Microenvironmental hypoxia orchestrating the cell stroma cross talk, tumor progression and antitumor response.
Crit Rev Immunol. 2011;31(5):357-77
Authors: Noman MZ, Messai Y, Carre T, Akalay I, Meron M, Janji B, Hasmim M, Chouaib S
Abstract
Hypoxia, a common feature of solid tumors and one of the hallmarks of tumor microenvironment, favors tumor survival and progression. Although hypoxia has been reported to play a major role in the acquisition of tumor resistance to cell death, the molecular mechanisms that control the survival of hypoxic cancer cells and the role of hypoxic stress in shaping the cross talk between immune cells and stroma components are not fully elucidated. Recently, several lines of investigation are pointing to yet another ominous outcome of hypoxia in the tumor microenvironment involving suppression of antitumor immune effector cells and enhancement of tumor escape from immune surveillance. Although the identification of tumor-associated antigens provided a new arsenal of approaches to enhance antigen-specific response, the immunotherapy approaches that are currently used in the clinic have only limited success. In fact, tumor stroma components including hypoxia are engaged in an active molecular cross talk that has serious implications for immunological recognition of tumor in shaping the microenvironment. In this review, we will focus on the impact of hypoxia on the regulation of the antitumor response and the subsequent tumor progression. We will also in particular discuss data that indicate that manipulation of hypoxic stress may represent an innovative strategy for a better immunotherapy of cancer.
LPS-induced cytokine production in human monocytes and macrophages.
Crit Rev Immunol. 2011;31(5):379-446
Authors: Rossol M, Heine H, Meusch U, Quandt D, Klein C, Sweet MJ, Hauschildt S
Abstract
Lipopolysaccharide (LPS) from Gram-negative bacteria is one of the most potent innate immune-activating stimuli known. Here we review the current understanding of LPS effects on human monocyte and macrophage function. We provide an overview of LPS signal transduction with attention given to receptor cooperativity and species differences in LPS responses, as well as the role of tyrosine phosphorylation and lysine acetylation in signalling. We also review LPS-regulated transcription, with emphasis on chromatin remodeling and primary versus secondary transcriptional control mechanisms. Finally, we review the regulation and function of LPS-inducible cytokines produced by human monocytes and macrophages including TNFα, the IL-1 family, IL-6, IL-8, the IL-10 family, the IL-12 family, IL-15 and TGFβ.
An initiating T cell response requires both costimulatory signaling and T cell receptor/MHC binding. The immune system balances positive and negative costimulatory signal pathways to activate and deactivate T cells. This review focuses primarily on PD-1 and its ligands, which form a crucial inhibitory costimulatory pathway for maintaining peripheral tolerance, and their contribution to autoimmunity. Since 1992, when PD-1 was isolated, many studies have described the physiological roles of PD-1 signaling, reported relationships between Pdcd-1 gene polymorphism and autoimmune diseases, and applied PD-1/PD-1 ligand modulation to clinical trials. This review summarizes recent advances and future therapeutic applications of PD-1 and its ligands to autoimmune diseases.
Intracellular pattern recognition receptors and renal ischemia.
Crit Rev Immunol. 2011;31(4):297-306
Authors: McKay DB
Abstract
Renal ischemia is a common cause of acute kidney injury in hospitalized patients. In certain settings renal ischemia is unavoidable, such as in kidneys harvested for transplantation. The molecular and cellular mechanisms that lead to the syndrome of ischemic renal injury are complicated and involve multiple cell types within the kidney, including renal epithelium and vasculature. Although it has been difficult to define pharmacologic targets for AKI, emerging information about a newly discovered host defense system is providing hope for novel pharmacologic targets to prevent and treat AKI. Molecular initiators of damage associated with hypoxia involve a phylogenically conserved host defense system called the innate immune system. Data point to an essential role for receptors of the innate immune system, particularly the membrane-bound Toll-like receptors and the intracellular nucleotide-binding oligomerization domain-like receptors. These receptors have been identified in human and rodent kidneys, and many investigators have shown that their deletion protects from experimental ischemia/reperfusion injury (a model for ischemic acute kidney injury). This review details current information about the innate immune system and the ischemic kidney with a focus on the emerging role of intracellular innate immune receptors.
Mechanisms Behind the Anti-inflammatory Actions of Insulin.
Crit Rev Immunol. 2011;31(4):307-40
Authors: Hyun E, Ramachandran R, Hollenberg MD, Vergnolle N
Abstract
The epidemic of diabetes mellitus is worsening worldwide. Diabetes mellitus is a chronic metabolic disease characterized by inappropriate recurrent or persistent hyperglycemia. Numerous studies have demonstrated that hyperglycemia, the most significant predictor of poor clinical outcome in diabetes mellitus patients, can directly promote an inflammatory response and oxidative stress. Although there are various causes of DM, all eventually lead to absolute or relative insulin deficiency and death of pancreatic β-cells. Thus, insulin inevitably becomes the primary medication used to treat the disease and prevent diabetic complications in all DM patients. Interestingly, an emerging body of evidence suggests that insulin suppresses the inflammatory process, not only through preventing hyperglycemia but also by modulating key inflammatory molecules. In this review, we discuss the findings of studies done in vitro as well as clinical trials that have demonstrated an anti-inflammatory action of insulin and that have pointed to mechanisms responsible for this effect. Further, we discuss how the anti-inflammatory action of insulin bears on our current understanding of the pathophysiology and complications of both type 1 and type 2 diabetes.
Chemokines in respiratory viral infections: focus on their diagnostic and therapeutic potential.
Crit Rev Immunol. 2011;31(4):341-56
Authors: Amanatidou V, Zaravinos A, Apostolakis S, Spandidos DA
Abstract
Chemokines are small chemoattractant cytokines involved in cell trafficking and activation. Despite the general nonspecific nature of chemokine activity in certain instances, specific chemokine expression patterns have been associated with specific disease states. In the field of respiratory viral infection, evidence suggests that response to viral invasion is regulated by a distinct chemokine expression profile involving more CC chemokines than CXC chemokines. Moreover, among the CC chemokines, CCL3 and CCL5 appear to be most commonly implicated in viral respiratory disease. Most data available in this field have been derived from in vitro studies, as well as studies conducted in animal models with limited evidence obtained in settings of actual human disease. In the present review, we focus on the diagnostic, prognostic, and therapeutic potential of virus-induced chemokine activity as reflected by studies conducted in actual disease states, either in animal models or humans. We further discuss whether these data advocate chemokines as a realistic clinical tool for the management of viral infection.
The contribution of thymic stromal abnormalities to autoimmune disease.
Crit Rev Immunol. 2011;31(3):171-87
Authors: Fletcher AL, Calder A, Hince MN, Boyd RL, Chidgey AP
In essence, normal thymus function involves the production of a broad repertoire of αβT cells capable of responding to foreign antigens with low risk of autoreactivity. Thymic epithelial cells are an essential component of the thymic stromal microenvironment, promoting the growth and export of self-tolerant thymocytes. Autoimmune disease, resulting from a loss of self-tolerance, is clinically and genetically complex, and accordingly has many potential etiological origins. However, it is commonly linked to defects in the thymic epithelial microenvironment. The study of autoimmune-linked thymic stromal dysfunction has indisputably advanced our understanding of T cell tolerance; notably, a field-wide paradigm shift occurred when autoimmune regulator (Aire) was found to drive expression of a multitude of peripheral tissue-restricted antigens in medullary thymic epithelial cells. Many other associations with polygenically controlled autoimmune diseases have been reported but are more difficult to definitively dissect. Paradoxically, immunodeficiency and age-related immunosenescence are also linked with increased autoimmunity. Here we discuss the theoretical basis and the evidence gathered thus far to support these associations.
Regulatory T cells for tolerance therapy: revisiting the concept.
Crit Rev Immunol. 2011;31(3):189-207
Authors: Leguern C
The discovery of regulatory T cells (Tregs) as a crucial component of peripheral down-regulation of immunity to self and allogeneic antigens has raised legitimate hope for the development of Treg-based clinical protocols for tolerance to allografts. The present review addresses the question of whether therapeutic Tregs are ready to enter the clinical transplantation arena. In light of recent experimental observations, we will revisit some fundamentals of T cell and Treg biology that stress the need for further studies prior to applications and provide conceptual cues for novel therapeutic approaches.
Thymic T cell differentiation to peripheral T cells aims to assist the generation of effector cells mediating adaptive immune responses. During this process, which takes place during embryogenesis and in adulthood, proliferation is coupled with changes in chromatin organization and transcription. Moreover, B and T lymphocytes start to proliferate and rapidly expand their numbers when activated following an encounter with an antigen. This expansion phase is accompanied by differentiation of naпve T cells and is followed by a period of population contraction, resulting in only a small fraction of the expanded population surviving and entering the memory cell pool. The kinetics of the expansion and contraction affect the speed of antigen clearance and the clinical course of disease. Molecules that are involved in the coordination of proliferation, chromatin reorganization, and transcriptional regulation are likely to play an important role in T cell generation, homeostasis, and disease. Here we review how cell cycle regulators affect lymphoid system development and homeostasis and discuss recent evidence implicating the cell cycle inhibitor Geminin in this process. Geminin has been shown to coordinate proliferation and differentiation by regulating cell cycle progression, chromatin organization, and transcription in the nervous system. In the immune system, progenitor T cell commitment and differentiation progresses normally in the absence of Geminin. However, Geminin is required for TCR response in vitro and T cell proliferation upon lymphopenia-induced proliferation, suggesting that Geminin might be an essential factor for T cell expansion during the immune response.
Function of histone deacetylase inhibitors in inflammation.
Crit Rev Immunol. 2011;31(3):233-63
Authors: Grabiec AM, Tak PP, Reedquist KA
Histone deacetylases (HDACs) display multi-faceted roles in coordinating the interaction of intracellular signaling pathways with chromatin remodeling and transcription factor function to finely specify gene alterations and maintenance of gene expression during cellular activation, proliferation, and differentiation. These processes, epigenetic and non-epigenetic, are critical to the development of both the adaptive and innate arms of the mammalian immune system, and the measured initiation and resolution of immune responses. Pharmacological modulators of HDAC activity have demonstrated uniformly potent anti-inflammatory effects in experimental animal models of these diseases, in relevant immune and stromal cell populations from patients, as well as initial successes in the clinic. Recent studies have identified key roles for specific HDACs in regulating immune function, as well as alterations in HDAC expression and function in a number of immune-mediated inflammatory diseases (IMIDs), which may contribute to pathology in these diseases. Here, we review recent advances in our understanding of HDAC function in the immune system, their contribution to IMIDs, and the therapeutic potential of altering HDAC activity in IMIDs.
PMID: 21740352 [PubMed - in process]
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