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Systemic immunotherapeutics have been a clinical staple in the treatment of cancer, infectious diseases, organ and cell transplantation, autoimmunity, and allergies. Although their utility remains unquestioned, systemic administration of these drugs is associated with limited efficacy, significant adverse off-target effects, transient activity, and the requirement for frequent repeated dosing. To this end, recent technological advancements have provided novel means for sustained drug delivery to specific tissues and targeted localized approaches for immunotherapeutics. In this article, we present various cutting-edge platform technologies, including implants, multireservoir systems, and scaffolds encapsulating immunomodulatory agents for local administration. Examples of their application in cancer, cell transplantation, allergy, and infectious diseases are discussed, highlighting the potential of such systems for innovative immunomodulatory intervention., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The family of cytokines that comprises IL-3, IL-5, and GM-CSF was discovered over 30 years ago, and their biological activities and resulting impact in clinical medicine has continued to expand ever since. Originally identified as bone marrow growth factors capable of acting on hemopoietic progenitor cells to induce their proliferation and differentiation into mature blood cells, these cytokines are also recognized as key mediators of inflammation and the pathobiology of diverse immunologic diseases. This increased understanding of the functional repertoire of IL-3, IL-5, and GM-CSF has led to an explosion of interest in modulating their functions for clinical management. Key to the successful clinical translation of this knowledge is the recognition that these cytokines act by engaging distinct dimeric receptors and that they share a common signaling subunit called β-common or βc. The structural determination of how IL-3, IL-5, and GM-CSF interact with their receptors and linking this to their differential biological functions on effector cells has unveiled new paradigms of cell signaling. This knowledge has paved the way for novel mAbs and other molecules as selective or pan inhibitors for use in different clinical settings., (Copyright © 2022. Published by Elsevier Inc.)

Background: Alternative splicing is important for increasing the complexity of the human proteome from a limited genome. Previous studies have shown that for some autoantigens, there is differential immunogenicity among alternatively spliced isoforms., Objectives: Herein, we tested the hypothesis that alternative splicing is a common feature for transcripts of autologous proteins that are autoantigens. The corollary hypothesis tested was that nonautoantigen transcripts have a lower frequency of alternative splicing., Methods: The extent of alternative splicing within 45 randomly selected self-proteins associated with autoimmune diseases was compared with 9554 randomly selected proteins in the human genome by using bioinformatics analyses. Isoform-specific regions that resulted from alternative splicing were studied for their potential to be epitopes for antibodies or T-cell receptors., Results: Alternative splicing occurred in 100% of the autoantigen transcripts. This was significantly higher than the approximately 42% rate of alternative splicing observed in the 9554 randomly selected human gene transcripts ( P < .001). Within the isoform-specific regions of the autoantigens, 92% and 88% encoded MHC class I and class II-restricted T-cell antigen epitopes, respectively, and 70% encoded antibody binding domains. Furthermore, 80% of the autoantigen transcripts underwent noncanonical alternative splicing, which is also significantly higher than the less than 1% rate in randomly selected gene transcripts ( P < .001)., Conclusion: These studies suggest that noncanonical alternative splicing may be an important mechanism for the generation of untolerized epitopes that may lead to autoimmunity. Furthermore, the product of a transcript that does not undergo alternative splicing is unlikely to be a target antigen in autoimmunity.

IL-3, IL-5, and GM-CSF are related hematopoietic cytoines that are important for allergic inflammation. The receptors for human IL-5, IL-3, and GM-CSF are members of the hematopoietin receptor superfamily and are comprised of a cytokine-specific alpha chain and the common beta chain that is shared among these cytokines for signaling. Each of these cytokines contributes to the differentiation and function of leukocyte subpopulations and have clinical importance in protective immunity and in the pathophysiology of a spectrum of immunologic diseases that are as diverse as allergy and asthma, pulmonary alveolar proteinosis, neurodegenerative diseases, and malignancies. Delineating the biology of these cytokines is enabling the development of new strategies for diagnosing and treating these diseases and modulating immune responses.

Background: IL-5 is central to the pathogenesis of airway eosinophilic inflammation and hyperresponsiveness associated with both atopic and nonatopic asthma. The therapeutic potential of IL-5 antagonists in asthma is supported by the inhibition of airway eosinophilia and hyperresponsiveness in animal models receiving neutralizing anti-IL-5 mAbs intravenously or intraperitoneally., Objective: The purpose of this study was to test the hypothesis that mAbs against IL-5 delivered by way of the respiratory tract are as effective as those delivered intraperitoneally in diminishing the pulmonary eosinophilic inflammation and airway hyperresponsiveness in a murine model of ovalbumin-induced asthma., Methods: Ovalbumin-sensitized Balb/c mice were given an anti-IL-5 mAb delivered intranasally or an isotype-matched control mAb delivered intranasally before respiratory challenge with ovalbumin. Outcome variables included respiratory system resistance responses to methacholine, bronchoalveolar lavage fluid cellularity, and lung histopathology., Results: Anti-IL-5 mAbs administered intranasally to ovalbumin-sensitized and challenged mice significantly decreased eosinophil counts in bronchoalveolar lavage fluid and lung tissue and significantly reduced airway hyperresponsiveness relative to ovalbumin-sensitized and challenged mice that received either no mAb treatment or an isotype-matched control mAb. Similar results were obtained when an anti-IL-5 mAb was given intraperitoneally., Conclusion: This is the first study to demonstrate that delivery of anti-IL-5 mAbs into the respiratory tract is efficacious in attenuating the asthma phenotype in a murine model. These results provide impetus for the development of inhaled IL-5 antagonists for the treatment of human asthma.

Bronchial antigen challenge of sensitized atopic patients with asthma results in an early fall in FEV1, followed in a proportion of patients by a late (4 to 24 hours) fall. The late response is accompanied by an increase in bronchial reactivity, which is widely believed to reflect local influx and degranulation of inflammatory cells, particularly eosinophils, in association with elevated local secretion of cytokines. We hypothesized that the development of a late-phase bronchoconstrictor response and airway eosinophilia after allergen challenge of sensitized atopic patients with asthma is associated with elevated induced sputum concentrations of the eosinophil-active cytokines IL-5 and granulocyte-macrophage colony-stimulating factor and the proinflammatory cytokine tumor necrosis factor-alpha. We counted inflammatory leukocytes and measured cytokine concentrations in induced sputum at baseline and 24 hours after inhalational allergen challenge of 15 atopic patients with asthma who had previously demonstrated a late response. We observed significant increases in the numbers of eosinophils and the concentrations of their granule products, eosinophil cationic protein and eosinophil peroxidase. In contrast, the numbers of neutrophils and concentrations of two of their products, myeloperoxidase and human neutrophil lipocalin, did not significantly change. The numbers of sputum eosinophils correlated with the maximal late-phase fall in FEV1. Concentrations of IL-5 and tumor necrosis factor-alpha, but not granulocyte-macrophage colony-stimulating factor, were significantly elevated after allergen challenge. We conclude that the relatively noninvasive technique of induced sputum production can be used to monitor the effect of bronchial provocation on cytokine concentrations in asthma.

Background: The late-phase allergic reaction is an eosinophilic inflammatory response that begins several hours after allergen exposure, may persist for 24 hours, and is an important pathogenic mechanism in allergic disease., Objective: Cultured naive human mast cells were used to investigate whether mast cells are a direct source of the eosinophil-promoting cytokines IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF)., Methods: Naive human mast cells were derived from bone marrow mononuclear cells cultured in the presence of stem-cell factor. Cytokine message and protein production in response to high-affinity IgE receptor ligation of cultured mast cells were measured by semiquantitative polymerase chain reaction and ELISA, respectively., Results: IL-5, IL-3, and GM-CSF messenger RNA increased within 2 hours of mast cell activation, with IL-5 and GM-CSF message remaining elevated for 24 hours, whereas IL-3 mRNA rapidly declined. IL-5 and GM-CSF protein were measurable 4 to 6 hours after stimulation and peaked by 24 and 12 hours, respectively. IL-3 protein was not detectable., Conclusion: These findings demonstrate that naive mast cells do not constitutively produce IL-5 or GM-CSF protein but are a major source of these eosinophilotropic cytokines on high-affinity IgE receptor ligation.

Sustained and significant reversal of antibody deficiencies is uncommon, although it has been noted in some cases during childhood and after viral infections. We report a case of reversal of IgG2 deficiency after splenectomy. A 46-year-old man who suffered recurrent sinusitis despite antibiotic therapy was noted to have IgG2 deficiency and cutaneous anergy. Replacement therapy with intravenous immunoglobulin ameliorated his symptoms. After 13 months of therapy, the patient had a diagnostic laparotomy and splenectomy because of portal hypertension, hypersplenism, and consideration of underlying malignancy. No evidence of malignancy or infection, including human immunodeficiency virus, active cytomegalovirus, or Epstein-Barr virus infection, was found. After splenectomy, the patient's serum IgG2 level normalized without replacement therapy. Subsequently, it fell, then normalized once more, and remains normal. The patient also demonstrated positive reactions to delayed hypersensitivity testing after splenectomy, but, subsequently, became anergic and remains anergic at the present time. Since the splenectomy he has remained clinically well without antibiotics or immunoglobulin replacement. In vitro analysis of his lymphocyte function demonstrated impaired T cell proliferation as well as an intrinsic B cell differentiation defect. This case demonstrates the potentially dynamic nature of IgG subclass deficiencies.

The efficacy of nifedipine, a calcium channel antagonist, in the treatment of chronic idiopathic urticaria, was evaluated in a double-blinded, placebo-controlled, crossover trial. Ten patients with chronic urticaria refractory to maximally tolerated doses of H1 and H2 antihistamines and in whom extensive evaluation failed to identify a cause for their urticaria were entered into the study. Patients continued with their prestudy antihistamine regimens. A study drug dosage was titrated in each patient and maintained throughout the trial. Patients were treated with placebo or nifedipine for 4 weeks and then crossed over to the other medication for 4 weeks. One patient withdrew because of unrelated medical illness, two patients withdrew after crossover to placebo because of intolerable urticaria, and seven patients completed the study. A beneficial effect of nifedipine was clearly demonstrated. Hive count, hive index, and itch index were all significantly improved at the end of 4 weeks of nifedipine treatment (p = 0.023, 0.003, and 0.003, respectively) but not placebo treatment (p = 0.194, 0.664, and 0.944, respectively). Additionally, end point hive index and itch index scores with nifedipine compared to corresponding placebo scores were significantly improved (p = 0.010 and 0.008, respectively). Nifedipine was well tolerated. Thus, when nifedipine is used as an adjunct to antihistamines, it appears to be a safe, efficacious drug for the treatment of chronic idiopathic urticaria.