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
Diabetes mellitus is a major public health problem, affecting about 10% of the population. Pharmacotherapy aims to protect against microvascular complications, including blindness, end-stage kidney disease, and amputations. Landmark clinical trials have demonstrated that intensive glycemic control slows progression of microvascular complications (retinopathy, nephropathy, and neuropathy). Long-term follow-up has demonstrated that intensive glycemic control also decreases risk of macrovascular disease, albeit rigorous evidence of macrovascular benefit did not emerge for over a decade. The US FDA’s recent requirement for dedicated cardiovascular outcome trials ushered in a golden age for understanding the clinical profiles of new type 2 diabetes drugs. Some clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) receptor agonists reported data demonstrating cardiovascular benefit (decreased risk of major adverse cardiovascular events and hospitalization for heart failure) and slower progression of diabetic kidney disease. This Review discusses current guidelines for use of the 12 classes of drugs approved to promote glycemic control in patients with type 2 diabetes. The Review also anticipates future developments with potential to improve the standard of care: availability of generic dipeptidylpeptidase-4 (DPP4) inhibitors and SGLT2 inhibitors; precision medicine to identify the best drugs for individual patients; and new therapies to protect against chronic complications of diabetes.
Simeon I. Taylor, Zhinous Shahidzadeh Yazdi, Amber L. Beitelshees
Both basal and glucose-stimulated insulin release occur primarily by insulin secretory granule exocytosis from pancreatic β cells, and both are needed to maintain normoglycemia. Loss of insulin-secreting β cells, accompanied by abnormal glucose tolerance, may involve simple exhaustion of insulin reserves (which, by immunostaining, appears as a loss of β cell identity), or β cell dedifferentiation, or β cell death. While various sensing and signaling defects can result in diminished insulin secretion, somewhat less attention has been paid to diabetes risk caused by insufficiency in the biosynthetic generation and maintenance of the total insulin granule storage pool. This Review offers an overview of insulin biosynthesis, beginning with the preproinsulin mRNA (translation and translocation into the ER), proinsulin folding and export from the ER, and delivery via the Golgi complex to secretory granules for conversion to insulin and ultimate hormone storage. All of these steps are needed for generation and maintenance of the total insulin granule pool, and defects in any of these steps may, weakly or strongly, perturb glycemic control. The foregoing considerations have obvious potential relevance to the pathogenesis of type 2 diabetes and some forms of monogenic diabetes; conceivably, several of these concepts might also have implications for β cell failure in type 1 diabetes.
Ming Liu, Yumeng Huang, Xiaoxi Xu, Xin Li, Maroof Alam, Anoop Arunagiri, Leena Haataja, Li Ding, Shusen Wang, Pamela Itkin-Ansari, Randal J. Kaufman, Billy Tsai, Ling Qi, Peter Arvan
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
The molecular mechanisms of cellular insulin action have been the focus of much investigation since the discovery of the hormone 100 years ago. Insulin action is impaired in metabolic syndrome, a condition known as insulin resistance. The actions of the hormone are initiated by binding to its receptor on the surface of target cells. The receptor is an α2β2 heterodimer that binds to insulin with high affinity, resulting in the activation of its tyrosine kinase activity. Once activated, the receptor can phosphorylate a number of intracellular substrates that initiate discrete signaling pathways. The tyrosine phosphorylation of some substrates activates phosphatidylinositol-3-kinase (PI3K), which produces polyphosphoinositides that interact with protein kinases, leading to activation of the kinase Akt. Phosphorylation of Shc leads to activation of the Ras/MAP kinase pathway. Phosphorylation of SH2B2 and of Cbl initiates activation of G proteins such as TC10. Activation of Akt and other protein kinases produces phosphorylation of a variety of substrates, including transcription factors, GTPase-activating proteins, and other kinases that control key metabolic events. Among the cellular processes controlled by insulin are vesicle trafficking, activities of metabolic enzymes, transcriptional factors, and degradation of insulin itself. Together these complex processes are coordinated to ensure glucose homeostasis.
Alan R. Saltiel
2021 to 2022 marks the one hundredth anniversary of ground-breaking research in Toronto that changed the course of what was, then, a universally fatal disease: type 1 diabetes. Some would argue that insulin’s discovery by Banting, Best, Macleod, and Collip was the greatest scientific advance of the 20th century, being one of the first instances in which modern medical science was able to provide lifesaving therapy. As with all scientific discoveries, the work in Toronto built upon important advances of many researchers over the preceding decades. Furthermore, the Toronto work ushered in a century of discovery of the purification, isolation, structural characterization, and genetic sequencing of insulin, all of which influenced ongoing improvements in therapeutic insulin formulations. Here we discuss the body of knowledge prior to 1921 localizing insulin to the pancreas and establishing insulin’s role in glucoregulation, and provide our views as to why researchers in Toronto ultimately achieved the purification of pancreatic extracts as a therapy. We discuss the pharmaceutical industry’s role in the early days of insulin production and distribution and provide insights into why the discoverers chose not to profit financially from the discovery. This fascinating story of bench-to-beside discovery provides useful considerations for scientists now and in the future.
Gary F. Lewis, Patricia L. Brubaker
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