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  • Tissue-specific tumor microenvironments influence responses to immunotherapies.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-11-27
    Amanda J Oliver,Ashleigh S Davey,Simon P Keam,Sherly Mardiana,Jack D Chan,Bianca von Scheidt,Paul A Beavis,Imran G House,Jonas Rm Van Audernaerde,Phillip K Darcy,Michael H Kershaw,Clare Y Slaney

    Objectives Investigation of variable response rates to cancer immunotherapies has exposed the immunosuppressive tumor microenvironment (TME) as a limiting factor of therapeutic efficacy. A determinant of TME composition is the tumor location, and clinical data have revealed associations between certain metastatic sites and reduced responses. Preclinical models to study tissue-specific TMEs have eliminated genetic heterogeneity, but have investigated models with limited clinical relevance. Methods We investigated the TMEs of tumors at clinically relevant sites of metastasis (liver and lungs) and their impact on αPD-1/αCTLA4 and trimAb (αDR5, α4-1BB, αCD40) therapy responses in the 67NR mouse breast cancer and Renca mouse kidney cancer models. Results Tumors grown in the lungs were resistant to both therapies whereas the same tumor lines growing in the mammary fat pad (MFP), liver or subcutaneously could be completely eradicated, despite greater tumor burden. Assessment of tumor cells and drug delivery in 67NR lung or MFP tumors revealed no differences and prompted investigation into the immune TME. Lung tumors had a more immunosuppressive TME with increased myeloid-derived suppressor cell infiltration, decreased T cell infiltration and activation, and decreased NK cell activation. Depletion of various immune cell subsets indicated an equivalent role for NK cells and CD8+ T cells in lung tumour control. Thus, targeting T cells with αPD-1/αCTLA4 or trimAb was not sufficient to elicit a robust antitumor response in lung tumors. Conclusion Taken together, these data demonstrate that tissue-specific TMEs influence immunotherapy responses and highlight the importance in defining tissue-specific response patterns in patients.

    更新日期:2019-11-01
  • Cross-reactive antibody-dependent cellular cytotoxicity antibodies are increased by recent infection in a household study of influenza transmission.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-11-26
    Sophie A Valkenburg,Vicky J Fang,Nancy Hl Leung,Daniel Kw Chu,Dennis Km Ip,Ranawaka Apm Perera,Yizhuo Wang,Athena Py Li,Js Malik Peiris,Benjamin J Cowling,Leo Lm Poon

    Objectives Influenza causes a spectrum of disease from asymptomatic infection to fatal outcome, and pre-existing immunity can alter susceptibility and disease severity. In a household transmission study, we recruited outpatients with confirmed influenza virus infection and prospectively identified secondary infections in their household contacts, therefore identifying infection cases with baseline samples for determining immune-mediated protection from influenza infection. Methods We examined baseline broadly reactive immune correlates of relevance to universal vaccine development, specifically antibody-dependent cytotoxic (ADCC) antibodies and T-cell responses in functional assays. Antibodies were assessed in a cell-based NK cell degranulation assay by flow cytometry, and T-cell responses were assessed by IFN-γ intracellular cytokine staining flow cytometry assay. Results The magnitude of antibody responses and ADCC function for multiple influenza-specific proteins was lower in participants who became infected, consolidating the role of pre-existing antibodies in protection from seasonal influenza virus infection. Among H1N1-infected contacts, we found that higher levels of pre-existing H1-haemagglutinin ADCC responses correlated with reduced symptom severity. Recent infection boosted the titre and magnitude of haemagglutinin-, neuraminidase- and nucleoprotein-specific ADCC antibodies. Limited T-cell samples precluded conclusions on the role of pre-existing T-cell responses. Conclusions Overall, ADCC responses are a protective correlate against influenza virus infection that should be considered in future vaccine development and evaluation.Influenza-specific ADCC responses are elevated in uninfected subjects, associated with reduced symptoms and boosted by recent infection, whilst HA stem and NA IgG are also elevated in uninfected participants irrespective of ADCC function.

    更新日期:2019-11-01
  • The interplay of type 2 immunity, helminth infection and the microbiota in regulating metabolism.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-11-14
    Mati Moyat,Gillian Coakley,Nicola L Harris

    Type 2 immunity has recently emerged as a critical player in metabolic status, with numerous studies investigating the role of type 2 immune cells within adipose tissue. Metabolic dysfunction is often characterised as a low-grade or chronic inflammatory state within tissues, and type 2 immunity may facilitate a return to metabolic homeostasis. A complex network of type 2 resident cells including M2 macrophages, eosinophils and ILC2s has been identified within adipose tissue. Although the effector cells in this equilibrium have not been clearly identified, any alteration of the type 2 microenvironment resulted in an altered metabolic state. Historically, the type 2 immune response has been associated with helminth infection. The type 2 immune response drives host resistance and plays an important role in promoting tissue repair following the migration of helminth larvae through tissues. Although helminths are largely eradicated in developed countries, infection rates remain high in poor communities within the developing world. Interestingly, there is strong evidence that helminth infection is inversely correlated with autoimmune or inflammatory disorders. Recently, an increasing amount of epidemiological and field studies suggest that it could be the same for obesity and metabolic syndrome. In the current review, we summarise the literature linking type 2 immunity to improved adipose tissue function. We then discuss more recent evidence indicating that helminth infection can provide protection against metabolic syndrome. Lastly, we explore the possible contributions of altered nutrient uptake, adipose tissue function and/or the intestinal microbiota with the ability of helminths to alter metabolic status.

    更新日期:2019-11-01
  • Rapid sequencing-based diagnosis of infectious bacterial species from meningitis patients in Zambia.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-11-12
    So Nakagawa,Shigeaki Inoue,Kirill Kryukov,Junya Yamagishi,Ayumu Ohno,Kyoko Hayashida,Ruth Nakazwe,Mox Kalumbi,Darlington Mwenya,Nana Asami,Chihiro Sugimoto,Mable M Mutengo,Tadashi Imanishi

    Objectives We have developed a portable system for the rapid determination of bacterial composition for the diagnosis of infectious diseases. Our system comprises of a nanopore technology-based sequencer, MinION, and two laptop computers. To examine the accuracy and time efficiency of our system, we provided a proof-of-concept for the detection of the causative bacteria of 11 meningitis patients in Zambia. Methods We extracted DNA from cerebrospinal fluid samples of each patient and amplified the 16S rRNA gene regions. The sequencing library was prepared, and the sequenced reads were simultaneously processed for bacterial composition determination using the minimap2 software and the representative prokaryote genomes. Results The sequencing results of four of the six culture-positive samples were consistent with those of conventional culture-based methods. The dominant bacterial species in each of these samples were identified from the sequencing data within only 3 min. Although the major bacterial species were also detected from the other two culture-positive samples and five culture-negative samples, their presence could not be confirmed. Moreover, as a whole, although the number of sequencing reads obtained within a short sequencing run was small, there was no change in the major bacterial species over time with prolonged sequencing. In addition, the processing time strongly correlated with the number of sequencing reads used for the analysis. Conclusion Our results suggest that time-effective analysis could be achieved by determining the number of sequencing reads required for the rapid diagnosis of infectious bacterial species depending on the complexity of bacterial species in a sample.

    更新日期:2019-11-01
  • Idiopathic and immune-related pulmonary fibrosis: diagnostic and therapeutic challenges.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-11-12
    Andrew McLean-Tooke,Irene Moore,Fiona Lake

    Interstitial lung disease (ILD) encompasses a large group of pulmonary conditions sharing common clinical, radiological and histopathological features as a consequence of fibrosis of the lung interstitium. The majority of ILDs are idiopathic in nature with possible genetic predisposition, but is also well recognised as a complication of connective tissue disease or with certain environmental, occupational or drug exposures. In recent years, a concerted international effort has been made to standardise the diagnostic criteria in ILD subtypes, formalise multidisciplinary pathways and standardise treatment recommendations. In this review, we discuss some of the current challenges around ILD diagnostics, the role of serological testing, especially, in light of the new classification of Interstitial Pneumonia with Autoimmune Features (IPAF) and discuss the evidence for therapies targeted at idiopathic and immune-related pulmonary fibrosis.

    更新日期:2019-11-01
  • Immunological observations and transcriptomic analysis of trimester-specific full-term placentas from three Zika virus-infected women.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-11-12
    Fok-Moon Lum,Vipin Narang,Susan Hue,Jie Chen,Naomi McGovern,Ravisankar Rajarethinam,Jeslin Jl Tan,Siti Naqiah Amrun,Yi-Hao Chan,Cheryl Yp Lee,Tze-Kwang Chua,Wearn-Xin Yee,Nicholas Kw Yeo,Thiam-Chye Tan,Xuan Liu,Sam Haldenby,Yee-Sin Leo,Florent Ginhoux,Jerry Ky Chan,Julian Hiscox,Chia-Yin Chong,Lisa Fp Ng

    Objectives Effects of Zika virus (ZIKV) infection on placental development during pregnancy are unclear. Methods Full-term placentas from three women, each infected with ZIKV during specific pregnancy trimesters, were harvested for anatomic, immunologic and transcriptomic analysis. Results In this study, each woman exhibited a unique immune response with raised IL-1RA, IP-10, EGF and RANTES expression and neutrophil numbers during the acute infection phase. Although ZIKV NS3 antigens co-localised to placental Hofbauer cells, the placentas showed no anatomic defects. Transcriptomic analysis of samples from the placentas revealed that infection during trimester 1 caused a disparate cellular response centred on differential eIF2 signalling, mitochondrial dysfunction and oxidative phosphorylation. Despite these, the babies were delivered without any congenital anomalies. Conclusion These findings should translate to improve clinical prenatal screening procedures for virus-infected pregnant patients.

    更新日期:2019-11-01
  • Fluorescent antibiotics, vomocytosis, vaccine candidates and the inflammasome.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-11-09
    Rachel J Lundie,Karla J Helbig,Jaclyn S Pearson,Kirsten A Fairfax

    This article summarises recent advances reported at the 9th Lorne Infection and Immunity Conference. This exciting conference hosted speakers in the fields of innate and adaptive responses to infection including host-pathogen interactions as well as novel strategies for the detection, control and treatment of infectious diseases such as fluorescent antibiotics and vaccine development. Host-pathogen studies focused on a broad range of pathogens including malaria, CMV, influenza, dengue and Zika viruses, listeria and tuberculosis.

    更新日期:2019-11-01
  • γδ T cells take the stage.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-11-07
    Emily M Eriksson,Martin S Davey

    更新日期:2019-11-01
  • γδ T cells in cancer: a small population of lymphocytes with big implications.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-10-19
    Mathilde Raverdeau,Stephen P Cunningham,Cathal Harmon,Lydia Lynch

    γδ T cells are a small population of mostly tissue-resident lymphocytes, with both innate and adaptive properties. These unique features make them particularly attractive candidates for the development of new cellular therapy targeted against tumor development. Nevertheless, γδ T cells may play dual roles in cancer, promoting cancer development on the one hand, while participating in antitumor immunity on the other hand. In mice, γδ T-cell subsets preferentially produce IL-17 or IFN-γ. While antitumor functions of murine γδ T cells can be attributed to IFN-γ+ γδ T cells, recent studies have implicated IL-17+ γδ T cells in tumor growth and metastasis. However, in humans, IL-17-producing γδ T cells are rare and most studies have attributed a protective role to γδ T cells against cancer. In this review, we will present the current knowledge and most recent findings on γδ T-cell functions in mouse models of tumor development and human cancers. We will also discuss their potential as cellular immunotherapy against cancer.

    更新日期:2019-11-01
  • Successful treatment of idiopathic mast cell activation syndrome with low-dose Omalizumab.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-10-03
    Renee Berry,Peter Hollingsworth,Michaela Lucas

    Objectives Idiopathic mast cell disorders, a recently defined and recognised syndrome in clinical practice, are similar to the previously termed non-clonal mast cell disorder. Patients with idiopathic mast cell activation syndrome (MCAS) suffer all the classical signs of mast cell activation but do not have evidence of mast cell clonality. Furthermore, treatment of these patients can be limited and burdensome in those with refractory symptoms. Methods Here, we describe treatment of a patient with idiopathic MCAS utilising a single monthly subcutaneous injection of omalizumab and review the current classification and therapeutic options for clonal and non-clonal MCAS. Results Low-dose omalizumab treatment has successfully led to a 5-year, sustained clinical response, controlled debilitating symptoms of mast cell activation and allowed for reintroduction and long-term maintenance of bee venom subcutaneous immunotherapy. Conclusion Low-dose omalizumab of 150 mg monthly should be considered for maintenance management of patients with idiopathic MCAS for its cost and quality-of-life benefits.

    更新日期:2019-11-01
  • Dual targeting of RANKL and PD-1 with a bispecific antibody improves anti-tumor immunity.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-10-02
    William C Dougall,Amelia Roman Aguilera,Mark J Smyth

    Objectives The addition of RANKL/RANK blockade to immune checkpoint inhibitors (ICIs) such as anti-PD-1/PD-L1 and anti-CTLA4 antibodies is associated with increased anti-tumor immunity in mice. Recent retrospective clinical studies in patients with advanced melanoma and lung cancer suggest the addition of anti-RANKL antibody to ICI increases the overall response rate relative to ICI treatment alone. Based on this rationale, we developed a novel bispecific antibody (BsAb) co-targeting RANKL and PD-1. Methods We characterized target binding and functional activity of the anti-RANKL/PD-1 BsAb in cell-based assays. Anti-tumor activity was confirmed in experimental lung metastasis models and in mice with established subcutaneously transplanted tumors. Results The anti-RANKL/PD-1 BsAb retained binding to both RANKL and PD-1 and blocked the interaction with respective counter-structures RANK and PD-L1. The inhibitory effect of anti-RANKL/PD-1 BsAb was confirmed by demonstrating a complete block of RANKL-dependent osteoclast formation. Monotherapy activity of anti-RANKL/PD-1 BsAb was observed in anti-PD-1 resistant tumors and, when combined with anti-CTLA-4 mAb, increased anti-tumor responses. An equivalent or superior anti-tumor response was observed with the anti-RANKL/PD-1 BsAb compared with the combination of parental anti-RANKL plus anti-PD-1 antibodies depending upon the tumor model. Discussion Mechanistically, the anti-tumor activity of anti-RANKL/PD-1 BsAb required CD8+T cells, host PD-1 and IFNγ. Targeting RANKL and PD-1 simultaneously within the tumor microenvironment (TME) improved anti-tumor efficacy compared with combination of two separate mAbs. Conclusion In summary, the bispecific anti-RANKL/PD-1 antibody demonstrates potent tumor growth inhibition in settings of ICI resistance and represents a novel modality for clinical development in advanced cancer.

    更新日期:2019-11-01
  • Human γδ T-cell receptor repertoire is shaped by influenza viruses, age and tissue compartmentalisation.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-09-29
    Sneha Sant,Misty R Jenkins,Pradyot Dash,Katherine A Watson,Zhongfang Wang,Angela Pizzolla,Marios Koutsakos,Thi Ho Nguyen,Martha Lappas,Jane Crowe,Tom Loudovaris,Stuart I Mannering,Glen P Westall,Tom C Kotsimbos,Allen C Cheng,Linda Wakim,Peter C Doherty,Paul G Thomas,Liyen Loh,Katherine Kedzierska

    Background Although γδ T cells comprise up to 10% of human peripheral blood T cells, questions remain regarding their role in disease states and T-cell receptor (TCR) clonal expansions. We dissected anti-viral functions of human γδ T cells towards influenza viruses and defined influenza-reactive γδ TCRs in the context of γδ-TCRs across the human lifespan. Methods We performed 51Cr-killing assay and single-cell time-lapse live video microscopy to define mechanisms underlying γδ T-cell-mediated killing of influenza-infected targets. We assessed cytotoxic profiles of γδ T cells in influenza-infected patients and IFN-γ production towards influenza-infected lung epithelial cells. Using single-cell RT-PCR, we characterised paired TCRγδ clonotypes for influenza-reactive γδ T cells in comparison with TCRs from healthy neonates, adults, elderly donors and tissues. Results We provide the first visual evidence of γδ T-cell-mediated killing of influenza-infected targets and show distinct features to those reported for CD8+ T cells. γδ T cells displayed poly-cytotoxic profiles in influenza-infected patients and produced IFN-γ towards influenza-infected cells. These IFN-γ-producing γδ T cells were skewed towards the γ9δ2 TCRs, particularly expressing the public GV9-TCRγ, capable of pairing with numerous TCR-δ chains, suggesting their significant role in γδ T-cell immunity. Neonatal γδ T cells displayed extensive non-overlapping TCRγδ repertoires, while adults had enriched γ9δ2-pairings with diverse CDR3γδ regions. Conversely, the elderly showed distinct γδ-pairings characterised by large clonal expansions, a profile also prominent in adult tissues. Conclusion Human TCRγδ repertoire is shaped by age, tissue compartmentalisation and the individual's history of infection, suggesting that these somewhat enigmatic γδ T cells indeed respond to antigen challenge.

    更新日期:2019-11-01
  • The complex existence of γδ T cells following transplantation: the good, the bad and the simply confusing.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-09-25
    Lucy C Sullivan,Evangeline M Shaw,Sanda Stankovic,Gregory I Snell,Andrew G Brooks,Glen P Westall

    Gamma delta (γδ) T cells are a highly heterogeneous population of lymphocytes that exhibit innate and adaptive immune properties. Despite comprising the majority of residing lymphocytes in many organs, the role of γδ T cells in transplantation outcomes is under-researched. γδ T cells can recognise a diverse array of ligands and exert disparate effector functions. As such, they may potentially contribute to both allograft acceptance and rejection, as well as impacting on infection and post-transplant malignancy. Here, we review the current literature on the role and function of γδ T cells following solid organ and hematopoietic stem cell transplantation.

    更新日期:2019-11-01
  • A pathologic two-way street: how innate immunity impacts lung fibrosis and fibrosis impacts lung immunity.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-07-12
    Helen I Warheit-Niemi,Elissa M Hult,Bethany B Moore

    Lung fibrosis is characterised by the accumulation of extracellular matrix within the lung and is secondary to both known and unknown aetiologies. This accumulation of scar tissue limits gas exchange causing respiratory insufficiency. The pathogenesis of lung fibrosis is poorly understood, but immunologic-based treatments have been largely ineffective. Despite this, accumulating evidence suggests that innate immune cells and receptors play important modulatory roles in the initiation and propagation of the disease. Paradoxically, while innate immune signalling may be important for the pathogenesis of fibrosis, there is also evidence to suggest that innate immune function against pathogens may be impaired, leading to dysregulated and/or impaired host defence. This review summarises the evidence for this pathologic two-way street, highlights new concepts of pathogenesis and recommends future directions for research emphasis.

    更新日期:2019-11-01
  • Intercellular transfer of HLA-G: its potential in cancer immunology.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-09-07
    Aifen Lin,Wei-Hua Yan

    Intercellular protein transfer between cancer cells and immune cells is a very common phenomenon that can affect different stages of host antitumor immune responses. HLA-G, a non-classical HLA class I antigen, has been observed to be widely expressed in various malignancies, and its immune-suppressive functions have been well recognised. HLA-G expression in cancer cells can directly mediate immune tolerance by interacting with inhibitory receptors such as ILT2 and ILT4 expressed on immune cells. Moreover, a network of multiple directional intercellular transfers of HLA-G among cancer cells and immune cells through trogocytosis, exosomes and tunnelling nanotubes provides malignant cells with an alternative ploy for antigen sharing and induces more complex heterogeneity, to modulate immune responses, ultimately leading to immune evasion, therapy resistance, disease progression and poor clinical outcome. Herein, we discuss the relative aspects of the intercellular transfer of HLA-G between tumor cells and immune cells and its potential use in tumor immunology research and translational cancer therapy.

    更新日期:2019-11-01
  • The role and therapeutic implications of T cells in cancer of the lung.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-09-06
    Samuel C Neeve,Bruce Ws Robinson,Vanessa S Fear

    Lung cancer remains the leading cause of cancer-related death worldwide. The disease is classified into two major subtypes, small-cell lung cancer (SCLC) and the more prevalent non-small-cell lung cancer (NSCLC). First-line conventional therapies, such as chemotherapy, radiotherapy and surgery, have offered limited benefit, and patient prognosis remains poor with post-treatment recurrences representing a major cause of morbidity. Consequently, there is an urgent need for improved therapeutic options. Historically, NSCLC has been considered a non-immunogenic disease. However, increased understanding of tumor-immune interactions has challenged this paradigm in both lung and other malignancies, with cancer elimination by tumor-specific T cells increasingly well described in a myriad of solid tumors. Recent evidence has demonstrated that absent or weak anticancer responses are likely a product of tumor-derived immunosuppression. This knowledge, along with a greater appreciation for the role of T cells in lung cancer elimination, has driven development of novel immunotherapeutic approaches which are demonstrating remarkable clinical efficacy. This review examines the role of T cells in lung cancer, discussing the direction and clinical significance of current and future immunotherapeutic strategies.

    更新日期:2019-11-01
  • Emerging role of γδ T cells in vaccine-mediated protection from infectious diseases.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-09-06
    Kathleen W Dantzler,Lauren de la Parte,Prasanna Jagannathan

    γδ T cells are fascinating cells that bridge the innate and adaptive immune systems. They have long been known to proliferate rapidly following infection; however, the identity of the specific γδ T cell subsets proliferating and the role of this expansion in protection from disease have only been explored more recently. Several recent studies have investigated γδ T-cell responses to vaccines targeting infections such as Mycobacterium, Plasmodium and influenza, and studies in animal models have provided further insight into the association of these responses with improved clinical outcomes. In this review, we examine the evidence for a role for γδ T cells in vaccine-induced protection against various bacterial, protozoan and viral infections. We further discuss results suggesting potential mechanisms for protection, including cytokine-mediated direct and indirect killing of infected cells, and highlight remaining open questions in the field. Finally, building on current efforts to integrate strategies targeting γδ T cells into immunotherapies for cancer, we discuss potential approaches to improve vaccines for infectious diseases by inducing γδ T-cell activation and cytotoxicity.

    更新日期:2019-11-01
  • Expression of IL-34 correlates with macrophage infiltration and prognosis of diffuse large B-cell lymphoma.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-08-17
    Osamu Noyori,Yoshihiro Komohara,Hesham Nasser,Masateru Hiyoshi,Chaoya Ma,Cheng Pan,Joaquim Carreras,Naoya Nakamura,Ai Sato,Kiyoshi Ando,Yutaka Okuno,Kisato Nosaka,Masao Matsuoka,Shinya Suzu

    Objectives Infiltration of macrophages through the tyrosine kinase receptor CSF1R is a poor prognosis factor in various solid tumors. Indeed, these tumors produce CSF1R ligand, macrophage colony-stimulating factor (M-CSF) or interleukin-34 (IL-34). However, the significance of these cytokines, particularly, the newly discovered IL-34 in haematological malignancies, is not fully understood. We therefore analysed the role of IL-34 in diffuse large B-cell lymphoma (DLBCL), the most common subtype of malignant lymphoma. Methods We analysed formalin-fixed paraffin-embedded lymphoma tissues of 135 DLBCL patients for the expression of IL-34 and the number of macrophages, and the survival of these patients. The expression of IL-34 in DLBCL cell lines and the activity of IL-34 to induce the migration of monocytic cells were also characterised. Results Several lymphoma tissues showed a clear IL-34 signal, and such signal was detectable in 36% of patients. DLBCL cell lines also expressed IL-34. Interestingly, the percentage of IL-34+ patients in the activated B-cell subtype was significantly higher than that in the germinal centre B-cell subtype. More interestingly, IL-34+ patients showed shorter survival periods and higher number of macrophages in lymphoma tissues. The recruitment of monocytes is likely the first step for the higher macrophage density in the IL-34+ lymphoma tissues. Indeed, IL-34 induced the migration of monocytic cells. Conclusion Our results raise the possibility that IL-34 in lymphoma tissues of DLBCL patients recruits monocytes, leading to the higher number of macrophages in the tissues and poor prognosis of patients. IL-34 may be an additional therapeutic target of DLBCL.

    更新日期:2019-11-01
  • Furin-mediated protein processing in infectious diseases and cancer.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-08-14
    Elisabeth Braun,Daniel Sauter

    Proteolytic cleavage regulates numerous processes in health and disease. One key player is the ubiquitously expressed serine protease furin, which cleaves a plethora of proteins at polybasic recognition motifs. Mammalian substrates of furin include cytokines, hormones, growth factors and receptors. Thus, it is not surprising that aberrant furin activity is associated with a variety of disorders including cancer. Furthermore, the enzymatic activity of furin is exploited by numerous viral and bacterial pathogens, thereby enhancing their virulence and spread. In this review, we describe the physiological and pathophysiological substrates of furin and discuss how dysregulation of a simple proteolytic cleavage event may promote infectious diseases and cancer. One major focus is the role of furin in viral glycoprotein maturation and pathogenicity. We also outline cellular mechanisms regulating the expression and activation of furin and summarise current approaches that target this protease for therapeutic intervention.

    更新日期:2019-11-01
  • Novel differential linear B-cell epitopes to identify Zika and dengue virus infections in patients.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-08-03
    Siti Naqiah Amrun,Wearn-Xin Yee,Farhana Abu Bakar,Bernett Lee,Yiu-Wing Kam,Fok-Moon Lum,Jeslin Jl Tan,Vanessa Wx Lim,Wanitda Watthanaworawit,Clare Ling,Francois Nosten,Laurent Renia,Yee-Sin Leo,Lisa Fp Ng

    Objectives Recent Zika virus (ZIKV) outbreaks challenged existing laboratory diagnostic standards, especially for serology-based methods. Because of the genetic and structural similarity of ZIKV with other flaviviruses, this results in cross-reactive antibodies, which confounds serological interpretations. Methods Plasma from Singapore ZIKV patients was screened longitudinally for antibody responses and neutralising capacities against ZIKV. Samples from healthy controls, ZIKV patients and DENV patients were further assessed using ZIKV and DENV peptides of precursor membrane (prM), envelope (E) or non-structural 1 (NS1) viral proteins in a peptide-based ELISA for epitope identification. Identified epitopes were re-validated and diagnostically evaluated using sera of patients with DENV, bacteria or unknown infections from Thailand. Results Long-lasting ZIKV-neutralising antibodies were elicited during ZIKV infection. Thirteen potential linear B-cell epitopes were identified, and of these, four common flavivirus, three ZIKV-specific and one DENV-specific differential epitopes had more than 50% sensitivity and specificity. Notably, ZIKV-specific peptide 26 on domain I/II of E protein (amino acid residues 271-288) presented 80% sensitivity and 85.7% specificity. Importantly, the differential epitopes also showed significance in differentiating non-flavivirus patient samples. Conclusion Linear B-cell epitope candidates to differentiate between ZIKV and DENV infections were identified, providing the first step towards the design of a much-needed serology-based assay.

    更新日期:2019-11-01
  • Crohn's disease is facilitated by a disturbance of programmed death-1 ligand 2 on blood dendritic cells.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-08-02
    Rebecca Faleiro,Ji Liu,Deshapriya Karunarathne,Aleksandra Edmundson,Clay Winterford,Tam Hong Nguyen,Lisa A Simms,Graham Radford-Smith,Michelle Wykes

    Objective Crohn's disease (CD) is characterised by inflammation, predominantly associated with ilea. To investigate the basis for this inflammation in patients with CD, we examined dendritic cells (DC) which are pivotal for maintenance of immunological tolerance in the gut. Methods Ileal biopsies and blood DCs from CD patients and controls were examined by microscopy and flow cytometry for PD-L1 and PD-L2 expression, as PD-L1 has been implicated in colitis but the contribution of PD-L2 is less clear. In vitro studies, of blood samples from CD patients, were used to demonstrate a functional role for PD-L2 in disease pathogenesis. Results Quantitative microscopy of CD11c+ DCs in inflamed and noninflamed ilea from CD patient showed > 75% loss of these cells from the villi, lamina propria and Peyer's patches compared with non-CD controls. Given this loss of DCs from ilia of CD patients, we hypothesised DCs may have migrated to the blood as these patients can have extra-intestinal symptoms. We thus examined blood DCs from CD patients by flow cytometry and found significant increases in PD-L1 and PD-L2 expression compared with control samples. Microscopy revealed an aggregated form of PD-L2 expression, known to drive Th1 immunity, in CD patients but not in controls. In vitro functional studies with PD-L2 blockade confirmed PD-L2 contributes significantly to the secretion of pro-inflammatory cytokines known to cause disease pathogenesis. Conclusion Taken together, this study shows that PD-L2 can influence the progression of CD and blockade of PD-L2 may have therapeutic potential.

    更新日期:2019-11-01
  • CAR T cells take centre stage.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-08-02
    Paul A Beavis,Phillip K Darcy

    更新日期:2019-11-01
  • Associations of pathogen-specific and host-specific characteristics with disease outcome in patients with Staphylococcus aureus bacteremic pneumonia.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-07-31
    Batu K Sharma-Kuinkel,Christine Tkaczyk,Jessica Bonnell,Li Yu,Andrey Tovchigrechko,David E Tabor,Lawrence P Park,Felicia Ruffin,Mark T Esser,Bret R Sellman,Vance G Fowler,Alexey Ruzin

    Objective To understand the relationships of Staphylococcus aureus (SA) bacteremic pneumonia (SABP) outcome with patient-specific and SA-specific variables. Methods We analysed SA bloodstream isolates and matching sera in SABP patients by sequencing SA isolates (n = 50) and measuring in vitro AT production, haemolytic activity and expression of ClfA and ClfB. Controls were sera from gram-negative bacteremia patients with or without pneumonia and uninfected subjects. Levels of IgGs, IgMs and neutralizing antibodies (NAbs) against SA antigens were quantified and analysed by one-way ANOVA. Associations of patient outcomes with patient variables, antibody levels and isolate characteristics were evaluated by univariate and multivariate logistic regression analyses. Results SABP patients had higher levels of IgGs against eight virulence factors and anti-alpha toxin (AT) NAbs than uninfected controls. Levels of IgG against AT and IgMs against ClfA, FnbpA and SdrC were higher in clinically cured SABP patients than in clinical failures. Anti-LukAB NAb levels were elevated in all cohorts. Increased odds of cure correlated with higher haemolytic activity of SA strains, longer time between surgery and bacteremia (> 30 days), longer duration of antibiotic therapy, lower acute physiology and total APACHE II scores, lack of persistent fever for > 72 h and higher levels of antibodies against AT (IgG), ClfA (IgM), FnbpA (IgM) and SdrC (IgM). Discussion Limitations included the cross-sectional observational nature of the study, small sample size and inability to measure antibody levels against all SA virulence factors. Conclusion Our results suggest that SABP patients may benefit from immunotherapy targeting multiple SA antigens.

    更新日期:2019-11-01
  • γδ T-cell responses during HIV infection and antiretroviral therapy.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-07-20
    Jennifer A Juno,Emily M Eriksson

    HIV infection is associated with a rapid and sustained inversion of the Vδ1:Vδ2 T-cell ratio in peripheral blood. Studies of antiretroviral therapy (ART)-treated cohorts suggest that ART is insufficient to reconstitute either the frequency or function of the γδ T-cell subset. Recent advances are now beginning to shed light on the relationship between microbial translocation, chronic inflammation, immune ageing and γδ T-cell immunology. Here, we review the impact of acute, chronic untreated and treated HIV infection on circulating and mucosal γδ T-cell subsets and highlight novel approaches to harness γδ T cells as components of anti-HIV immunotherapy.

    更新日期:2019-11-01
  • Harnessing host-virus evolution in antiviral therapy and immunotherapy.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-07-18
    Steven M Heaton

    Pathogen resistance and development costs are major challenges in current approaches to antiviral therapy. The high error rate of RNA synthesis and reverse-transcription confers genome plasticity, enabling the remarkable adaptability of RNA viruses to antiviral intervention. However, this property is coupled to fundamental constraints including limits on the size of information available to manipulate complex hosts into supporting viral replication. Accordingly, RNA viruses employ various means to extract maximum utility from their informationally limited genomes that, correspondingly, may be leveraged for effective host-oriented therapies. Host-oriented approaches are becoming increasingly feasible because of increased availability of bioactive compounds and recent advances in immunotherapy and precision medicine, particularly genome editing, targeted delivery methods and RNAi. In turn, one driving force behind these innovations is the increasingly detailed understanding of evolutionarily diverse host-virus interactions, which is the key concern of an emerging field, neo-virology. This review examines biotechnological solutions to disease and other sustainability issues of our time that leverage the properties of RNA and DNA viruses as developed through co-evolution with their hosts.

    更新日期:2019-11-01
  • Erratum: Genome-wide association studies of multiple sclerosis.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2018-08-22
    Chris Cotsapas,Mitja Mitrovic

    [This corrects the article DOI: 10.1002/cti2.1018.].

    更新日期:2019-11-01
  • Chimeric antigen receptors designed to overcome transforming growth factor-β-mediated repression in the adoptive T-cell therapy of solid tumors.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-06-27
    Jordan Hartley,Hinrich Abken

    Adoptive cell therapy with chimeric antigen receptor (CAR)-engineered T cells produced lasting remissions in the treatment of advanced, so far refractory B-cell malignancies; however, the elimination of solid tumors remains so far elusive. The low efficacy of CAR T cells is thought to be due to the immune-repressive milieu within the tumor lesion, predominantly mediated by transforming growth factor-β (TGF-β) that represses effector T-cell activities and drives differentiation towards regulatory T cells (Tregs). Seeking to boost antitumor immunity, TGF-β is currently targeted by different means in pre-clinical studies. While a recent clinical trial showed the utility of shielding CAR T cells from TGF-β repression, further strategies in counteracting TGF-β in the adoptive cell therapy warrant exploration. We here discuss the most recent advances in the field and draw future developments to make CAR T-cell therapy more potent in the treatment of solid cancer.

    更新日期:2019-11-01
  • Post-transcriptional control of immune responses and its potential application.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-06-27
    Masanori Yoshinaga,Osamu Takeuchi

    Inflammation is the host response against stresses such as infection. Although the inflammation process is required for the elimination of pathogens, uncontrolled inflammation leads to tissue destruction and inflammatory diseases. To avoid this, the inflammatory response is tightly controlled by multiple layers of regulation. Post-transcriptional control of inflammatory mRNAs is increasingly understood to perform critical roles in this process. This is mediated primarily by a set of RNA binding proteins (RBPs) including tristetraprolin, Roquin and Regnase-1, and RNA methylases. These key regulators coordinate the inflammatory response by modulating mRNA pools in both immune and local nonimmune cells. In this review, we provide an overview of the post-transcriptional coordination of immune responses in various tissues and discuss how RBP-mediated regulation of inflammation may be harnessed as a potential class of treatments for inflammatory diseases.

    更新日期:2019-11-01
  • Effects of interleukin-6 receptor blockade on allergen-induced airway responses in mild asthmatics.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-06-22
    Joana A Revez,Lisa M Bain,Rick M Watson,Michelle Towers,Tina Collins,Kieran J Killian,Paul M O'Byrne,Gail M Gauvreau,John W Upham,Manuel Ar Ferreira

    Background Interleukin (IL)-6 signalling has been implicated in allergic asthma by animal, genetic association and clinical studies. In this study, we tested the hypothesis that tocilizumab (TCZ), a human monoclonal antibody that blocks IL-6 signalling, can prevent the development of allergen-induced bronchoconstriction in humans. Methods We performed a randomised, double-blind, placebo-controlled study, with eligible participants completing two allergen inhalation challenge tests, conducted before and after treatment with a single dose of TCZ or placebo. The primary efficacy endpoint was the magnitude of the late asthmatic response recorded between 3 and 7 after allergen challenge. The secondary efficacy endpoint was the early asthmatic response, measured 20 min to 2 h after allergen challenge. Results A total of 66 patients enrolled between September 2014 and August 2017, when the trial was stopped for futility based on results from an interim analysis. Eleven patients fulfilled all eligibility criteria assessed at baseline and were subsequently randomised to the TCZ (n = 6) or placebo (n = 5) groups. Both the primary and secondary efficacy endpoints were not significantly different between the two groups. Five patients reported adverse events (AEs), three in the TCZ group (11 AEs) and two in the placebo group (four AEs). Only one AE was TCZ-related (mild neutropenia), and there were no serious AEs. Significant treatment effects were observed for serum levels of C-reactive protein, IL-6 and soluble IL-6R levels. Conclusion In a small proof-of-concept clinical trial, we found no evidence that a single dose of tocilizumab was able to prevent allergen-induced bronchoconstriction. (Trial registered in the Australian New Zealand Clinical Trials Registry, number ACTRN12614000123640).

    更新日期:2019-11-01
  • Clinical chimeric antigen receptor-T cell therapy: a new and promising treatment modality for glioblastoma.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-05-30
    Michael P Brown,Lisa M Ebert,Tessa Gargett

    Chimeric antigen receptor (CAR)-T cell therapy is now approved in the United States and Europe as a standard treatment for relapsed/refractory B-cell malignancies. It has also been approved recently by the Therapeutic Goods Administration in Australia and may soon be publicly reimbursed. This advance has accentuated scientific, clinical and commercial interest in adapting this exciting technology for the treatment of solid cancers where it is widely recognised that the challenges of overcoming a hostile tumor microenvironment are most acute. Indeed, CAR-T cell technology may be of the greatest value for those cancers that lack pre-existing immunity because they are immunologically 'cold', or have a low somatic tumor mutation load, or both. These cancers are generally not amenable to therapeutic immune checkpoint blockade, but CAR-T cell therapy may be effective because it provides an abundant supply of autologous tumor-specific T cells. This is achieved by using genetic engineering to re-direct autologous T-cell cytotoxicity towards a tumor-associated antigen, bypassing endogenous T-cell requirements for antigen processing, MHC-dependent antigen presentation and co-stimulation. One of the most challenging solid cancers is glioblastoma, which has among the least permissive immunological milieu of any cancer, and which is almost always fatal. Here, we argue that CAR-T cell technology may counter some glioblastoma defences and provide a beachhead for furthering our eventual therapeutic aims of restoring effective antitumor immunity. Although clinical investigation of CAR-T cell therapy for glioblastoma is at an early stage, we discuss three recently published studies, which feature significant differences in target antigen, CAR-T cell phenotype, route of administration and tumor response. We discuss the lessons, which may be learned from these studies and which may guide further progress in the field.

    更新日期:2019-11-01
  • Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-05-22
    Robert Weinkove,Philip George,Nathaniel Dasyam,Alexander D McLellan

    Costimulatory signals are required to achieve robust chimeric antigen receptor (CAR) T cell expansion, function, persistence and antitumor activity. These can be provided by incorporating intracellular signalling domains from one or more T cell costimulatory molecules, such as CD28 or 4-1BB, into the CAR. The selection and positioning of costimulatory domains within a CAR construct influence CAR T cell function and fate, and clinical experience of autologous anti-CD19 CAR T cell therapies suggests that costimulatory domains have differential impacts on CAR T cell kinetics, cytotoxic function and potentially safety profile. The clinical impacts of combining costimulatory domains and of alternative costimulatory domains are not yet clearly established, and may be construct- and disease-specific. The aim of this review is to summarise the function and effect of established and emerging costimulatory domains and their combinations within CAR T cells.

    更新日期:2019-11-01
  • Switching on the green light for chimeric antigen receptor T-cell therapy.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-05-11
    Sherly Mardiana,Junyun Lai,Imran Geoffrey House,Paul Andrew Beavis,Phillip Kevin Darcy

    Adoptive cellular therapy involving genetic modification of T cells with chimeric antigen receptor (CAR) transgene offers a promising strategy to broaden the efficacy of this approach for the effective treatment of cancer. Although remarkable antitumor responses have been observed following CAR T-cell therapy in a subset of B-cell malignancies, this has yet to be extended in the context of solid cancers. A number of promising strategies involving reprogramming the tumor microenvironment, increasing the specificity and safety of gene-modified T cells and harnessing the endogenous immune response have been tested in preclinical models that may have a significant impact in patients with solid cancers. This review will discuss these exciting new developments and the challenges that must be overcome to deliver a more sustained and potent therapeutic response.

    更新日期:2019-11-01
  • Analysis of serum B cell-activating factor from the tumor necrosis factor family (BAFF) and its soluble receptors in systemic lupus erythematosus.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-04-27
    Fabien B Vincent,Rangi Kandane-Rathnayake,Rachel Koelmeyer,Alberta Y Hoi,James Harris,Fabienne Mackay,Eric F Morand

    Objectives To determine the presence and clinical associations of the soluble receptors of B cell-activating factor from the tumor necrosis factor family (BAFF) in serum of patients with systemic lupus erythematosus (SLE). Methods Serum BAFF and soluble BAFF receptor (sBAFF-R) were quantified using ELISA, and soluble B cell maturation antigen (sBCMA) and transmembrane activator and cyclophilin ligand interactor (sTACI) by Luminex, in 87 SLE patients and 17 healthy controls (HC). Disease activity and organ damage were assessed using SLE Disease Activity Index 2000 (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics (SLICC) SLE Damage Index (SDI), respectively. Results BAFF and all receptors were detectable in all serum samples. Serum sBCMA and sTACI, but not sBAFF-R, were significantly higher in SLE than in HC. Serum BAFF was also increased in SLE, but this association was attenuated after adjusting for age and ethnicity. Increased serum BAFF was associated with flare and organ damage. Increased serum sBCMA was associated with the presence of anti-dsDNA, but not with overall or organ-specific disease activity, flare or organ damage. Neither sTACI nor sBAFF-R was associated with any SLE clinical parameters in multivariable analysis. While serum BAFF correlated negatively with sBAFF-R in HC, no statistically significant correlations were observed between BAFF and its receptors in SLE patients. Conclusion Serum BAFF was associated with flare and organ damage independent of the presence of its soluble receptors. While sBCMA was associated with anti-dsDNA positivity, other soluble BAFF receptors were not associated with SLE clinical indicators.

    更新日期:2019-11-01
  • Analysis of serum interleukin(IL)-1α, IL-1β and IL-18 in patients with systemic sclerosis.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-04-19
    Emily Lin,Fabien B Vincent,Joanne Sahhar,Gene-Siew Ngian,Rangi Kandane-Rathnayake,Rachel Mende,Eric F Morand,Tali Lang,James Harris

    Objectives Systemic sclerosis (SSc) is an autoimmune disease characterised by fibrosis, vascular dysfunction and immune dysregulation. The pathogenesis of SSc remains poorly understood, although studies have indicated a role for the innate immune response. Methods Here, we measured serum interleukin (IL)-1α, IL-1β and IL-18 levels in 105 SSc patients and 47 healthy controls (HC) and analysed them with respect to multiple clinical parameters. Results Serum IL-18 concentrations were significantly higher in SSc patients than in HC, while no significant differences in concentrations of IL-1α and IL-1β were observed between SSc and HC. In both SSc and HC serum, IL-1α and IL-1β were positively correlated, while in SSc, both cytokines negatively correlated with IL-18. Serum IL-18 was significantly negatively correlated with both carbon monoxide transfer coefficient (KCO) and diffusing capacity of the lungs for carbon monoxide (DLCO). Serum IL-1β was positively correlated with the modified Rodnan skin score (mRSS), particularly in patients with limited subtype. DLCO, KCO and tricuspid regurgitation (TR) velocity were significantly higher in patients with high serum IL-1β. Serum IL-1α was significantly lower in SSc patients with low KCO and positively correlated with KCO. SSc patients with high serum IL-1α concentrations were more likely to have digital ulcers. Conclusions Our data suggest that these IL-1 family cytokines may have different roles in the pathogenesis of SSc fibrotic complications.

    更新日期:2019-11-01
  • Repeat pneumococcal polysaccharide vaccination does not impair functional immune responses among Indigenous Australians.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2017-11-09
    Paul V Licciardi,Edwin Hoe,Zheng Quan Toh,Anne Balloch,Sarah Moberley,Paula Binks,Rachel Marimla,Amanda Leach,Sue Skull,Kim Mulholland,Ross Andrews

    Indigenous Australians experience one of the highest rates of pneumococcal disease globally. In the Northern Territory of Australia, a unique government-funded vaccination schedule for Indigenous Australian adults comprising multiple lifetime doses of the pneumococcal polysaccharide vaccine is currently implemented. Despite this programme, rates of pneumococcal disease do not appear to be declining, with concerns raised over the potential for immune hyporesponse associated with the use of this vaccine. We undertook a study to examine the immunogenicity and immune function of a single and repeat pneumococcal polysaccharide vaccination among Indigenous adults compared to non-Indigenous adults. Our results found that immune function, as measured by opsonophagocytic and memory B-cell responses, were similar between the Indigenous groups but lower for some serotypes in comparison with the non-Indigenous group. This is the first study to document the immunogenicity following repeat 23-valent pneumococcal polysaccharide vaccine administration among Indigenous Australian adults, and reinforces the continued need for optimal pneumococcal vaccination programmes among high-risk populations.

    更新日期:2019-11-01
  • Agammaglobulinaemia despite terminal B-cell differentiation in a patient with a novel LRBA mutation.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2017-07-12
    Nashat Al Sukaiti,Khwater AbdelRahman,Jalila AlShekaili,Sumaya Al Oraimi,Aisha Al Sinani,Nasser Al Rahbi,Vicky Cho,Matt Field,Matthew C Cook

    Mutations in lipopolysaccharide-responsive vesicle trafficking, beach and anchor-containing protein (LRBA) cause immune deficiency and inflammation. Here, we are reporting a novel homozygous mutation in LRBA allele in 7-year-old Omani boy, born to consanguineous parents. He presented with type 1 diabetes, autoimmune haematological cytopenia, recurrent chest infections and lymphocytic interstitial lung disease. The patient was treated with CTLA4-Ig (abatacept) with good outcome every 2 weeks for a period of 3 months. He developed complete IgG deficiency, but remarkably, histological examination revealed germinal centres and plasma cells in lymphoid and inflamed lung tissue. Further charatecterisation showed these cells to express IgM but not IgG. This ex vivo analysis suggests that LRBA mutation confers a defect in class switching despite plasma cell formation.

    更新日期:2019-11-01
  • Adoptive T-cell immunotherapy for ganciclovir-resistant CMV disease after lung transplantation.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2015-04-11
    Chien-Li Holmes-Liew,Mark Holmes,Leone Beagley,Peter Hopkins,Daniel Chambers,Corey Smith,Rajiv Khanna

    Infections with cytomegalovirus (CMV) can induce severe complications after solid organ transplantation (SOT). The prognosis for ganciclovir-resistant CMV infection and disease is particularly poor. Whereas adoptive transfer of CMV-specific T cells has emerged as a powerful tool in hematopoietic stem cell transplant patients, its translation into the SOT setting remains a significant challenge as underlying immunosuppression inhibits the virus-specific T-cell response in vivo. Here, we demonstrate successful expansion and adoptive transfer of autologous CMV-specific T cells from a seronegative recipient of a seropositive lung allograft with ganciclovir-resistant CMV disease, resulting in the long-term reconstitution of protective anti-viral immunity, CMV infection, disease-free survival and no allograft rejection.

    更新日期:2019-11-01
  • A high burden of cytomegalovirus marks poor vascular health in transplant recipients more clearly than in the general population.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2019-02-23
    Silvia Lee,Emily Brook,Jacquita Affandi,Prue Howson,Selita Agnes Tanudjaja,Satvinder Dhaliwal,Ashley Irish,Patricia Price

    Objectives Meta-analyses have now confirmed that persistent infections with cytomegalovirus (CMV) can accelerate the onset of diseases of ageing, notably cardiovascular pathologies. We address the circumstances in which the association may be strong enough to warrant intervention to reduce the viral burden. Results We compare markers of the burden of CMV with established indices of vascular pathology in healthy adults (n = 82) and in renal transplant recipients (RTR; n = 81). Levels of all inflammatory and vascular biomarkers and CMV antibodies were higher in RTR, and flow-mediated dilation (FMD) values were lower indicating inferior endothelial function. In multivariable regression models without adjustment for estimated glomerular filtration rate (eGFR), CMV antibody levels, age and gender were independently associated with FMD in RTR, whilst only CRP associated with FMD in healthy adults. After adjustment for eGFR, associations between CMV antibody and FMD in RTR were reduced. Methods Carotid intima-media thickness, FMD, eGFR and plasma levels of CMV antibodies (reactive with a lysate, CMV IE-1 or CMV gB), ICAM-1, VCAM-1, P-selectin, sIFNαR2, sTNFR1, sCD14 and CRP were determined. Conclusion Levels of CMV antibody predict declining endothelial health in RTR and not in healthy adults, presumably by reflecting a high burden of CMV. The levels of CMV antibodies were a poor reflection of plasma biomarkers thought to reflect 'inflammaging' or vascular damage.

    更新日期:2019-11-01
  • Platelets regulate leucocyte responses to Toll-like receptor stimulation.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2018-08-02
    Kathryn E Hally,Anne C La Flamme,Scott A Harding,Peter D Larsen

    Objectives Platelets are important regulators of vascular thrombosis and inflammation and are known to express Toll-like receptors (TLRs). Through TLRs, platelets mediate a number of responses by interacting with leucocytes. Here, we report the extent to which platelets modulate in vitro peripheral blood mononuclear cells (PBMCs) and granulocyte responses to TLR4, TLR2/1 and TLR2/6 stimulation in healthy subjects. Methods Peripheral blood mononuclear cells and granulocytes from 10 healthy volunteers were cultured alone or cocultured with platelets. Cultures were left unstimulated or stimulated with 1 or 100 ng mL-1 of either LPS (TLR4 agonist), Pam3CSK4 (TLR2/1 agonist) or fibroblast-stimulating lipopeptide (FSL)-1 (TLR2/6 agonist). Neutrophil activation (CD66b expression), monocyte activation (HLA-DR), granulocyte elastase production and PBMC cytokine and chemokine production were examined. Results Platelet coculture decreased neutrophil CD66b expression in response to LPS, Pam3CSK4 and FSL-1, and modestly decreased monocyte HLA-DR expression in response to low-dose LPS. Platelets reduced granulocyte elastase secretion in response to low doses of all TLR agonists tested. In response to LPS, platelet coculture reduced IL-6, tumor necrosis factor (TNF)-α and MIP-1β production, and increased IL-10 production by PBMCs. In response to FSL-1, platelets increased IL-6, IL-10 and MIP-1β production, but reduced TNF-α production. Platelet coculture did not alter PBMC cytokine/chemokine production in response to Pam3CSK4. Conclusion This study challenges the notion that platelets act solely in a pro-inflammatory manner. Rather, platelets are complex immunomodulators that regulate leucocyte responses to TLR stimulation in a TLR agonist-specific manner. Platelets may modulate leucocyte responses to dampen inflammation, and this platelet effect may play an important role in reducing inflammation-mediated host damage.

    更新日期:2019-11-01
  • Regulatory T cells in renal disease.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2018-02-28
    Maliha A Alikhan,Megan Huynh,A Richard Kitching,Joshua D Ooi

    The kidney is vulnerable to injury, both acute and chronic from a variety of immune and metabolic insults, all of which at least to some degree involve inflammation. Regulatory T cells modulate systemic autoimmune and allogenic responses in glomerulonephritis and transplantation. Intrarenal regulatory T cells (Tregs), including those recruited to the kidney, have suppressive effects on both adaptive and innate immune cells, and probably also intrinsic kidney cells. Evidence from autoimmune glomerulonephritis implicates antigen-specific Tregs in HLA-mediated dominant protection, while in several human renal diseases Tregs are abnormal in number or phenotype. Experimentally, Tregs can protect the kidney from injury in a variety of renal diseases. Mechanisms of Treg recruitment to the kidney include via the chemokine receptors CCR6 and CXCR3 and potentially, at least in innate injury TLR9. The effects of Tregs may be context dependent, with evidence for roles for immunoregulatory roles both for endogenous Tbet-expressing Tregs and STAT-3-expressing Tregs in experimental glomerulonephritis. Most experimental work and some of the ongoing human trials in renal transplantation have focussed on unfractionated thymically derived Tregs (tTregs). However, induced Tregs (iTregs), type 1 regulatory T (Tr1) cells and in particular antigen-specific Tregs also have therapeutic potential not only in renal transplantation, but also in other kidney diseases.

    更新日期:2019-11-01
  • Regulatory T-cell heterogeneity and the cancer immune response.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2017-10-07
    Kirsten A Ward-Hartstonge,Roslyn A Kemp

    The frequency of circulating or tumour-infiltrating regulatory T cells (Tregs) has been associated with poor patient survival in many cancers including breast, melanoma and lung. It has been hypothesised that Tregs impact the anti-tumour function of effector T cells, resulting in worse outcomes for patients. However, high infiltrates of Tregs have been associated with a positive outcome of patients in a minority of cancers including colorectal, bladder and oesophageal. In addition, many studies have shown no impact of Tregs in patient outcome. Traditionally, research has identified Tregs as forkhead box P3 (FOXP3+) T cells in order to make such associations. Recently, it has become evident that regulatory populations are very heterogeneous, and this heterogeneity is essential for Treg function. Treg heterogeneity likely affects predictions of patient outcome, and different Treg populations may have different influences on tumours. The study of Tregs in cancer must include a better definition of the cells analysed. This review will focus primarily on colorectal cancer in humans, due to mixed data on the impact of Tregs on patient outcome in this disease.

    更新日期:2019-11-01
  • Dengue virus antibodies enhance Zika virus infection.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2017-01-17
    Lauren M Paul,Eric R Carlin,Meagan M Jenkins,Amanda L Tan,Carolyn M Barcellona,Cindo O Nicholson,Scott F Michael,Sharon Isern

    For decades, human infections with Zika virus (ZIKV), a mosquito-transmitted flavivirus, were sporadic, associated with mild disease, and went underreported since symptoms were similar to other acute febrile diseases. Recent reports of severe disease associated with ZIKV have greatly heightened awareness. It is anticipated that ZIKV will continue to spread in the Americas and globally where competent Aedes mosquito vectors are found. Dengue virus (DENV), the most common mosquito-transmitted human flavivirus, is both well-established and the source of outbreaks in areas of recent ZIKV introduction. DENV and ZIKV are closely related, resulting in substantial antigenic overlap. Through antibody-dependent enhancement (ADE), anti-DENV antibodies can enhance the infectivity of DENV for certain classes of immune cells, causing increased viral production that correlates with severe disease outcomes. Similarly, ZIKV has been shown to undergo ADE in response to antibodies generated by other flaviviruses. We tested the neutralizing and enhancing potential of well-characterized broadly neutralizing human anti-DENV monoclonal antibodies (HMAbs) and human DENV immune sera against ZIKV using neutralization and ADE assays. We show that anti-DENV HMAbs, cross-react, do not neutralize, and greatly enhance ZIKV infection in vitro. DENV immune sera had varying degrees of neutralization against ZIKV and similarly enhanced ZIKV infection. Our results suggest that pre-existing DENV immunity may enhance ZIKV infection in vivo and may lead to increased disease severity. Understanding the interplay between ZIKV and DENV will be critical in informing public health responses and will be particularly valuable for ZIKV and DENV vaccine design and implementation strategies.

    更新日期:2019-11-01
  • Role of human milk oligosaccharides in Group B Streptococcus colonisation.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2016-09-03
    Nicholas J Andreas,Asmaa Al-Khalidi,Mustapha Jaiteh,Edward Clarke,Matthew J Hyde,Neena Modi,Elaine Holmes,Beate Kampmann,Kirsty Mehring Le Doare

    Group B Streptococcus (GBS) infection is a major cause of morbidity and mortality in infants. The major risk factor for GBS disease is maternal and subsequent infant colonisation. It is unknown whether human milk oligosaccharides (HMOs) protect against GBS colonisation. HMO production is genetically determined and linked to the Lewis antigen system. We aimed to investigate the association between HMOs and infant GBS colonisation between birth and postnatal day 90. Rectovaginal swabs were collected at delivery, as well as colostrum/breast milk, infant nasopharyngeal and rectal swabs at birth, 6 days and days 60-89 postpartum from 183 Gambian mother/infant pairs. GBS colonisation and serotypes were determined using culture and PCR. (1)H nuclear magnetic resonance spectroscopy was used to characterise the mother's Lewis status and HMO profile in breast milk. Mothers who were Lewis-positive were significantly less likely to be colonised by GBS (X (2)=12.50, P<0.001). Infants of Lewis-positive mothers were less likely GBS colonised at birth (X (2)=4.88 P=0.03) and more likely to clear colonisation between birth and days 60-89 than infants born to Lewis-negative women (P=0.05). There was no association between Secretor status and GBS colonisation. In vitro work revealed that lacto-N-difucohexaose I (LNDFHI) correlated with a reduction in the growth of GBS. Our results suggest that HMO such as LNDFHI may be a useful adjunct in reducing maternal and infant colonisation and hence invasive GBS disease. Secretor status offers utility as a stratification variable in GBS clinical trials.

    更新日期:2019-11-01
  • Targeted therapeutics in SLE: emerging strategies to modulate the interferon pathway.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2016-06-29
    Shereen Oon,Nicholas J Wilson,Ian Wicks

    Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by impaired immune tolerance, resulting in the generation of pathogenic autoantibodies and immune complexes. Although autoreactive B lymphocytes have been the first targets for biologic therapies in SLE, the importance of the innate immune system, and in particular, pathways involved in interferon (IFN) signaling, has emerged. There are now data supporting a central role for a plasmacytoid dendritic cell-derived type I IFN pathway in SLE, with a number of biologic therapeutics and small-molecule inhibitors undergoing clinical trials. Monoclonal antibodies targeting IFN-α have completed phase II clinical trials, and an antibody against the type I IFN receptor is entering a phase III trial. However, other IFNs, such as IFN gamma, and the more recently discovered type III IFNs, are also emerging as targets in SLE; and blockade of upstream components of the IFN signaling pathway may enable inhibition of more than one IFN subtype. In this review, we discuss the current understanding of IFNs in SLE, focusing on emerging therapies.

    更新日期:2019-11-01
  • Delayed adaptive immunity is related to higher MMR vaccine-induced antibody titers in children.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2016-05-20
    Anna Strömbeck,Anna-Carin Lundell,Inger Nordström,Kerstin Andersson,Ingegerd Adlerberth,Agnes E Wold,Anna Rudin

    There are notable inter-individual variations in vaccine-specific antibody responses in vaccinated children. The aim of our study was to investigate whether early-life environmental factors and adaptive immune maturation prior and close to measles-mumps-rubella (MMR) immunization relate to magnitudes of vaccine-specific antibody titers. In the FARMFLORA birth cohort, including both farming and non-farming families, children were immunized with the MMR vaccine at 18 months of age. MMR vaccine-induced antibody titers were measured in plasma samples obtained at 36 months of age. Infants' blood samples obtained at birth, 3-5 days and at 4 and 18 months of age were analyzed for T- and B-cell numbers, proportions of naive and memory T and B cells, and fractions of putative regulatory T cells. Multivariate factor analyses show that higher anti-MMR antibody titers were associated with a lower degree of adaptive immune maturation, that is, lower proportions of memory T cells and a lower capacity of mononuclear cells to produce cytokines, but with higher proportions of putative regulatory T cells. Further, children born by cesarean section (CS) had significantly higher anti-measles titers than vaginally-born children; and CS was found to be associated with delayed adaptive immunity. Also, girls presented with significantly higher anti-mumps and anti-rubella antibody levels than boys at 36 months of age. These results indicate that delayed adaptive immune maturation before and in close proximity to immunization seems to be advantageous for the ability of children to respond with higher anti-MMR antibody levels after vaccination.

    更新日期:2019-11-01
  • The cell surface environment for pathogen recognition and entry.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2016-05-20
    Jennifer L Stow,Nicholas D Condon

    The surface of mammalian cells offers an interface between the cell interior and its surrounding milieu. As part of the innate immune system, macrophages have cell surface features optimised for probing and sampling as they patrol our tissues for pathogens, debris or dead cells. Their highly dynamic and constantly moving cell surface has extensions such as lamellipodia, filopodia and dorsal ruffles that help detect pathogens. Dorsal ruffles give rise to macropinosomes for rapid, high volume non-selective fluid sampling, receptor internalisation and plasma membrane turnover. Ruffles can also generate phagocytic cups for the receptor-mediated uptake of pathogens or particles. The membrane lipids, actin cytoskeleton, receptors and signalling proteins that constitute these cell surface domains are discussed. Although the cell surface is designed to counteract pathogens, many bacteria, viruses and other pathogens have evolved to circumvent or hijack these cell structures and their underlying machinery for entry and survival. Nevertheless, these features offer important potential for developing vaccines, drugs and preventative measures to help fight infection.

    更新日期:2019-11-01
  • A generalized quantitative antibody homeostasis model: antigen saturation, natural antibodies and a quantitative antibody network.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2017-05-13
    József Prechl

    In a pair of articles, we present a generalized quantitative model for the homeostatic function of clonal humoral immune system. In this second paper, we describe how antibody production controls the saturation of antigens and the network of antibody interactions that emerges in the epitome space with the establishment of the immune system. Efficient control of antigens, be it self or foreign, requires the maintenance of antibody concentrations that saturate antigen to relevant levels. Simple calculations suggest that the observed diverse recognition of antigens by natural antibodies is only possible by cross-reactivity whereby particular clones of antibodies bind to diverse targets and shared recognition of particular antigens by multiple antibody clones contribute to the maintenance of antigen control. We also argue that natural antibodies are none else than the result of thymus-independent responses against immunological self. We interpret and explain antibody production and function in a virtual molecular interaction space and as a network of interactions. Indeed, the general quantitative (GQM) model we propose is in agreement with earlier models, confirms some assumptions and presumably provides the theoretical basis for the construction of a real antibody network using the sequence and interaction database data.

    更新日期:2019-11-01
  • A generalized quantitative antibody homeostasis model: regulation of B-cell development by BCR saturation and novel insights into bone marrow function.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2017-03-08
    József Prechl

    In a pair of articles, we present a generalized quantitative model for the homeostatic function of clonal humoral immune system. In this first paper, we describe the cycles of B-cell expansion and differentiation driven by B-cell receptor engagement. The fate of a B cell is determined by the signals it receives via its antigen receptor at any point of its lifetime. We express BCR engagement as a function of apparent affinity and free antigen concentration, using the range of 10-14-10-3 M for both factors. We assume that for keeping their BCR responsive, B cells must maintain partial BCR saturation, which is a narrow region defined by [Ag]≈KD. To remain in this region, B cells respond to changes in [Ag] by proliferation or apoptosis and modulate KD by changing BCR structure. We apply this framework to various niches of B-cell development such as the bone marrow, blood, lymphoid follicles and germinal centers. We propose that clustered B cells in the bone marrow and in follicles present antigen to surrounding B cells by exposing antigen captured on complement and Fc receptors. The model suggests that antigen-dependent selection in the bone marrow results in (1) effector BI cells, which develop in blood as a consequence of the inexhaustible nature of soluble antigens, (2) memory cells that survive in antigen rich niches, identified as marginal zone B cells. Finally, the model implies that memory B cells could derive survival signals from abundant non-cognate antigens.

    更新日期:2019-11-01
  • Non-small cell lung cancer is characterised by a distinct inflammatory signature in serum compared with chronic obstructive pulmonary disease.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2016-12-19
    Hanne Astrid Eide,Ann Rita Halvorsen,Vandana Sandhu,Anne Fåne,Janna Berg,Vilde Drageset Haakensen,Elin H Kure,Odd Terje Brustugun,Cecilie Essholt Kiserud,Jon Amund Kyte,Åslaug Helland

    Development of lung cancer is closely related to smoking in a majority of patients. Most smokers, however, do not develop lung cancer in spite of a high mutational load accumulating in the lung tissue. Here we investigate whether a cancer-specific footprint can be revealed by investigating circulating inflammatory markers in patients with non-small cell lung cancer (NSCLC) compared with patients with chronic obstructive pulmonary disease (COPD), both cohorts characterised by similar smoking history. Serum concentrations of 57 cytokines and matrix metalloproteinases (MMPs) from 43 patients with advanced NSCLC were evaluated by multiplex immunoassays and compared with serum samples from 35 patients with COPD. Unsupervised hierarchical clustering and non-parametric analyses were performed. False discovery rate was used to adjust for multiple testing. Clustering of cytokine and MMP concentrations in the serum revealed a distinct separation of the NSCLC patients from the COPD group. Individual concentrations of thymus and activation-regulated cytokine (C-C motif chemokine ligand 17), Gro-b (C-X-C motif chemokine ligand 2 (CXCL2)), CXCL13, interleukin (IL)-1ra, IL-6, IL-8 (CXCL8), IL-16, IL-17A, macrophage migration inhibitory factor (MIF), granulocyte colony-stimulating factor, platelet-derived growth factor subunit B, MMP-2, MMP-8 and MMP-12 were significantly different in serum from NSCLC and COPD patients. Moreover, the interferon-γ/IL-10 ratio was lower in cancer patients compared with COPD patients, consistent with a cytokine milieu favouring tumour tolerance. Our results suggest that NSCLC is characterised by a distinct inflammatory signature in serum. The different cytokine profiles in NSCLC and COPD patients may represent tumour-promoting and tumour-suppressing immune responses developing in response to mucosal inflammation and mutations induced by smoking.

    更新日期:2019-11-01
  • Histone deacetylases in monocyte/macrophage development, activation and metabolism: refining HDAC targets for inflammatory and infectious diseases.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2016-02-24
    Kaustav Das Gupta,Melanie R Shakespear,Abishek Iyer,David P Fairlie,Matthew J Sweet

    Macrophages have central roles in danger detection, inflammation and host defense, and consequently, these cells are intimately linked to most disease processes. Major advances in our understanding of the development and function of macrophages have recently come to light. For example, it is now clear that tissue-resident macrophages can be derived from either blood monocytes or through local proliferation of phagocytes that are originally seeded during embryonic development. Metabolic state has also emerged as a major control point for macrophage activation phenotypes. Herein, we review recent literature linking the histone deacetylase (HDAC) family of enzymes to macrophage development and activation, particularly in relation to these recent developments. There has been considerable interest in potential therapeutic applications for small molecule inhibitors of HDACs (HDACi), not only for cancer, but also for inflammatory and infectious diseases. However, the enormous range of molecular and cellular processes that are controlled by different HDAC enzymes presents a potential stumbling block to clinical development. We therefore present examples of how classical HDACs control macrophage functions, roles of specific HDACs in these processes and approaches for selective targeting of drugs, such as HDACi, to macrophages. Development of selective inhibitors of macrophage-expressed HDACs and/or selective delivery of pan HDACi to macrophages may provide avenues for enhancing efficacy of HDACi in therapeutic applications, while limiting unwanted side effects.

    更新日期:2019-11-01
  • Analysis of serum macrophage migration inhibitory factor and D-dopachrome tautomerase in systemic sclerosis.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2018-12-14
    Fabien B Vincent,Emily Lin,Joanne Sahhar,Gene-Siew Ngian,Rangi Kandane-Rathnayake,Rachel Mende,Alberta Y Hoi,Eric F Morand,Tali Lang,James Harris

    Objectives Macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (DDT), members of the same cytokine superfamily, are linked to the pathogenesis of a number of inflammatory diseases. The aim of this study was to investigate their clinical relevance in systemic sclerosis (SSc). Methods Serum MIF and DDT were quantified in 105 SSc patients by ELISA and levels compared to healthy controls (HC) (47) and patients with systemic lupus erythematosus (SLE) (184). Clinical parameters included organ involvement, serum laboratory markers and results of pulmonary function tests, and overall disease activity assessed using the European Scleroderma Trials and Research group (EUSTAR) activity index. Results There was no significant difference in serum DDT concentrations between patients with SSc and HC. However, serum MIF was significantly increased in SSc compared to both HC and SLE cohorts. Serum MIF was increased in SSc patients with low forced vital capacity (FVC) and was also associated with the use of angiotensin II receptor blockers and beta blockers in SSc, confirmed after adjusting for the presence of systemic hypertension and low FVC. Serum DDT was significantly higher in SSc patients with low FEV1 and negatively correlated with EUSTAR score, particularly in patients with limited disease. Conclusion Although not significantly linked to specific clinical parameters, serum MIF was significantly higher in SSc patients than in HC and SLE patients, suggesting a fundamental role for MIF in SSc. DDT, while closely related to MIF, did not show a similar expression profile, suggesting functional differences between these molecules.

    更新日期:2019-11-01
  • 2018 Nobel Prize in physiology or medicine.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2018-11-06
    Mark J Smyth,Michele Wl Teng

    更新日期:2019-11-01
  • Contemporary analysis of functional immune recovery to opportunistic and vaccine-preventable infections after allogeneic haemopoietic stem cell transplantation.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2018-10-17
    Harini D de Silva,Rosemary A Ffrench,Maya Korem,Eva Orlowski,David J Curtis,Andrew Spencer,Sharon Avery,Sushrut Patil,Catherine Orla Morrissey

    Objectives Infections are a major cause of mortality after allogeneic haemopoietic stem cell transplantation (alloHSCT), and immune recovery is necessary for prevention. Novel transplant procedures have changed the epidemiology of infections but contemporary data on functional immune recovery are limited. In this pilot study, we aimed to measure immune recovery in the current era of alloHSCT. Methods Twenty, 13, 11, 9 and 9 alloHSCT recipients had blood collected at baseline (time of conditioning) and 3-, 6-, 9-, and 12-months post-alloHSCT, respectively. Clinical data were collected, and immune recovery was measured using immunophenotyping, lymphocyte proliferation, cytokine analysis and antibody isotyping. Results Median absolute T- and B-cell counts were below normal from baseline until 9- to 12-months post-alloHSCT. Median absolute CD4+ T-cell counts recovered at 12-months post-alloHSCT. Positive proliferative responses to Aspergillus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), influenza and tetanus antigens were detected from 9 months. IL-6 was the most abundant cytokine in cell cultures. In cultures stimulated with CMV, EBV, influenza and tetanus peptides, the CD4+ T-cell count correlated with IL-1β (P = 0.045) and CD8+ T-cell count with IFNγ (P = 0.013) and IL-1β (P = 0.012). The NK-cell count correlated with IL-1β (P = 0.02) and IL-17a (P = 0.03). Median serum levels of IgG1, IgG2 and IgG3 were normal while IgG4 and IgA were below normal range throughout follow-up. Conclusions This pilot study demonstrates that immune recovery can be measured using CD4+ T-cell counts, in vitro antigen stimulation and selected cytokines (IFNγ, IL-1β, IL-4, IL-6, IL-17, IL-21, IL-31) in alloHSCT recipients. While larger studies are required, monitoring immune recovery may have utility in predicting infection risk post-alloHSCT.

    更新日期:2019-11-01
  • Upregulation of HLA-E by dengue and not Zika viruses.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2018-09-29
    Elena Drews,Awadalkareem Adam,Phone Htoo,Elizabeth Townsley,Anuja Mathew

    Introduction The most severe form of dengue virus (DENV) illness, dengue haemorrhagic fever, is characterised by plasma leakage and increased vascular permeability. Objectives Given the critical role that endothelial cells play in the pathogenesis of DENV, we wanted to determine whether infection with DENV altered the expression of MHC class I related genes including HLA-E. Results In this study, we provide evidence that HLA-E but not MICA/B or HLA-G is upregulated by all four serotypes of DENV in an endothelial cell line human microvascular endothelial cells (HMEC)-1. In contrast, Zika virus (ZIKV), a related flavivirus, where plasma leakage is not a major manifestation of disease, did not upregulate HLA-E. We found modest levels of soluble HLA-E in supernatants from DENV but not ZIKV-infected cells. Coculture experiments found minimal activation of natural killer (NK) cells in the presence of both uninfected and infected HMEC-1 cells. HLA-E induced by DENV infection could not dampen the degranulation of activated NK cells by interacting with its ligand NKG2a. Conclusions Our results suggest that while DENV infection induces HLA-E, the high MHC class I expression on uninfected and infected HMEC-1 cells may dominate the diverse signals generated between inhibitory and activating receptors on NK cells and ligands on target cells.

    更新日期:2019-11-01
  • Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2018-08-22
    Lilian Cha,Anderson P Jones,Stephanie Trend,Scott N Byrne,Marzena J Fabis-Pedrini,William M Carroll,Robyn M Lucas,Judith M Cole,David R Booth,Allan G Kermode,Prue H Hart

    Objectives Clinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A study of circulating cells from patients with CIS may help us understand the transition to, and processes associated with, the development of MS. Methods As immune cell activity can be determined by flux through metabolic pathways, the mRNA expression of l-tryptophan- and l-arginine-catabolising enzymes, indoleamine 2,3-dioxygenase (IDO) 1 and IDO2 and arginase (ARG) 1 and ARG2, respectively, was compared between peripheral blood mononuclear cells (PBMCs) from healthy controls, and patients with CIS and definite MS. As one measure of cell function, cytokine mRNA levels were analysed directly ex vivo and in cells after culture for 4 h in the absence of regulatory factors in autologous serum. Results When measured directly ex vivo, the expression of IDO and ARG was greater in cells from patients with CIS and MS than cells from healthy controls. Although not linked to IDO and ARG expression, PBMCs from the CIS patients were characterised by low IL-10 and TGFB mRNA levels and not by greater expression of proinflammatory cytokines. When the cells were cultured for 4 h without autologous serum, pro- and anti-inflammatory cytokine mRNA levels positively correlated with IDO1 expression, and TGFB mRNA levels correlated with ARG1 expression. Conclusion Higher IDO and ARG expression in CIS and MS provides one sustained homeostatic mechanism to control MS-associated inflammation. However, potent extrinsic mediators in serum may regulate immune cell function in CIS and associations between IDO, ARG and cytokine expression.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • High molecular weight hyaluronic acid: a two-pronged protectant against infection of the urogenital tract?
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2018-06-22
    Catherine A Mowbray,Syema Shams,Git Chung,Anna Stanton,Phillip Aldridge,Andrejus Suchenko,Robert S Pickard,Ased Sm Ali,Judith Hall

    Objectives Recurrent urinary tract infections are associated with uropathogenic Escherichia coli (UPEC) ascending and infecting the urinary tract. Antibiotics provide only symptomatic relief, not prevent recurrence. Clinical evidence suggests that intravesical glycosaminoglycan therapy, such as hyaluronic acid (HA), helps reduce UTI recurrence. This has been investigated here using in vitro systems modelling the urogenital tract tissues. Methods RT4 bladder cells were preconditioned with high molecular weight HA (> 1500 kDa) at 2 mg mL-1 and challenged with UPEC to analyse barrier protection and bacterial adherence. Untreated and HA-preconditioned VK2 E6/E7 vaginal cells were challenged with E. coli flagellin (50 ng mL-1) to mimic bacterial challenge, and media analysed for lipocalin-2, human β-defensin 2 and interleukin-8 by ELISA. Experiments were repeated after siRNA knockdown of Toll-like receptors 2, 4 and 5, and CD44 to investigate signalling. Results Microscopic analyses showed reduced bacterial adherence and urothelial disruption with HA, suggesting that HA functions as a barrier protecting the epithelium from bacterial infection. Cells treated with HA and flagellin simultaneously produced more of the host antimicrobial peptide LCN2 and pro-inflammatory IL-8 (P < 0.05) compared to the no HA/flagellin challenges. Increased gene expression of DEFB4 (P < 0.05), but not the hBD2 peptide, was observed in the HA/flagellin-challenged cells. Conclusion These data suggest that exogenous HA has potential to protect the urogenital epithelia from UPEC infection via a two-pronged approach that involves the physical enhancement of the epithelial barrier and augmentation of its innate immune response.

    更新日期:2019-11-01
  • Oxidative and endoplasmic reticulum stress in respiratory disease.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2018-06-22
    Alice C-H Chen,Lucy Burr,Michael A McGuckin

    Oxidative stress and endoplasmic reticulum (ER) stress are related states that can occur in cells as part of normal physiology but occur frequently in diseases involving inflammation. In this article, we review recent findings relating to the role of oxidative and ER stress in the pathophysiology of acute and chronic nonmalignant diseases of the lung, including infections, cystic fibrosis, idiopathic pulmonary fibrosis and asthma. We also explore the potential of drugs targeting oxidative and ER stress pathways to alleviate disease.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Genome-wide association studies of multiple sclerosis.
    Clin. Transl. Immunol. (IF 7.271) Pub Date : 2018-06-09
    Chris Cotsapas,Mitja Mitrovic

    Large-scale genetic studies of multiple sclerosis have identified over 230 risk effects across the human genome, making it a prototypical common disease with complex genetic architecture. Here, after a brief historical background on the discovery and definition of the disease, we summarise the last fifteen years of genetic discoveries and map out the challenges that remain to translate these findings into an aetiological framework and actionable clinical understanding.

    更新日期:2019-11-01
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