Inhibitory effect of adenosine on adaptive antitumor immunity and intervention strategies / 浙江大学学报·医学版

Tumors in which the microenvironment is characterized by lack of immune cell infiltration are referred as "cold tumors" and typically exhibit low responsiveness to immune therapy. Targeting the factors contributing to "cold tumors" formation and converting them into "hot tumors" is a novel strategy for improving the efficacy of immunotherapy. Adenosine, a hydrolysis product of ATP, accumulates with a significantly higher concentration in the tumor microenvironments compared with normal tissue and exerts inhibitory effects on tumor-specific adaptive immunity. Tumor cells, dendritic cells, macrophages, and T cells express abundant adenosine receptors on their surfaces. The binding of adenosine to these receptors initiates downstream signaling pathways that suppress tumor antigen presentation and immune cell activation, consequently dampening adaptive immune responses against tumors. Adenosine down-regulates the expression of major histocompatibility complex Ⅱ and co-stimulatory factors on dendritic cells and macrophages, thereby inhibiting antigen presentation to T cells. Adenosine also inhibits ligand-receptor binding and transmembrane signaling on T cells, concomitantly suppressing the secretion of anti-tumor cytokines and impairing T cell activation. Furthermore, adenosine hinders effector T cell trafficking to tumor sites and infiltration by inhibiting chemokine secretion and KCa3.1 channels. Additionally, adenosine promotes the secretion of immunosuppressive cytokines, increases immune checkpoint protein expression, and enhances the activity of immunosuppressive cells, collectively curbing cytotoxic T cell-mediated tumor cell killing. Given the immunosuppressive role of adenosine in adaptive antitumor immunity, several inhibitors targeting adenosine generation or adenosine receptor blockade are currently in preclinical or clinical development with the aim of enhancing the effectiveness of immunotherapies. This review provides an overview of the inhibitory effects of adenosine on adaptive antitumor immunity, elucidate the molecular mechanisms involved, and summarizes the latest advances in application of adenosine inhibition strategies for antitumor immunotherapy.

Síndromes mielodisplásicos y sistema inmunitario / Myelodysplastic Syndrome and Immune System

Introducción: Los síndromes mielodisplásicos constituyen un grupo heterogéneo de desórdenes hematológicos clonales adquiridos, que afectan la célula madre. Se caracterizan morfológicamente por: hematopoyesis ineficaz, citopenias periféricas progresivas, displasia en uno o más linajes celulares y tendencia evolutiva a leucemia aguda. Los avances recientes en la comprensión de los mecanismos genéticos y moleculares de los síndromes mielodisplásicos, han revelado la asociación entre alteraciones inmunológicas y las mutaciones recurrentes. Las células de la respuesta inmune innata y adaptativa, así como diversos mediadores solubles liberados por ellas, pueden establecer una respuesta antitumoral protectora o, por el contrario, inducir eventos de inflamación crónica que favorezcan la promoción y progresión de esta enfermedad. Objetivos: Resumir los conocimientos actuales de la relación sistema inmune-síndromes mielodisplásicos, enfatizando en las células inmunes del microambiente de la médula ósea y su importancia en la clínica de la enfermedad. Métodos: Se realizó investigación bibliográfica-documental acerca del tema. Se consultaron las bases de datos Scielo y Pubmed. Conclusiones: La comprensión de la función dual que ejerce el sistema inmune en los síndromes mielodisplásicos, constituye un desafío y son necesarios estudios clínicos rigurosos para poder establecer el valor de la manipulación del sistema inmune como una forma posible de tratamiento de esta enfermedad(AU)

Introduction: Myelodysplastic syndromes (MDS) constitute a heterogeneous group of acquired clonal hematological disorders that affect the stem cell. These are characterized morphologically and clinically by: ineffective hematopoiesis, progressive peripheral cytopenia, dysplasia in one or more cell lineages, in most of cases and evolutionary tendency to acute leukemia. Recent advances in understanding the genetic and molecular mechanisms of MDS have revealed the association between immunological alterations and recurrent mutations. Cells of the innate and adaptive immune response, as well as various soluble mediators released by them, can establish a protective antitumor response or, on the contrary, induce events of chronic inflammation that favor the promotion and progression of this disease. Objective: To summarize the current knowledge of the immune system-MDS relationship, emphasizing the immune cells of the bone marrow microenvironment and their importance in the clinic of the disease. Methods: A bibliographic-documentary research was carried out on the subject. The Scielo and Pubmed databases were consulted. Conclusions: Understanding the dual role of the immune system in MDS constitutes a challenge and rigorous clinical studies are necessary to establish the value of manipulating the immune system as a possible form of treatment of this disease(AU)

Evaluación de la efectividad de las vacunas contra la COVID-19: orientación provisional / Evaluation of COVID-19 vaccine effectiveness

En este documento se presenta orientación provisional sobre las mejores prácticas para evaluar la efectividad de las vacunas contra la COVID-19 usando el diseño de estudio observacional. Se examinan las consideraciones esenciales del diseño, el análisis y la interpretación de las evaluaciones de la efectividad de las vacunas contra la COVID-19, dado que se pueden obtener resultados sesgados aun en entornos en los que la exhaustividad y la calidad de los datos son altas. Esta orientación se dirige principalmente a las evaluaciones realizadas en los países de ingresos bajos o medianos, pero la mayoría de los conceptos también son aplicables en entornos de ingresos altos.

Since its emergence in December 2019, SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), has taken a tremendous toll globally; by 28 February 2021, there have been over 110 million cases and 2.5 million deaths worldwide from COVID-19 (1). Although most COVID-19 deaths occur among older adults and persons with chronic comorbid medical conditions, deaths have occurred in persons of all ages. Moreover, the pandemic has caused widespread morbidity and necessitated control measures that have devastated economies worldwide. In response to the pandemic, the global efforts to develop multiple vaccines to protect against COVID-19 disease have been unrivalled in the history of public health. By the end of 2020, three COVID-19 vaccines have received Emergency Use Approval/Listing (EUA/EUL) by maturity level 4 regulatory authorities, based on reaching predefined criteria for safety and efficacy, and at least several dozen more are in clinical trials.

Innate and Th1/Th17 adaptive immunity in acute and convalescent Brazilian borreliosis disease

ABSTRACT Introduction: Brazilian borreliosis (BB) disease is an infectious disease transmitted by ticks that mimics Lyme disease (LD) from the Northern Hemisphere. The BB clinical picture is characterized by a pathognomonic skin lesion (migratory erythema) and joint, neurological, cardiac and psychiatric symptoms. Innate and Th1/Th17 adaptive immunity seem to play an important role in the pathogenesis of Lyme disease. Objective: The aim of this study was to characterize the role of innate and Th1/Th17 adaptive immunity in BB patients with acute (<3 months) and convalescent (>3 months) disease. Methods: Fifty BB patients (28 with acute and 22 with convalescent disease) without treatment and 30 healthy subjects were evaluated. Levels of 20 cytokines or chemokines associated with innate and Th1/Th17 adaptive immunity were analyzed using Luminex (Millipore Corp., Billerica, MA). Results: Overall, BB patients had increased levels of IL-8 (6.29 vs 2.12 p = 0.002) and MIP-1α/CCL3 (5.20 vs 2.06, p = 0.030), associated with innate immunity, and MIP3B/CCL19 (Th1; 297.86 vs 212.41, p = 0.031) and IL-17A (Th17; 3.11 vs 2.20, p = 0.037), associated with adaptive immunity, compared with the levels of healthy controls. When comparing acute BB vs. convalescent BB subjects vs. healthy controls, IL-1β, IL-8 and MIP-1α/CCL3 (innate mediators) levels were highest in patients in the acute phase of disease (p < 0.05). TNF-α was associated with disseminated symptoms and with humoral reactivity against Borrelia burgdorferi. IL-10 was significantly correlated with IL-6 (r = 0.59, p = 0.003), IL-8 (r = 0.51, p < 0.001), MIP-1α/CCL3 (r = 0.42, p < 0.001) and MIP-3β/CCL19 (r = 0.40, p = 0.002) in all BB patients. Conclusions: This is the first study describing that innate and Th1/Th17 adaptive immunity play a crucial role in BB disease. Furthermore, innate mediators are particularly important in acute BB disease, and TNF-α is associated with evolution of BB symptoms.

Comparative evaluation of memory T cells in COVID-19 patients and the predictive role of CD4+CD8+ double positive T lymphocytes as a new marker

SUMMARY BACKGROUND: The COVID-19 pandemic has affected the entire world, posing a serious threat to human health. T cells play a critical role in the cellular immune response against viral infections. We aimed to reveal the relationship between T cell subsets and disease severity. METHODS: 40 COVID-19 patients were randomly recruited in this cross-sectional study. All cases were confirmed by quantitative RT-PCR. Patients were divided into two equivalent groups, one severe and one nonsevere. Clinical, laboratory and flow cytometric data were obtained from both clinical groups and compared. RESULTS: Lymphocyte subsets, CD4+ and CD8+ T cells, memory CD4+ T cells, memory CD8+ T cells, naive CD4+ T cells, effector memory CD4+ T cells, central memory CD4+ T cells, and CD3+CD4+ CD25+ T cells were significantly lower in severe patients. The naive T cell/CD4 + EM T cell ratio, which is an indicator of the differentiation from naive T cells to memory cells, was relatively reduced in severe disease. Peripheral CD4+CD8+ double-positive T cells were notably lower in severe presentations of the disease (median DP T cells 11.12 µL vs 1.95 µL; p< 0.001). CONCLUSIONS: As disease severity increases in COVID-19 infection, the number of T cell subsets decreases significantly. Suppression of differentiation from naive T cells to effector memory T cells is the result of severe impairment in adaptive immune functions. Peripheral CD4+CD8+ double-positive T cells were significantly reduced in severe disease presentations and may be a useful marker to predict disease severity.

RESUMO OBJETIVO: A pandemia de COVID-19 tem afetado o mundo todo, constituindo uma ameaça grave para a saúde humana. As células T desempenham um papel crítico na imunidade celular contra infecções virais. Procuramos desvendar a relação entre sub grupos de células T e a severidade da doença. MÉTODOS: Um total de 40 pacientes com COVID-19 foram aleatoriamente recrutados para o presente estudo transversal. Todos os casos foram confirmados por RT-PCR quantitativo. Os pacientes foram divididos em dois grupos equivalentes, um grave e um não-grave. Os dados da avaliação clínica, laboratorial e da citometria de fluxo foram obtidos para ambos os grupos e comparados. RESULTADOS: Os subconjuntos de linfócitos, células T CD4+ e CD8+, células T de memória CD4+, células T de memória CD8+, células T CD4+ virgens, células T efetoras CD4+, células T de memória central CD4+ e células T CD3+ CD4+ CD25+ estavam significativamente mais baixas nos pacientes graves. A razão células T virgens/células T efetoras TCD4+, que é um indicador da diferenciação entre células T virgens e células de memória, estava relativamente reduzida em casos graves da doença. As células T duplo-positivas CD4+CD8+ periféricas estavam notavelmente mais baixas em casos graves da doença (mediana das células T DP: 11,12 µL vs. 1,95 µL; p< 0,001). CONCLUSÃO: Conforme aumenta a gravidade da doença nos casos de COVID-19, o número de subconjuntos de células T diminui significativamente. A supressão da diferenciação de células T virgens para células T efetoras é o resultado do comprometimento grave das funções imunológicas adaptativas. As células T duplo-positivas CD4+CD8+ periféricas estavam notavelmente mais baixas em casos graves da doença e podem ser um marcador útil para predizer a severidade da doença.

Critical Points on the Use of Biologicals in Allergic Diseases and Asthma

Improved understanding of the contribution of immune-inflammatory mechanisms in allergic diseases and asthma has encouraged development of biologicals and small molecules specifically targeting the innate and adaptive immune response. There are several critical points impacting the efficacy of this stratified approach, from the complexity of disease endotypes to the effectiveness in real-world settings. We discuss here how these barriers can be overcome to facilitate the development of implementation science for allergic diseases and asthma.

Anticoccidial Effect of CS 32 Compounds Against Eimeria tenella Infection in Chickens

Coccidiosis-causing Eimeria species are transmitted in poultry via the oral-fecal route and can lead to hemorrhagic diarrhea and mortality. This results in enormous economic losses in the poultry industry. Furthermore, its resistance to some currently used antibiotics is increasing. This has prompted the development of new alternative drug therapies that address the issue of chemical-free meat production. Effective management of infectious diseases in veterinary practice includes the induction of protective and adaptive immunity by treatment with an alternative agent. In this study, we evaluated the anticoccidial effects of dietary supplementation of Chosun University (CS) 32 compounds (0.1% and 1.0%) against Eimeria tenella, which was isolated and purified from the supernatant of culture broth of Bacillus strain (KCTC18250P), as well as its effect on the growth rate and feed efficiency in chickens. Overall, we observed a decrease in lesion scores and oocyte output in CS 32 compounds-treated chickens. We concluded that 0.1% CS 32 compounds displayed anticoccidial effects against E. tenella infection.

Durability of neutralizing antibodies and T-cell response post SARS-CoV-2 infection / 医学前沿

The ongoing pandemic of Coronavirus disease 19 (COVID-19) is caused by a newly discovered β Coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). How long the adaptive immunity triggered by SARS-CoV-2 can last is of critical clinical relevance in assessing the probability of second infection and efficacy of vaccination. Here we examined, using ELISA, the IgG antibodies in serum specimens collected from 17 COVID-19 patients at 6-7 months after diagnosis and the results were compared to those from cases investigated 2 weeks to 2 months post-infection. All samples were positive for IgGs against the S- and N-proteins of SARS-CoV-2. Notably, 14 samples available at 6-7 months post-infection all showed significant neutralizing activities in a pseudovirus assay, with no difference in blocking the cell-entry of the 614D and 614G variants of SARS-CoV-2. Furthermore, in 10 blood samples from cases at 6-7 months post-infection used for memory T-cell tests, we found that interferon γ-producing CD4

Innate Lymphoid Cells in the Airways: Their Functions and Regulators

Since the airways are constantly exposed to various pathogens and foreign antigens, various kinds of cells in the airways—including structural cells and immune cells—interact to form a precise defense system against pathogens and antigens that involve both innate immunity and acquired immunity. Accumulating evidence suggests that innate lymphoid cells (ILCs) play critical roles in the maintenance of tissue homeostasis, defense against pathogens and the pathogenesis of inflammatory diseases, especially at body surface mucosal sites such as the airways. ILCs are activated mainly by cytokines, lipid mediators and neuropeptides that are produced by surrounding cells, and they produce large amounts of cytokines that result in inflammation. In addition, ILCs can change their phenotype in response to stimuli from surrounding cells, which enables them to respond promptly to microenvironmental changes. ILCs exhibit substantial heterogeneity, with different phenotypes and functions depending on the organ and type of inflammation, presumably because of differences in microenvironments. Thus, ILCs may be a sensitive detector of microenvironmental changes, and analysis of their phenotype and function at local sites may enable us to better understand the microenvironment in airway diseases. In this review, we aimed to identify molecules that either positively or negatively influence the function and/or plasticity of ILCs and the sources of the molecules in the airways in order to examine the pathophysiology of airway inflammatory diseases and facilitate the issues to be solved.

Antimicrobial peptides: bridging innate and adaptive immunity in the pathogenesis of psoriasis / 中华医学杂志(英文版)

Antimicrobial peptides (AMPs) are small molecules produced by a myriad of cells and play important roles not only in protecting against infections and sustaining skin barrier homeostasis but also in contributing to immune dysregulation under pathological conditions. Recently, increasing evidence has indicated that AMPs, including cathelicidin (LL-37), human β-defensins, S100 proteins, lipocalin 2, and RNase 7, are highly expressed in psoriatic skin lesions. These peptides broadly regulate immunity by interacting with various immune cells and linking innate and adaptive immune responses during the progression of psoriasis. In this review, we summarize the recent findings regarding AMPs in the pathogenesis of psoriasis with a main focus on their immunomodulatory abilities.

Opioids in the immune system: from experimental studies to clinical practice

SUMMARY INTRODUCTION: Opioids interact with both innate and adaptive immune systems and have direct effects on opioid receptors located on immune cells. Research on this topic has provided evidence of the opioid influence on the immune response associated with surgical stress. The immunological effects of opioids are currently being investigated, particularly whether they influence the outcome of surgery or the underlying disease regarding important aspects like infection or cancer progression. This review addresses background research related to the influence of the opioid receptor on the immune system, the immunosuppressive effect associated with major opioids during the perioperative period, and their clinical relevance. The objective of the study was to review the effects of opioids on the immune system. Methods: A search strategy was conducted in PubMed, Embase, and the Cochrane databases using the terms "immunosuppression," "immune system," "surgical procedures," "analgesics," "opioids" and "perioperative care." Results: The immunosuppressive effect of opioids was identified over 30 years ago. They include signaling and acting directly through immune cells, including B and T lymphocytes, NK cells, monocytes, and macrophages, as well as activating the downstream pathways of the hypothalamic-pituitary-adrenal (HPA) axis leading to the production of immunosuppressive glucocorticoids in the peripheral and sympathetic nervous system.

RESUMO INTRODUÇÃO: Os opioides interagem com ambos os sistemas imunes, inato e adaptativo, através de efeitos diretos sobre os receptores dos opioides localizados nas células imunes. As pesquisas neste assunto têm fornecido evidência da influência dos opioides sobre a resposta imune associada ao estresse cirúrgico. Os efeitos imunológicos dos opioides estão sendo pesquisados na atualidade, principalmente se eles determinam o resultado da cirurgia ou doença consequente devido a fatos importantes como infecção ou progressão do câncer. Essa revisão tem como alvo ver antecedentes em pesquisa relativa à influência dos receptores dos opioides no sistema imunológico, o efeito imunossupressor associado com opioides maiores durante o período peri-operatório e sua importância clínica. O objectivo da pesquisa foi revisar os efeitos dos opioides no sistema imunológico. MÉTODOS: Uma estrategia de procura foi dirigida na mídia PubMed, e no cadastro de Embase e The Cochrane, usando os termos "imunosuppressão", "sistema imunológico", "procedimentos cirúrgicos", "analgésicos", "opioides" e "cuidado peri-operatório". RESULTADOS: O efeito imunosuppressor dos opioides foi identificado há mais de 30 anos. Os efeitos imunosupressores incluem sinalização e ação diretamente através das células imunes, mesmo com os linfócitos B e T, células NK, monócitos e macrófagos, também como ativando as vias de corrente do eixo hipotálamo- hipófise- adrenal (HPA) levando à produção de glucocorticoides imunossupresores no sistema nervoso periférico e simpático.

The epididymal immune balance: a key to preserving male fertility / 亚洲男科学杂志(英文版)

Up to 15% of male infertility has an immunological origin, either due to repetitive infections or to autoimmune responses mainly affecting the epididymis, prostate, and testis. Clinical observations and epidemiological data clearly contradict the idea that the testis confers immune protection to the whole male genital tract. As a consequence, the epididymis, in which posttesticular spermatozoa mature and are stored, has raised some interest in recent years when it comes to its immune mechanisms. Indeed, sperm cells are produced at puberty, long after the establishment of self-tolerance, and they possess unique surface proteins that cannot be recognized as self. These are potential targets of the immune system, with the risk of inducing autoantibodies and consequently male infertility. Epididymal immunity is based on a finely tuned equilibrium between efficient immune responses to pathogens and strong tolerance to sperm cells. These processes rely on incompletely described molecules and cell types. This review compiles recent studies focusing on the immune cell types populating the epididymis, and proposes hypothetical models of the organization of epididymal immunity with a special emphasis on the immune response, while also discussing important aspects of the epididymal immune regulation such as tolerance and tumour control.

CD24⁺ Cell Depletion Permits Effective Enrichment of Thymic iNKT Cells While Preserving Their Subset Composition

Invariant NKT (iNKT) cells are a small subset of thymus-generated T cells that produce cytokines to control both innate and adaptive immunity. Because of their very low frequency in the thymus, in-depth characterization of iNKT cells can be facilitated by their enrichment from total thymocytes. Magnetic-activated cell sorting (MACS) of glycolipid antigen-loaded CD1d-tetramer-binding cells is a commonly used method to enrich iNKT cells. Surprisingly, we found that this procedure also dramatically altered the subset composition of enriched iNKT cells. As such, NKT2 lineage cells that express large amounts of the transcription factor promyelocytic leukemia zinc finger were markedly over-represented, while NKT1 lineage cells expressing the transcription factor T-bet were significantly reduced. To overcome this limitation, here, we tested magnetic-activated depletion of CD24⁺ immature thymocytes as an alternative method to enrich iNKT cells. We found that the overall recovery in iNKT cell numbers did not differ between these 2 methods. However, enrichment by CD24⁺ cell depletion preserved the subset composition of iNKT cells in the thymus, and thus permitted accurate and reproducible analysis of thymic iNKT cells in further detail.

Osteoclasts in the Inflammatory Arthritis: Implications for Pathologic Osteolysis

The enhanced differentiation and activation of osteoclasts (OCs) in the inflammatory arthritis such as rheumatoid arthritis (RA) and gout causes not only local bone erosion, but also systemic osteoporosis, leading to functional disabilities and morbidity. The induction and amplification of NFATc1, a master regulator of OC differentiation, is mainly regulated by receptor activator of NF-κB (RANK) ligand-RANK and calcium signaling which are amplified in the inflammatory milieu, as well as by inflammatory cytokines such as TNFα, IL-1β and IL-6. Moreover, the predominance of CD4+ T cell subsets, which varies depending on the condition of inflammatory diseases, can determine the fate of OC differentiation. Anti-citrullinated peptide antibodies which are critical in the pathogenesis of RA can bind to the citrullinated vimentin on the surface of OC precursors, and in turn promote OC differentiation and function via IL-8. In addition to adaptive immunity, the activation of innate immune system including the nucleotide oligomerization domain leucine rich repeat with a pyrin domain 3 inflammasome and TLRs can regulate OC maturation. The emerging perspectives about the diverse and close interactions between the immune cells and OCs in inflammatory milieu can have a significant impact on the future direction of drug development.

The Interplay between Host Immunity and Respiratory Viral Infection in Asthma Exacerbation

Asthma is one of the most common and chronic diseases characterized by multidimensional immune responses along with poor prognosis and severity. The heterogeneous nature of asthma may be attributed to a complex interplay between risk factors (either intrinsic or extrinsic) and specific pathogens such as respiratory viruses, and even bacteria. The intrinsic risk factors are highly correlated with asthma exacerbation in host, which may be mediated via genetic polymorphisms, enhanced airway epithelial lysis, apoptosis, and exaggerated viral replication in infected cells, resulting in reduced innate immune response and concomitant reduction of interferon (types I, II, and III) synthesis. The canonical features of allergic asthma include strong Th2-related inflammation, sensitivity to non-steroidal anti-inflammatory drugs (NSAIDs), eosinophilia, enhanced levels of Th2 cytokines, goblet cell hyperplasia, airway hyper-responsiveness, and airway remodeling. However, the NSAID-resistant non-Th2 asthma shows a characteristic neutrophilic influx, Th1/Th17 or even mixed (Th17-Th2) immune response and concurrent cytokine streams. Moreover, inhaled corticosteroid-resistant asthma may be associated with multifactorial innate and adaptive responses. In this review, we will discuss the findings of various in vivo and ex vivo models to establish the critical heterogenic asthmatic etiologies, host-pathogen relationships, humoral and cell-mediated immune responses, and subsequent mechanisms underlying asthma exacerbation triggered by respiratory viral infections.

Aging and the Immune System: the Impact of Immunosenescence on Viral Infection, Immunity and Vaccine Immunogenicity

Immunosenescence is characterized by a progressive deterioration of the immune system associated with aging. Multiple components of both innate and adaptive immune systems experience aging-related changes, such as alterations in the number of circulating monocytic and dendritic cells, reduced phagocytic activities of neutrophils, limited diversity in B/T cell repertoire, T cell exhaustion or inflation, and chronic production of inflammatory cytokines known as inflammaging. The elderly are less likely to benefit from vaccinations as preventative measures against infectious diseases due to the inability of the immune system to mount a successful defense. Therefore, aging is thought to decrease the efficacy and effectiveness of vaccines, suggesting aging-associated decline in the immunogenicity induced by vaccination. In this review, we discuss aging-associated changes in the innate and adaptive immunity and the impact of immunosenescence on viral infection and immunity. We further explore recent advances in strategies to enhance the immunogenicity of vaccines in the elderly. Better understanding of the molecular mechanisms underlying immunosenescence-related immune dysfunction will provide a crucial insight into the development of effective elderly-targeted vaccines and immunotherapies.

A Salmonella Typhi ghost induced by the E gene of phage φX174 stimulates dendritic cells and efficiently activates the adaptive immune response

Previously, we genetically engineered a Salmonella Typhi bacterial ghost (STG) as a novel inactivated vaccine candidate against typhoid fever. The underlying mechanism employed by the ghost in stimulating the adaptive immune response remains to be investigated. In this study, we aimed to evaluate the immunostimulatory effect of STG on mouse bone marrow-derived dendritic cells (BMDCs) and its activation of the adaptive immune response in vitro. Immature BMDCs were stimulated with STG, which efficiently stimulated maturation events in BMDCs, as indicated by upregulated expressions of CD40, CD80, and major histocompatibility complex class II molecules on CD11⁺ BMDCs. Immature BMDCs responded to STG stimulation by significantly increasing the expression of interleukin (IL)-6, which might indicate the induction of dendritic cell maturation in vivo (p < 0.05). In addition, ghost-stimulated murine BMDCs showed significant expressions of interferon gamma and IL-4, which can drive the development of Th1 and Th2 cells, respectively, in co-cultured CD4⁺ T cells in vitro. These results suggest that STG can effectively stimulate maturation of BMDCs and facilitate subsequent immune responses via potent immunomodulatory cytokine responses.

Macrophages and Inflammation

Inflammation is a normal physiological response to an infection or injury, such as aggression by microbes, trauma, or heat and radiation. Inflammation works to maintain homeostasis and is a highly regulated process with both pro- and anti-inflammatory components to ensure the prompt resolution of noxious conditions. In the initial stages of inflammation, macrophages destroy the abnormal stimuli, and remove the apoptotic bodies of the dead neutrophils as well as any remaining hazard factor. The macrophages then present the antigen to T lymphocytes to initiate the mechanisms of acquired immunity, which leads to the production of antibodies, cytokines and memory cells. The macrophage activity then switches from pro-inflammatory to anti-inflammatory to remove any elements of aggression, thereby achieving homeostasis. Macrophages play a key role in the innate immune response and form a bridge between the innate and acquired immune response. In certain circumstances, however, when chronic inflammation is produced, macrophages may have a harmful effect and cause lesions. Therefore, inflammation is the classic “double-edged sword”, in which macrophages cut both ways. Activated macrophages have two different phenotypes related to different stimuli: M1 (classically activated) and M2 (alternatively activated). M1 macrophages are pro-inflammatory and play a key role in the host defense mechanism, while M2 are associated with the responses to anti-inflammatory reactions and tissue remodeling. The transformation of different phenotypes of macrophages regulates the initiation, development, and cessation of inflammatory diseases. An imbalance of macrophage M1~M2 polarization is often associated with a range of diseases or inflammatory conditions, such as rheumatoid arthritis and systemic lupus erythematous.

Innate and adaptive T cells in influenza disease / 医学前沿

Influenza is a major global health problem, causing infections of the respiratory tract, often leading to acute pneumonia, life-threatening complications and even deaths. Over the last seven decades, vaccination strategies have been utilized to protect people from complications of influenza, especially groups at high risk of severe disease. While current vaccination regimens elicit strain-specific antibody responses, they fail to generate cross-protection against seasonal, pandemic and avian viruses. Moreover, vaccines designed to generate influenza-specific T-cell responses are yet to be optimized. During natural infection, viral replication is initially controlled by innate immunity before adaptive immune responses (T cells and antibody-producing B cells) achieve viral clearance and host recovery. Adaptive T and B cells maintain immunological memory and provide protection against subsequent infections with related influenza viruses. Recent studies also shed light on the role of innate T-cells (MAIT cells, γδ cells, and NKT cells) in controlling influenza and linking innate and adaptive immune mechanisms, thus making them attractive targets for vaccination strategies. We summarize the current knowledge on influenza-specific innate MAIT and γδ T cells as well as adaptive CD8 and CD4 T cells, and discuss how these responses can be harnessed by novel vaccine strategies to elicit cross-protective immunity against different influenza strains and subtypes.