Protein kinase C-theta (PKC theta) is a protein kinase C (PKC) family member expressed predominantly in T lymphocytes, and extensive studies addressing its function have been conducted. PKC theta is the only T cell-expressed PKC that localizes selectively to the center of the immunological synapse (IS) following conventional T cell antigen stimulation, and this unique localization is essential for PKC theta-mediated downstream signaling. While playing a minor role in T cell development, early in vitro studies relying, among others, on the use of PKC theta-deficient (Prkcq(-/-)) T cells revealed that PKC theta is required for the activation and proliferation of mature T cells, reflecting its importance in activating the transcription factors nuclear factor kappa B, activator protein-1, and nuclear factor of activated T cells, as well as for the survival of activated T cells. Upon subsequent analysis of in vivo immune responses in Prkcq(-/-) mice, it became clear that PKC theta has a selective role in the immune system: it is required for experimental Th2- and Th17-mediated allergic and autoimmune diseases, respectively, and for alloimmune responses, but is dispensable for protective responses against pathogens and for graft-versus-leukemia responses. Surprisingly, PKC theta was recently found to be excluded from the IS of regulatory T cells and to negatively regulate their suppressive function. These attributes of PKC theta make it an attractive target for catalytic or allosteric inhibitors that are expected to selectively suppress harmful inflammatory and alloimmune responses without interfering with beneficial immunity to infections. Early progress in developing such drugs is being made, but additional studies on the role of PKC theta in the human immune system are urgently needed.
Protein-based drugs with their unequivocal specificity achieved the long sought milestone of selectively disrupting cytokine pathways to alleviate ongoing inflammation. Tumor necrosis factor (TNF), a member of the superfamily of cytokines involved in regulating immune and inflammatory processes, provides an exemplary model of protein therapeutics. Antibody and receptor-based inhibitors of TNF modify inflammation leading to dramatic improvement in patients with certain autoimmune diseases. Collectively, the structure, specificity and valence of these protein-based drugs provide direct evidence that the essential mechanism of action is antagonism of the ligand-receptor interaction. Accumulating clinical knowledge regarding TNF inhibitors also provide insights into the mechanisms involved in different autoimmune diseases. Experience in the development of an arsenal of biologics directed at TNF has additionally contributed to knowledge toward overcoming the challenges of protein drugs, which include production, delivery, antigenicity and pharmacodynamics. Dramatic clinical outcomes with TNF inhibitors are driving investigation and development of biologics toward other members of the TNF superfamily to selectively alter functional properties of the immune system.
Chronic persistent inflammation plays a significant role in disease pathology of cancer, cardiovascular disease, and metabolic syndrome (MetS). MetS is a constellation of diseases that include obesity, diabetes, hypertension, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. Nonalcoholic fatty liver disease (NAFLD) is associated with many of the MetS diseases. These metabolic derangements trigger a persistent inflammatory cascade, which includes production of lipid autacoids (eicosanoids) that recruit immune cells to the site of injury and subsequent expression of cytokines and chemokines that amplify the inflammatory response. In acute inflammation, the transcellular synthesis of antiinflammatory eicosanoids resolve inflammation, while persistent activation of the autacoid-cytokine-chemokine cascade in metabolic disease leads to chronic inflammation and accompanying tissue pathology. Many drugs targeting the eicosanoid pathways have been shown to be effective in the treatment of MetS, suggesting a common linkage between inflammation, MetS and drug metabolism. The cross-talk between inflammation and MetS seems apparent because of the growing evidence linking immune cell activation and metabolic disorders such as insulin resistance, dyslipidemia, and hypertriglyceridemia. Thus modulation of lipid metabolism through either dietary adjustment or selective drugs may become a new paradigm in the treatment of metabolic disorders. This review focuses on the mechanisms linking eicosanoid metabolism to persistent inflammation and altered lipid and carbohydrate metabolism in MetS.
Asthma is a chronic respiratory disorder canonically associated with type 2 airway inflammation as characterized by elevated levels of eosinophils, immunoglobulin E, and cytokines including interleukin (IL) 4, IL5, IL9, and IL13 and tumor necrosis factor (TNF) alpha. However, mounting evidence has shown that considerable heterogeneity exists in human asthma in terms of the nature and intensity of airway inflammation. While many asthma patients achieve acceptable control of symptoms with standard-of-care therapies such as beta(2)-adrenergic agonists and inhaled corticosteroids, a minority remains symptomatic despite maximal standard-of-care therapy and constitutes a significant unmet medical need. A growing number of investigational therapeutics under clinical development for asthma are biologic therapies that specifically target mediators of type 2 airway inflammation. In this chapter, we consider the biological functions of therapeutic targets in asthma and data from clinical trials of biologic agents directed against these targets. We discuss recent clinical trial results in terms of four key components of drug development: target selection, molecule selection, outcome selection, and patient selection, with particular attention paid to the emerging role of biomarkers in clinical development for asthma.
Originally shown to promote the growth and activation of B cells, thymic stromal lymphopoietin (TSLP) is now known to have wide-ranging impacts on both hematopoietic and nonhematopoietic cell lineages, including dendritic cells, basophils, eosinophils, mast cells, CD4(+), CD8(+) and natural killer T cells, B cells and epithelial cells. While TSLP's role in the promotion of TH2 responses has been extensively studied in the context of lung-and skin-specific allergic disorders, it is becoming increasingly clear that TSLP may impact multiple disease states within multiple organ systems, including the blockade of TH1/TH17 responses and the promotion of cancer and autoimmunity. This chapter will highlight recent advances in the understanding of TSLP signal transduction, as well as the role of TSLP in allergy, autoimmunity and cancer. Importantly, these insights into TSLP's multifaceted roles could potentially allow for novel therapeutic manipulations of these disorders.
The structural core of bacterial lipopolysaccharide, lipid A, has played a role in medicine since the 1890s when William Coley sought to harness its immunostimulatory properties in the form of a crude bacterial extract. Recent decades have brought remarkable clarity to the structure of lipid A and the multicomponent endotoxin receptor system that evolved to detect it. A range of therapeutically useful versions of lipid A now exists, including preparations of detoxified lipid A, synthetic copies of naturally occurring biological intermediates such as lipid IVa, and synthetic mimetics. These agents are finding use as vaccine adjuvants, antagonists and immunostimulants whose structural features have been refined to potentiate efficacy while decreasing the risk of inflammatory side effects.
