that an imbalance in intraalveolar procoagulant and fibrinolytic activities occurs in a variety of lung conditions. This imbalance may even herald a number of pulmonary diseases. Its sequelae have been observed in lung parenchyma of humans and in animal models of lung inflammation. As the pathogenesis of coagulation-related lung diseases continues to be unraveled, therapeutic measures to mitigate pulmonary disease-specific coagulopathy are emerging. Current efforts are directed at depicting multifaceted molecules capable of selective but simultaneous interference with relevant aspects of the dual coagulation-fibrinolytic pathway.

The central nervous system (CNS) has long been regarded as an immune privileged organ implying that the immune system avoids the CNS not to disturb its homeostasis, which is critical for proper function of neurons. Meanwhile, it is accepted that immune cells do in fact gain access to the CNS and that immune responses are mounted within this tissue. However, the unique CNS microenvironment strictly controls these immune reactions starting with tightly regulating immune cell entry into the tissue. The endothelial blood-brain barrier (BBB) and the epithelial bloodcerebrospinal fluid (CSF) barrier control immune cell entry into the CNS, which is rare under physiological conditions. During a variety of pathological conditions of the CNS such as viral or bacterial infections, or during inflammatory diseases such as multiple sclerosis (MS), immunocompetent cells readily traverse the BBB and subsequently enter the CNS parenchyma. Most of our current knowledge on the molecular mechanisms involved in immune cell entry into the CNS has been derived from studies performed in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Thus, a large part of our current knowledge on immune cell entry across the BBBs is based on the results obtained in this animal model. Similarly, knowledge on the benefits and potential risks associated with therapeutic targeting of immune cell recruitment across the BBB in human diseases are mostly derived from such treatment regimen in MS. Other mechanisms of immune cell entry into the CNS might therefore apply under different pathological conditions such as bacterial meningitis or stroke and need to be considered.

There is an increasing interest in ligands of nucleic acid-sensing Toll-like receptors (TLR), especially TLR7 and TLR9, for pharmacological intervention in various diseases. The TLR7 agonist imiquimod is currently used as a topical treatment for genital warts caused by human papillomavirus (HPV), actinic keratosis (AK) and superficial basal cell carcinoma. Oligodeoxynucleotides (ODN) TLR9 agonists are currently in clinical trials for use in lung cancer, as antiviral therapy, as adjuvants and as immune modulators in asthma and allergies. TLR7/9 antagonists, such as the antimalaria drugs chloroquine, hydroxychloroquine and quinacrine, have been used since the 1950s to treat immune-mediated inflammatory disorders (IMID) such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjogren's syndrome. However, the use of these anti-malarials in IMID is limited due to the side effects or suboptimal efficacy. Preclinical animal models as well as genetic linkage studies have indicated that TLR7/9 play a pivotal role in the aforementioned as well as other IMID such as multiple sclerosis (MS), inflammatory bowl disease (IBD)/colitis and psoriasis. Recent evidence has suggested that selective, specific antagonists for TLR7 and/or 9 might be more beneficial in certain diseases, such as SLE. Thus, the use of suppressive ODN or novel small molecule TLR7/9 inhibitors with a larger safety window and differentiated selectivity may potentially have significant clinical utility in these IMID. Herein, we review efforts to develop novel TLR7/9 antagonists and the rationale for the use of such therapeutics in a variety of IMID.

Allergic contact dermatitis is induced by chemicals or metal ions. A hallmark of this T cell mediated skin disease is the activation of the innate immune system by contact allergens. This immune response results in inflammation and is a prerequisite for the activation of the adaptive immune system with tissue-specific migration of effector and regulatory T cells. Recent studies have begun to address in detail the innate immune cells as well as the innate receptors on these cells and the associated signaling pathways which lead to skin inflammation. We review here recent findings regarding innate and adaptive immune responses and immune regulation of contact dermatitis and other skin diseases as well as recent developments towards an in vitro assessment of the allergenic potential of chemicals. The elucidation of the innate inflammatory pathways, cellular components and mediators will help to identify new drug targets for more efficient treatment of allergic contact dermatitis and hopefully also for its prevention.