Idiopathic pulmonary fibrosis (IPF) affects hundreds of thousands of people worldwide, reducing their quality of life and leading to death from respiratory failure within years of diagnosis. Treatment options remain limited, with only two FDA-approved drugs available in the United States, neither of which reverse the lung damage caused by the disease or prolong the life of individuals with IPF. The only cure for IPF is lung transplantation. In this review, we discuss recent major advances in our understanding of the role of the immune system in IPF that have revealed immune dysregulation as a critical driver of disease pathophysiology. We also highlight ways in which an improved understanding of the immune system’s role in IPF may enable the development of targeted immunomodulatory therapies that successfully halt or potentially even reverse lung fibrosis.
Kevin Shenderov, Samuel L. Collins, Jonathan D. Powell, Maureen R. Horton
Chimeric antigen receptor (CAR) T cell therapy has shown considerable promise for hematologic malignancies, leading to the US Food and Drug Administration approval of two CAR T cell–based therapies for the treatment of B cell acute lymphoblastic leukemia and large B cell lymphoma. Despite success in hematologic malignancies, the treatment landscape of CAR T cell therapy for solid tumors has been limited. There are unique challenges in the development of novel CAR T cell therapies to improve both safety and efficacy. Improved understanding of the immunosuppressive tumor microenvironment and resistance mechanisms has led to encouraging approaches to mitigating these obstacles. This Review will characterize challenges with current CAR T designs for hematologic malignancies and solid tumors and emphasize preclinical and clinical strategies to overcome them with novel CAR T cell therapies.
Emiliano Roselli, Rawan Faramand, Marco L. Davila
IL-36 is a member of the IL-1 superfamily and consists of three agonists and one receptor antagonist (IL-36Ra). The three endogenous agonists, IL-36α, –β, and –γ, act primarily as proinflammatory cytokines, and their signaling through the IL-36 receptor (IL-36R) promotes immune cell infiltration and secretion of inflammatory and chemotactic molecules. However, IL-36 signaling also fosters secretion of profibrotic soluble mediators, suggesting a role in fibrotic disorders. IL-36 isoforms and IL-36 have been implicated in inflammatory diseases including psoriasis, arthritis, inflammatory bowel diseases, and allergic rhinitis. Moreover, IL-36 has been connected to fibrotic disorders affecting the kidney, lung, and intestines. This review summarizes the expression, cellular source, and function of IL-36 in inflammation and fibrosis in various organs, and proposes that IL-36 modulation may prove valuable in preventing or treating inflammatory and fibrotic diseases and may reveal a mechanistic link between inflammation and fibrosis.
Michael Elias, Shuai Zhao, Hongnga T. Le, Jie Wang, Markus F. Neurath, Clemens Neufert, Claudio Fiocchi, Florian Rieder
Dietary modification is central to obesity treatment. Weight loss diets are available that include various permutations of energy restriction, macronutrients, foods, and dietary intake patterns. Caloric restriction is the common pathway for weight reduction, but different diets may induce weight loss by varied additional mechanisms, including by facilitating dietary adherence. This narrative Review of meta-analyses and select clinical trials found that lower-calorie diets, compared with higher-calorie regimens, reliably induced larger short-term (<6 months) weight losses, with deterioration of this benefit over the long term (>12 months). Few significant long-term differences in weight loss were observed for diets of varying macronutrient composition, although some regimens were found to have short-term advantages (e.g., low carbohydrate versus low fat). Progress in improving dietary adherence, which is critical to both short- and long-term weight loss, could result from greater efforts to identify behavioral and metabolic phenotypes among dieters.
Ariana M. Chao, Kerry M. Quigley, Thomas A. Wadden
The field of gene therapy has made considerable progress over the past several years. Adeno-associated virus (AAV) vectors have emerged as promising and attractive tools for in vivo gene therapy. Despite the recent clinical successes achieved with recombinant AAVs (rAAVs) for therapeutics, host immune responses against the vector and transgene product have been observed in numerous preclinical and clinical studies. These outcomes have hampered the advancement of AAV gene therapies, preventing them from becoming fully viable and safe medicines. The human immune system is multidimensional and complex. Both the innate and adaptive arms of the immune system seem to play a concerted role in the response against rAAVs. While most efforts have been focused on the role of adaptive immunity and developing ways to overcome it, the innate immune system has also been found to have a critical function. Innate immunity not only mediates the initial response to the vector, but also primes the adaptive immune system to launch a more deleterious attack against the foreign vector. This Review highlights what is known about innate immune responses against rAAVs and discusses potential strategies to circumvent these pathways.
Manish Muhuri, Yukiko Maeda, Hong Ma, Sanjay Ram, Katherine A. Fitzgerald, Phillip W.L. Tai, Guangping Gao
Interferons (IFNs) are pleiotropic cytokines critical for regulation of epithelial cell functions and for immune system regulation. In cancer, IFNs contribute to tumor-intrinsic and -extrinsic mechanisms that determine the quality of antitumor immunity and response to immunotherapy. In this Review, we focus on the different types of tumor IFN sensitivity that determine dynamic tumor-immune interactions and their coevolution during cancer progression and metastasis. We extend the discussion to new evidence supporting immunotherapy-mediated immunoediting and the dual opposing roles of IFNs that lead to immune checkpoint blockade response or resistance. Understanding the intricate dynamic responses to IFN will lead to novel immunotherapeutic strategies to circumvent protumorigenic effects of IFN while exploiting IFN-mediated antitumor immunity.
Michelle von Locquenghien, Catalina Rozalén, Toni Celià-Terrassa
Since the COVID-19 pandemic swept across the globe, researchers have been trying to understand its origin, life cycle, and pathogenesis. There is a striking variability in the phenotypic response to infection with SARS-CoV-2 that may reflect differences in host genetics and/or immune response. It is known that the human epigenome is influenced by ethnicity, age, lifestyle, and environmental factors, including previous viral infections. This review will examine the influence of viruses on the host epigenome. We will describe general lessons and methodologies that can be used to understand how the virus evades the host immune response. We will consider how variation in the epigenome may contribute to heterogeneity in the response to SARS-CoV-2 and may identify a precision medicine approach to treatment.
Elizabeth J. Hennessy, Garret A. FitzGerald
Human coronaviruses (hCoVs) cause severe respiratory illness in the elderly. Age-related impairments in innate immunity and sub-optimal virus-specific T cell and antibody responses are believed to cause severe disease upon respiratory virus infections. This phenomenon has recently received increased attention, as elderly patients are at substantially elevated risk for severe COVID-19 disease and experience increased rates of mortality following SARS-CoV-2 infection compared to younger populations. However, the basis for age-related fatal pneumonia following pathogenic hCoVs is not well understood. In this review article, we provide an overview of our current understanding of hCoV-induced fatal pneumonia in the elderly. We describe host immune response to hCoV infections derived from studies of young and aged animal models, and discuss the potential role of age-associated increases in sterile inflammation (inflammaging) and virus-induced dysregulated inflammation in causing age-related severe disease. We also highlight the existing gaps in our knowledge about virus replication and host immune responses to hCoV infection in young and aged individuals..
Rudragouda Channappanavar, Stanley Perlman
Muscular dystrophies are a heterogeneous group of genetic diseases, characterized by progressive degeneration of skeletal and cardiac muscle. Despite the intense investigation of different therapeutic options, a definitive treatment has not been yet developed for this debilitating class of pathologies. Cell-based therapies in muscular dystrophies have been pursued experimentally for the last three decades. Several cell types with different characteristics and tissues of origin, including myogenic stem and progenitor cells, stromal cells, and pluripotent stem cells, have been investigated over the years and have recently entered in the clinical arena with mixed results. In this review, we will do a roundup of the past attempts and describe the updated status of cell-based therapies aimed at counteracting the skeletal and cardiac myopathy present in dystrophic patients. We will present current challenges, summarize recent progresses, and make recommendations for future research and clinical trials.
Stefano Biressi, Antonio Filareto, Thomas A. Rando
Pulmonary hypertension (PH) is characterized by pulmonary artery remodeling that can subsequently culminate in right heart failure and premature death. Emerging evidence suggests that Hypoxia Inducible Factor (HIF) signaling plays a fundamental and pivotal role in the pathogenesis of PH. This review summarizes the regulation of HIF isoforms and their impact in various PH subtypes, as well as the elaborate conditional and cell specific knockout mouse studies that brought the role of this pathway to light. We also discuss the current preclinical status of pan- and isoform-selective HIF inhibitors, and propose new research areas that may facilitate HIF isoform-specific inhibition as a novel therapeutic strategy for PH and right heart failure.
Soni Savai Pullamsetti, Argen Mamazhakypov, Norbert Weissmann, Werner Seeger, Rajkumar Savai
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