The coronavirus disease 2019 (COVID-19) pandemic is among the most important public health crises of our generation. Despite the promise of prevention offered by effective vaccines, patients with severe COVID-19 will continue to populate hospitals and intensive care units for the foreseeable future. The most common clinical presentation of severe COVID-19 is hypoxemia and respiratory failure, typical of the acute respiratory distress syndrome (ARDS). Whether the clinical features and pathobiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia differ from those of pneumonia secondary to other pathogens is unclear. This uncertainty has created variability in the application of historically proven therapies for ARDS to patients with COVID-19. We review the available literature and find many similarities between patients with ARDS from pneumonia attributable to SARS-CoV-2 versus other respiratory pathogens. A notable exception is the long duration of illness among patients with COVID-19, which could result from its unique pathobiology. Available data support the use of care pathways and therapies proven effective for patients with ARDS, while pointing to unique features that might be therapeutically targeted for patients with severe SARS-CoV-2 pneumonia.
G.R. Scott Budinger, Alexander V. Misharin, Karen M. Ridge, Benjamin D. Singer, Richard G. Wunderink
B cells have a prominent role in the pathogenesis of systemic lupus erythematosus (SLE). They are mediators of inflammation through the production of pathogenic antibodies that augment inflammation and cause direct tissue and cell damage. Multiple therapeutic agents targeting B cells have been successfully used in mouse models of SLE; however, these preclinical studies have led to approval of only one new agent to treat patients with SLE: belimumab, a monoclonal antibody targeting B cell–activating factor (BAFF). Integrating the experience acquired from previous clinical trials with the knowledge generated by new studies about mechanisms of B cell contributions to SLE in specific groups of patients is critical to the development of new treatment strategies that will help to improve outcomes in patients with SLE. In particular, a sharper focus on B cell differentiation to plasma cells is warranted.
Yemil Atisha-Fregoso, Bahtiyar Toz, Betty Diamond
As a result of impressive increases in our knowledge of rodent and human immunology, the pathophysiological mechanisms underlying graft-versus-host disease (GVHD) have dramatically improved in the past 15 years. Despite improved knowledge, translation to clinical care has not proceeded rapidly, with results from experimental models being inconsistent in their ability to predict the clinical utility of new therapeutic agents. In parallel, new tools in immunology have allowed in depth analyses of the human system and have been recently been applied in the field of clinical GVHD. Notwithstanding these advances, there is a relative paucity of mechanistic insights into human translational research, and this remains an area of high unmet need. Here we review selected recent advances both in preclinical experimental transplantation and translational human studies, including new insights into human immunology, the microbiome, and regenerative medicine. We focus on the fact that both approaches can interactively improve our understanding of both acute and chronic GVHD biology and open the door to improved therapeutics and successes.
Gérard Socié, Leslie S. Kean, Robert Zeiser, Bruce R. Blazar
A small percentage of people living with HIV-1 can control viral replication without antiretroviral therapy (ART). These patients are called elite controllers (ECs) if they are able to maintain viral suppression without initiating ART and posttreatment controllers (PTCs) if they control HIV replication after ART has been discontinued. Both types of controllers may serve as a model of a functional cure for HIV-1 but the mechanisms responsible for viral control have not been fully elucidated. In this review, we highlight key lessons that have been learned so far in the study of ECs and PTCs and their implications for HIV cure research.
Jonathan Z. Li, Joel N. Blankson
In recent decades, cancer research has expanded exponentially beyond the study of abnormally dividing cells to include complex and extensive heterotypic interactions between cancer and noncancer cells that constitute the tumor microenvironment (TME). Modulation of stromal, immune, and endothelial cells by cancer cells promotes proliferation, survival, and metabolic changes that support tumor growth and metastasis. Recent evidence demonstrates that tumors can recruit peripheral nerves to the TME, leading to enhanced tumor growth in a range of cancer models through distinct mechanisms. This process, termed tumor innervation, is associated with an aggressive tumor phenotype and correlates with poor prognosis in clinical studies. Therefore, the peripheral nervous system may play an underrecognized role in cancer development, harboring targetable pathways that warrant investigation. To date, nerves have been implicated in driving proliferation, invasion, metastasis, and immune evasion through locally delivered neurotransmitters. However, emerging evidence suggests that cell-cell communication via exosomes induces tumor innervation, and thus exosomes may also mediate neural regulation of the TME. In this Review, seminal studies establishing tumor innervation are discussed, and known and putative signaling mechanisms between peripheral nerves and components of the TME are explored as a means to identify potential opportunities for therapeutic intervention.
Stefan M. Gysler, Ronny Drapkin
Iron plays an important role in mammalian physiological processes. It is a critical component for the function of many proteins, including enzymes that require heme and iron-sulfur clusters. However, excess iron is also detrimental because of its ability to catalyze the formation of reactive oxygen species. As a result, cellular and systemic iron levels are tightly regulated to prevent oxidative damage. Iron deficiency can lead to a number of pathological conditions, the most prominent being anemia. Iron deficiency should be corrected to improve adult patients’ symptoms and to facilitate normal growth during fetal development and childhood. However, inappropriate use of intravenous iron in chronic conditions, such as cancer and heart failure, in the absence of clear iron deficiency can lead to unwanted side effects. Thus, this form of therapy should be reserved for certain patients who cannot tolerate oral iron and need rapid iron replenishment. Here, we will review cellular and systemic iron homeostasis and will discuss complications of iron deficiency.
Navid Koleini, Jason S. Shapiro, Justin Geier, Hossein Ardehali
First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called “trained immunity.” In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG.
Alok K. Singh, Mihai G. Netea, William R. Bishai
The immunoprevention of cancer and cancer recurrence is an important area of concern for the scientific community and society as a whole. Researchers have been working for decades to develop vaccines with the potential to alleviate these health care and economic burdens. So far, vaccines have made more progress in preventing cancer than in eliminating already established cancer. In particular, vaccines targeting oncogenic viruses, such as the human papillomavirus and the hepatitis B virus, are exceptional examples of successful prevention of virus-associated cancers, such as cervical cancer and hepatocellular carcinoma. Cancer-preventive vaccines targeting nonviral antigens, such as tumor-associated antigens and neoantigens, are also being extensively tested. Here, we review the currently approved preventive cancer vaccines; discuss the challenges in this field by covering ongoing preclinical and clinical human trials in various cancers; and address various issues related to maximizing cancer vaccine benefit.
Tomohiro Enokida, Alvaro Moreira, Nina Bhardwaj
Tumor metastasis is a singularly important determinant of survival in most cancers. Historically, radiation therapy (RT) directed at a primary tumor mass was associated infrequently with remission of metastasis outside the field of irradiation. This away-from-target or “abscopal effect” received fringe attention because of its rarity. With the advent of immunotherapy, there are now increasing reports of abscopal effects upon RT in combination with immune checkpoint inhibition. This sparked investigation into underlying mechanisms and clinical trials aimed at enhancement of this effect. While these studies clearly attribute the abscopal effect to an antitumor immune response, the initial molecular triggers for its onset and specificity remain enigmatic. Here, we propose that DNA damage–induced inflammation coupled with neoantigen generation is essential during this intriguing phenomenon of systemic tumor regression and discuss the implications of this model for treatment aimed at triggering the abscopal effect in metastatic cancer.
Timothy P. Lippert, Roger A. Greenberg
Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. Considerable progress has been made in elucidating key components of this regulatory system, and in parallel with this effort has been the development of numerous biologics that have been tested in clinical trials for a wide range of indications, including muscular dystrophy, sporadic inclusion body myositis, spinal muscular atrophy, cachexia, muscle loss due to aging or following falls, obesity, and type 2 diabetes. Here, I review what is known about the MSTN regulatory system and the current state of efforts to target this pathway for clinical applications.
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