Current Trends in Immunology最新文献

Recognition of abnormal glycosylation in virtually any cancer type has raised a great interest in the glycan-based tumor biomarkers. Our team explored carbohydrate microarrays as a broad-spectrum immunoassay to probe the immunologically potent tumor glycan targets. This effort has led to the identification of a blood group precursor antigen SSEA-0 as a conserved breast cancer (BCA) marker. Since this immunogenic O-core glycan is normally hidden as a cryptic antigen but becomes overexpressed and surface-exposed by metastatic breast cancer cells (MBCA), its potential as a novel immunological target for precision immunotherapy against tumor metastasis warrants a focused investigation.

Cyclopia, a rare genetic anomaly and birth defect, was recently observed in our nonhuman primate study. A newborn rhesus macaque, delivered via cesarean section, exhibited facial abnormalities, including a single eye in the middle of the forehead. This macaque was born to a dam who had been inoculated with SIV in the first trimester and received antiretroviral therapy (ART) in the early third trimester of pregnancy. Prenatal ultrasound detected fetal defects, including the fusion of the thalami and absence of third ventricle during the third trimester of fetal development. Remarkably, the newborn macaque was diagnosed with severe alobar holoprosencephaly, characterized by a single eye located on the facial midline and proboscises positioned above and below the eye. This condition was accompanied by the absence of a nose, mouth, mandible, maxilla, nasal and oral cavities, tongue, as well as the esophagus. Subsequent genetic screening identified a significant down-regulation of craniofacial development-associated genes, although genetic mutations in the sonic hedgehog gene (SHH) were not present. As the fetal defects were identified prior to the initiation of antiretroviral therapy, it is possible that other environmental factors may have contributed to the development of cyclopia in this rhesus case. However, the etiology of this congenital HPE case remains essentially unknown.

Type 2 airway diseases including chronic rhinosinusitis, allergic rhinitis, and asthma remain a major health concern. These disorders are largely characterized by an uncontrolled type 2 immune response with elevated cytokines of IL-4, IL-5 and IL-13, eosinophilic inflammation, goblet cell hyperplasia as well as tissue remodeling. In the last few decades, critical potential roles of innate lymphoid cells (ILCs) in type 2 human diseases have emerged. Unlike their lymphocyte counterpart T cells, ILCs lack antigen-specific receptors and are largely tissue resident. Specifically, group 2 innate lymphoid cells (ILC2s) respond to airway epithelium-derived alarmins (TSLP, IL-33) and secrete high levels of type 2 cytokines. ILC2 responses can bypass the activation of T cells as well as develop corticosteroid-resistance. Currently approved biologics targeting the alarmin thymic stromal lymphopoietin (TSLP) or the IL-4/IL-13 receptor may reduce ILC2 activation, though novel treatments of type 2 airway diseases remain needed. In this review, we briefly discuss the pathogenesis of ILC2-mediated airway diseases followed by their current and potential treatments.

Our innate immune systems are evolved to provide the first line of immune defense against microbial infections. A key effector component is the adenosine deaminase acting on the RNA-1 (ADAR-1)/interferon (IFN) pathway of the innate cytoplasmic immunity that mounts rapid responses to many viral pathogens. As an RNA-editing enzyme, ADAR-1 targets viral RNA intermediates in the cytoplasmic compartment to interfere with the infection. However, ADAR-1 may also edit characteristic RNA structures of certain host genes, notably, the 5-hydroxytryptamine (serotonin) receptor 2C (5-HT_2CR). Dysfunction of 5-HT_2CR has been linked to the pathology of several human mental conditions, such as Schizophrenia, anxiety, bipolar disorder, major depression, and the mental illnesses of substance use disorders (SUD). Thus, the ADAR-1-mediated RNA editing may be either beneficial or harmful; these effects need to be tightly modulated to sustain innate antiviral immunity while restricting undesired off-target self-reactivity. In this communication, we discuss ideas and tools to identify the orphan drug candidates, including small molecules and biologics that may serve as effective modulators of the ADAR-1/IFN innate immunity and are thereby promising for use in treating or preventing SUD- and/or viral infection-associated mental illnesses.

A successful global healthcare response relies on versatile vaccines and production of broadly virus-neutralizing antibodies by the immune system to protect us from emerging infectious diseases. The present 2019 severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic highlights the urgent need for development of anti-viral biodefense. Due to the genetic and proteomic diversities of viral pathogens, establishing versatile anti-viral vaccines or therapeutic agents is highly challenging. Carbohydrate antigens represent an important class of immunological targets for vaccine development and immunotherapy against microbial infections. In this mini review, some concepts and strategies for exploring the potential of immunogenic sugar moieties as CoV vaccine candidates are presented.

Cytokines and cytokine signaling pathways are crucial for regulating cellular functions, including cell growth, proliferation, differentiation, and cell death. Cytokines regulate physiological processes such as immune responses and maintain immune homeostasis, and they also mediate pathological conditions such as autoimmune diseases and cancer. Hence, the precise control of the expression of cytokines and the transduction of cytokine signals is tightly regulated at transcriptional and post-transcriptional levels. In particular, post-transcriptional regulation at the level of mRNA stability is critical for coordinating cytokine expression and cytokine signaling. Numerous cytokine transcripts contain AU-rich elements (AREs), whereas transcripts encoding numerous components of cytokine signaling pathways contain GU-rich elements (GREs). AREs and GREs are mRNA decay elements that mediate rapid mRNA degradation. Through ARE- and GRE-mediated decay mechanisms, immune cells selectively and specifically regulate cytokine networks during immune responses. Aberrant expression and stability of ARE- or GRE-containing transcripts that encode cytokines or components of cytokine signaling pathways are observed in disease states, including cancer. In this review, we focus on the role of AREs and GREs in regulating cytokine expression and signal transduction at the level of mRNA stability.

The purpose of this study is to determine the effect of systemic blockade of Interleukin-6 (IL-6) on allosensitization, regulatory T cell frequencies and suppressive phenotype, and allograft survival rates in a mouse model of corneal transplantation. Allogeneic corneal transplantation was performed using C57BL/6 mice as donors and BALB/c mice as recipients. Graft recipients were injected daily with either anti-IL-6 antibody or an isotype control antibody (1.25 mg/ml) for the first 7 days and on alternate days thereafter until week 8 after transplantation. Allograft survival was evaluated for 8 weeks using Kaplan-Meier survival analysis. Draining lymph nodes (DLN) were harvested at week 3 after transplantation, and proliferation of isolated recipient T cells through direct and indirect pathways was determined using mixed lymphocyte reaction assay. Frequencies of CD4⁺CD25⁺Foxp3⁺ regulatory T cells, their expression of Foxp3, and frequencies of IFNy⁺CD4⁺ Th1 cells were determined in DLN using flow cytometry. Finally, CD4⁺ T cells were cultured with bone marrow-derived dendritic cells from either C57BL/6 or BALB/c mice in the presence of IL-6-blocking antibody to determine Treg induction through direct and indirect pathways, respectively. Treatment with anti-IL-6 antibody suppressed both the direct and indirect pathways of allosensitization in graft recipients and significantly improved allograft survival rates. Furthermore, in vivo blockade of IL-6 enhanced Foxp3 expression by Tregs in graft recipients undergoing rejection, but did not exert a significant effect on Treg frequencies. Finally, IL-6 neutralization in vitro enhanced the differentiation of Tregs from CD4⁺ T cells through both direct and indirect pathways. Our results demonstrate that systemic administration of IL-6-blocking antibody to corneal allograft recipients suppresses direct and indirect routes of allosensitization, is associated with increased expression of Foxp3 by Tregs, and improves allograft survival rates.

Highly active antiretroviral therapy has significantly improved the life of HIV-1-infected individuals, yet complete eradication of HIV-1 reservoirs (i.e., latently infected cells) remains a major challenge. We have previously shown that induction of the endogenous cytoprotective enzyme heme oxygenase-1 (HO-1) by its natural substrate hemin reduces susceptibility of T cells and macrophages to HIV-1 infection. In the present study, we demonstrate that hemin treatment stimulated virus production by latently infected ACH-2 cells, followed by cellular toxicity and death when stimulated with TNF-α or co-cultured with monocyte-derived macrophages (MDM). This cytotoxicity was associated with low levels of the iron-binding protein ferritin and the iron transporter ferroportin with lack of hemoglobin catabolic enzyme HO-1, resulting in substantial iron accumulation in the activated ACH-2 cells. Defective iron homeostasis in ACH-2 cells provides a model system for selective targeting of the latent HIV-1 reservoir by hemin-induced iron toxicity.