Organ and tissue transplantation are frequently life-extending procedures for patients with end-stage organ disease or hematological malignancies; however, the success of transplantation of organs and tissues to a recipient from a genetically non-identical donor is limited by immune-mediated complications, including rejection, graft dysfunction, graft-versus-host-disease, and the side-effects of preventing rejection. Despite over 100 years of research in this area, we are just now beginning to develop an in-depth understanding of the immune mechanisms that determine the success of allotransplantation. A detailed understanding of transplantation immunology will allow for better selection of donor/recipient pairs, the development of novel therapeutic strategies and, ultimately, better outcomes. Reviews in this series explore the role of cytokines in both acute and chronic graft-versus-host disease, the effects of sterile inflammation, danger signals, and the inflammasome in solid organ transplantation, the mechanisms of humoral and cellular rejection, cell-based therapies to combat rejection and transplantation-associated infections, and the effects of both host intrinsic and extrinsic factors in transplantation outcomes.
Nuclear receptors are a class of intracellular proteins that sense and respond to a variety of endogenous hormones, vitamins, and xenobiotic endocrine disruptors by modulating gene expression. These proteins have well-established roles in the regulation of energy balance and the skeletal system, and they are emerging as important players in other areas of human physiology and disease. Humans have 48 nuclear receptors that all possess an N-terminal transactivation domain, a highly conserved central region DNA-binding domain, and a C-terminal ligand-binding domain. Ligand binding results in the transactivation of specific genes within a given tissue. Notably, a number of nuclear receptors do not have a known endogenous ligand and structural studies indicate that they may not bind ligands at all, but instead recruit other nuclear receptors or chromatin modifiers to control gene expression. Nuclear receptor activity can be modulated through interactions with other nuclear receptors or transcriptional coactivator or corepressor proteins, as well as through modulation by numerous growth factor and cytokine signaling cascades that induce various posttranslational modifications. Reviews in this series examine the role of nuclear receptors in metabolic syndrome, cardiovascular disease, liver function, hormone-dependent cancers, responses to common therapeutic agents, genetic disorders, the effects of vitamin D, and parasitic disease.
Published April 2017
Metabolic syndrome constitutes a constellation of conditions, including central obesity, glucose intolerance, and dyslipidemia. These conditions enhance the risk of type 2 diabetes, cardiovascular disease, fatty liver/cirrhosis, hypertension, and cancer. The finding over 20 years ago that the inflammatory mediator TNF is overexpressed in adipose fundamentally changed our understanding of obesity and metabolic syndrome. We now know that metabolic syndrome in humans is characterized by chronic low-grade inflammation in multiple organs and we are now beginning to delineate the mechanisms by which inflammation and metabolism influence each other. Reviews in this series examine the activation of the innate and adaptive immune system in obesity; inflammation within diabetic islets, brain, liver, gut, and muscle; the role of inflammation in fibrosis and angiogenesis; the factors that contribute to the initiation of inflammation; and therapeutic approaches to modulate inflammation in the context of obesity and metabolic syndrome. We now know that an inflammatory program is activated early in adipose expansion and during chronic obesity, permanently skewing the immune system to a pro-inflammatory phenotype.
Published January 2017
Inflammation is a primary response to injury and or infection, allowing the body to eliminate pathogens and/or damaged tissue and to initiate repair processes. Low oxygen levels, or hypoxia, is a key feature of inflamed tissue and is due to damage to the local vasculature and increased oxygen consumption by pathogens and infiltrating immune cells. In addition to being a feature of inflammation, hypoxia also induces and regulates the inflammatory response by inducing the release of inflammatory cytokines, directing immune cell infiltration, and tuning the responses of the immune cells themselves. These effects are largely mediated by a family of hypoxia-inducible transcription factors (HIFs), which serve as the master regulators of cellular responses to inadequate oxygenation and HIFs and their regulatory factors are now emerging as therapeutic targets in a number of disease states. Reviews in this series discuss the roles of hypoxia and HIFs in the regulation of inflammatory pathways, immune cell metabolism, mucosal inflammation, the tumor microenvironment, intestinal inflammation and colorectal cancer, and recovery from radiation-induced gastrointestinal toxicity. Together, these reviews identify a number of hypoxia-regulated processes that could potentially be targeted to modulate inflammation.
Published October 2016
Cell-to-cell communication is an essential component in multicellular organisms, allowing for rapid, coordinated responses to changes within the environment. Classical signaling mediators include direct cell-cell contact as well as secreted factors, such as cytokines, metabolites, and hormones. In the past decade, extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, have emerged as important mediators of intercellular communication. EVs are double-membrane vesicles containing cargoes of multiple proteins, lipids, and nucleic acids, which are derived from their cells of origin, and EV cargoes can change depending on the status of their originating cells. Importantly, EVs are found in all body fluids and can carry their cargoes to distant sites within the body as well as neighboring cells. Reviews in this series discuss the role of EV-mediated signaling in physiological and pathophysiological conditions, including infection, host immune responses, and cancer. Additionally, these reviews cover the potential clinical use of EVs as therapeutics and diagnostic biomarkers.
Published April 2016
The development of combination antiretroviral therapy (ART) in the mid-1990s initially raised hopes that HIV was a curable disease; however, further studies revealed that the virus persists, even in patients with undetectable levels of HIV in their plasma. Resting CD4+ T cells harbor stably integrated viral genomes that can produce infectious virus following T cell activation. Importantly, treatment interruption leads to a rapid recrudescence of infection from this latent reservoir, usually within 2 to 3 weeks. Several distinct areas of HIV research are now focused on the development of strategies to prevent the latent reservoir from replicating or to eliminate it entirely. Reviews in this series detail progress in our understanding of the molecular and cellular mechanisms of viral latency, efforts to accurately assess the size and composition of the latent viral reservoir, the characterization and development of HIV-targeted broadly neutralizing antibodies and cytolytic T lymphocytes, as well as animal models for the study of HIV latency and therapeutic strategies.
Published February 2016
In the mid-1800s, Rudolf Virchow noted the presence of surfeit inflammatory cells in many tumors. Roughly 50 years later, Paul Ehrlich postulated that the immune system both recognizes and protects against cancer. Since then, researchers have been trying to elucidate the relationship between cancer, inflammation, and the innate and adaptive immune systems, starting with the theory of immunosurveillance introduced by Lewis Thomas and further developed by Sir MacFarlane Burnet. We now know that tumor cells display antigens that are recognized by immune cells, but that anti-tumor immunity can be circumvented directly by tumor cells themselves via a variety of escape mechanisms. The goal of cancer immunotherapy is to mount an effective anti-tumor immune response by repairing, stimulating or, enhancing the immune system’s response to cancer cells. Reviews in this series detail progress in cancer immunoediting, immunosuppressive cells in the tumor microenvironment, cancer-associated inflammation, therapeutic cancer vaccines, genomic approaches in immunotherapy, adoptive transfer of genetically engineered T cells, and checkpoint blockade therapy.
Published September 2015
Autoimmune disease encompasses a diverse group of over 80 chronic disorders. Each of these diseases has distinct clinical manifestations that are due to the differences in the cells and organ systems involved; however, these diseases are universally characterized by a loss of self-tolerance, resulting in autoreactive immune cells, autoantibodies, and elevated levels of inflammatory cytokines. Reviews in this series examine mechanisms underlying autoimmunity, including failure of B cell tolerance checkpoints, the generation of autoantibodies, cytokine dysregulation, aberrant T cell signaling, and the loss of immune suppressive cells and functions. They also explore the influence of genetic background, environment, microRNAs, and sex-specific factors on the loss of immune homeostasis.
Published June 2015
The enteric nervous system (ENS) encompasses extrinsic and intrinsic neurons, glia, and sensory epithelial cells that are embedded throughout the gastrointestinal tract. The circuits formed by these cells are responsible for interpreting sensory information in the gut lumen in order to regulate gut motility, secretion, food intake, and immune function. The ENS communicates with the CNS in a bidirectional manner, allowing stimuli in the gut to influence mood, food intake, and other behaviors. Reviews in this series examine the mechanisms by which the ENS develops from neural crest cells, chemosensory mechanisms that allow for the detection of and response to fats and other nutrients within the gut lumen, the role of the enteric glia, regulation of ENS function by the immune system and inflammation, and the impact of surgery and the gut microbiota on ENS communication with the brain.
Published March 2015
The term autophagy, or “self-eating”, refers to the processes by which cells deliver cytoplasmic constituents to lysosomes for degradation. Autophagy provides biosynthetic precursors and energy sources to sustain metabolism and cell growth and prevent the accumulation of toxic components. These processes are invoked in response to stressors, including changing nutrient conditions, damage to organelles, intracellular pathogens, and accumulation of reactive oxygen species, among others, in order to maintain cellular homeostasis. Autophagy becomes insufficient with age and is perturbed in multiple disease states; consequently, pathogenic aberrations in autophagy have emerged as a major focus in the development of novel therapeutic strategies. Reviews in this series detail specific autophagic mechanisms; the role of autophagy in cardiovascular disease, cancer, neurodegeneration, lifespan, and the immune system; and methods to develop autophagy-centered therapeutic modalities.
Published January 2015