197 results found
Pinato DJ, Gramenitskaya D, Altmann DM, et al., Antibiotic therapy and outcome from immune-checkpoint inhibitors, Journal for ImmunoTherapy of Cancer, ISSN: 2051-1426
Sensitivity to immune checkpoint inhibitor (ICPI) therapy is governed by a complex interplay of tumor and host-related determinants. Epidemiological studies have highlighted that exposure to antibiotic therapy influences the probability of response to ICPI and predict for shorter patient survival across malignancies. Whilst a number of studies have reproducibly documented the detrimental effect of broad-spectrum antibiotics, the immune-biologic mechanisms underlying the association with outcome are poorly understood. Perturbation of the gut microbiota, an increasingly well-characterized factor capable of influencing ICPI-mediated immune reconstitution, has been indicated as a putative mechanism to explain the adverse effects attributed to antibiotic exposure in the context of ICPI therapy. Prospective studies are required to validate antibiotic-mediated gut perturbations as a mechanism of ICPI refractoriness and guide the development of strategies to overcome this barrier to an effective delivery of anti-cancer immunotherapy.
Boyton RJ, Altmann DM, 2019, Muco-Obstructive Lung Diseases, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 381, Pages: E20-+, ISSN: 0028-4793
Chambers E, Byrne C, Morrison D, et al., 2019, Dietary supplementation with inulin-propionate ester or inulin improves insulin sensitivity in adults with overweight and obesity with distinct effects on the gut microbiota, plasma metabolome and systemic inflammatory responses: a randomised cross-over trial, Gut, Vol: 68, Pages: 1430-1438, ISSN: 0017-5749
Objective: To investigate the underlying mechanisms behind changes in glucose homeostasis with delivery of propionate to the human colon by comprehensive and coordinated analysis of gut bacterial composition, plasma metabolome and immune responses.Design: Twelve non-diabetic adults with overweight and obesity received 20g/day of inulin-propionate ester (IPE), designed to selectively deliver propionate to the colon, a high-fermentable fibre control (inulin) and a low-fermentable fibre control (cellulose) in a randomised, double-blind, placebo controlled, crossover design. Outcome measurements of metabolic responses, inflammatory markers and gut bacterial composition were analysed at the end of each 42-day supplementation period.Results: Both IPE and inulin supplementation improved insulin resistance compared to cellulose supplementation, measured by homeostatic model assessment (HOMA) 2 (Mean±SEM 1.23±0.17 IPE vs. 1.59±0.17 cellulose, P=0.001; 1.17±0.15 inulin vs. 1.59±0.17 cellulose, P=0.009), with no differences between IPE and inulin (P=0.272). Fasting insulin was only associated positively with plasma tyrosine and negatively with plasma glycine following inulin supplementation. IPE supplementation decreased pro-inflammatory IL-8 levels compared to cellulose, whilst inulin had no impact on the systemic inflammatory markers studied. Inulin promoted changes in gut bacterial populations at the class level (increased Actinobacteria and decreased Clostridia) and order level (decreased Clostridales) compared to cellulose, with small differences at the species level observed between IPE and cellulose. Conclusion: These data demonstrate a distinctive physiological impact of raising colonic propionate delivery in humans, as improvements in insulin sensitivity promoted by IPE and inulin were accompanied with different effects on the plasma metabolome, gut bacterial populations and markers of systemic inflammation.
Sim M, Rajagopalan S, Altmann D, et al., 2019, Human NK cell receptor KIR2DS4 detects a conserved bacterial epitope presented by HLA-C, Proceedings of the National Academy of Sciences, ISSN: 0027-8424
Natural killer (NK) cells have an important role in immune defense against viruses and cancer. Activation of human NK cell cytotoxicity toward infected or tumor cells is regulated by killer cell immunoglobulin-like receptors (KIRs) that bind to human leukocyte antigen class I (HLA-I). Combinations of KIR with HLA-I are genetically associated with susceptibility to disease. KIR2DS4, an activating member of the KIR family with poorly defined ligands, is a receptor of unknown function. Here, we show that KIR2DS4 has a strong preference for rare peptides carrying a Trp at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. The complex of a peptide bound to HLA-C*05:01 with a Trp at p8 was sufficient for activation of primary KIR2DS4+ NK cells, independent of activation by other receptors and of prior NK cell licensing. HLA-C*05:01+ cells that expressed the peptide epitope triggered KIR2DS4+ NK cell degranulation. We show an inverse correlation of the worldwide allele frequency of functional KIR2DS4 with that of HLA-C*05:01, indicative of functional interaction and balancing selection. We found a highly conserved peptide sequence motif for HLA-C*05:01–restricted activation of human KIR2DS4+ NK cells in bacterial recombinase A (RecA). KIR2DS4+ NK cells were stimulated by RecA epitopes from multiple human pathogens, including Helicobacter, Chlamydia, Brucella, and Campylobacter. We predict that over 1,000 bacterial species could activate NK cells through KIR2DS4, and propose that human NK cells also contribute to immune defense against bacteria through recognition of a conserved RecA epitope presented by HLA-C*05:01.
Altmann DM, 2019, Knowns and unknowns of tissue-resident memory T cells, Immunology, Vol: 157, Pages: 1-2, ISSN: 0019-2805
Advances in transcriptomics and other approaches are shedding considerable light on tissue‐resident immune cells as distinct from recirculating cells. The advances encompass antigen‐presenting cell subsets, Tregs and importantly, tissue‐resident memory cells (TRM). What are the transcriptional programmes and functional properties that distinguish the requirements for an effective tissue resident cell in brain relative to lung, skin, adipose tissue or the genital tract? Another important conundrum has been the extent to which TRM cells are specialized either as a ‘sense and alarm’ population or as a local, primed, effector cell population in themselves. These are questions that challenge immunologists to stop thinking in terms of a generic, model, immune response and focus instead on events in the tissue in question.
Boyton R, Reynolds C, Chong D, et al., 2019, Bioluminescent reporting of in vivo interferon gamma immune responses during infection and autoimmunity, Journal of Immunology, Vol: 202, Pages: 2502-2510, ISSN: 1550-6606
IFN-γ is a key cytokine of innate and adaptive immunity. It is important to understand temporal changes in IFN-γ production and how these changes relate to the role of IFN-γ in diverse models of infectious and autoimmune disease, making the ability to monitor and track IFN-γ production in vivo of a substantial benefit. IFN-γ ELISPOTs have been a central methodology to measure T cell immunity for many years. In this study, we add the capacity to analyze IFN-γ responses with high sensitivity and specificity, longitudinally, in vitro and in vivo. This allows the refinement of experimental protocols because immunity can be tracked in real-time through a longitudinal approach. We have generated a novel murine IFN-γ reporter transgenic model that allows IFN-γ production to be visualized and quantified in vitro and in vivo as bioluminescence using an imaging system. At baseline, in the absence of an inflammatory stimulus, IFN-γ signal from lymphoid tissue is detectable in vivo. Reporter transgenics are used in this study to track the IFN-γ response to Pseudomonas aeruginosa infection in the lung over time in vivo. The longitudinal development of the adaptive T cell immunity following immunization with Ag is identified from day 7 in vivo. Finally, we show that we are able to use this reporter transgenic to follow the onset of autoimmune T cell activation after regulatory T cell depletion in an established model of systemic autoimmunity. This IFN-γ reporter transgenic, termed “Gammaglow,” offers a valuable new modality for tracking IFN-γ immunity, noninvasively and longitudinally over time.
Altmann DM, 2019, "Just 17 if you know what I mean' ... but what do we really mean to say about Th17 immunity?, IMMUNOLOGY, Vol: 156, Pages: 297-298, ISSN: 0019-2805
Altmann DM, 2019, The immune regulatory role of neutrophils, Immunology, Vol: 156, Pages: 215-216, ISSN: 0019-2805
Neutrophils are appreciated to perform a wide range of pro‐ and anti‐inflammatory effector functions in diverse settings. These go far beyond the response to acute infection, encompassing sterile injury, autoimmunity, allergy and tumours. There is growing appreciation of the nuances of their modes of action, especially elucidation of the nature and consequences of NETosis. New work suggests that it is time to give greater consideration to the anti‐inflammatory role of neutrophils, such as in the control of cytokine release during sepsis.
Altmann DM, 2019, Natural killer cell transcriptional control, subsets, receptors and effector function, IMMUNOLOGY, Vol: 156, Pages: 109-110, ISSN: 0019-2805
Altmann DM, 2018, T-cell immunology of the lung: maintaining the balance between host defence and immune pathology, IMMUNOLOGY, Vol: 156, Pages: 1-2, ISSN: 0019-2805
Altmann DM, 2018, Functions of adipose-resident immune subsets and the impact on metabolic syndrome, IMMUNOLOGY, Vol: 155, Pages: 405-406, ISSN: 0019-2805
Reynolds CJ, Quigley K, Cheng X, et al., 2018, Lung defense through interleukin-8 carries a cost of chronic lung remodeling and impaired function, American Journal of Respiratory Cell and Molecular Biology, Vol: 59, Pages: 557-571, ISSN: 1044-1549
RATIONALE: IL-8 dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases including COPD, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible pathologic, changes associated with elevated levels of IL-8 in the lung. OBJECTIVES: To better understand the duality of IL-8 dependent host immunity to bacterial infection and lung pathology, we targeted human IL-8 to express transgenically in murine bronchial epithelium, investigating the impact of over-expression on lung bacterial clearance, host immunity, lung pathology and function. MEASUREMENTS AND MAIN RESULTS: Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation, activation and chemtoaxis. There was enhanced protection from challenge with Pseudomonas aeruginosa and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL2 and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen, OprF, indicating a regulatory T cell phenotype. However, this enhanced bacterial immunity comes at the high price of progressive lung remodelling, with increased inflammation, mucus hyper-secretion, and fibrosis. There is increased expression of Ccl3 and reduced expressioh of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all resulting in impaired lung function with reduced compliance, increased resistance and bronchial hyperreactivity measured by whole body plethysmography. CONCLUSIONS: IL-8 over-expression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodelling and damaged tight junctions, leading to impaired lung function.
Altmann DM, 2018, A Nobel Prize-worthy pursuit: cancer immunology and harnessing immunity to tumour neoantigens, IMMUNOLOGY, Vol: 155, Pages: 283-284, ISSN: 0019-2805
Altmann DM, 2018, Regulatory T-cells: receptors, repertoires and roles in disease, IMMUNOLOGY, Vol: 155, Pages: 153-154, ISSN: 0019-2805
Altmann DM, 2018, Bioinformatics for immunologists, IMMUNOLOGY, Vol: 155, Pages: 1-2, ISSN: 0019-2805
Altmann DM, 2018, Establishing the new playbook for interactions among microbiota, bacterial metabolites, adaptive immunity, autoimmune disease and metabolic syndrome, IMMUNOLOGY, Vol: 154, Pages: 533-534, ISSN: 0019-2805
Altmann DM, 2018, New tools for MHC research from machine learning and predictive algorithms to the tumour immunopeptidome, IMMUNOLOGY, Vol: 154, Pages: 329-330, ISSN: 0019-2805
Altmann DM, Reynolds CJ, Boyton RJ, 2018, Immunology of the microbiome: Implications for rheumatoid arthritis and other autoimmune diseases, The Microbiome in Rheumatic Diseases and Infection, Pages: 55-62, ISBN: 9783319790251
Altmann DM, 2018, Neuroimmunology and neuroinflammation in autoimmune, neurodegenerative and psychiatric disease, IMMUNOLOGY, Vol: 154, Pages: 167-168, ISSN: 0019-2805
Altmann DM, 2018, Mapping innate and adaptive immune function in arbovirus infections, IMMUNOLOGY, Vol: 154, Pages: 1-2, ISSN: 0019-2805
Nithichanon A, Rinchai D, Buddhisa S, et al., 2018, Immune control of Burkholderia pseudomallei––common, high-frequency T-cell responses to a broad repertoire of immunoprevalent epitopes, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224
Burkholderia pseudomallei (Bp) is an environmental bacterial pathogen that causes potentially lethal sepsis in susceptible individuals and is considered a Category B, Tier-1 biothreat agent. As such, it is crucial to gain an improved understanding of protective immunity and potential vaccine candidates. The nature of immune correlates dictating why most exposed individuals in endemic regions undergo asymptomatic seroconversion while others succumb to life-threatening sepsis is largely uncharted. Bp seroreactive, immunogenic proteins have previously been identified by antigen microarray. We here set out to conduct an analysis of T-cell recognition of the Bp immunome using serodominant antigens represented in the original antigen microarray, examining immune correlates of disease in healthy seropositive individuals and those with acute disease or in convalescence. By screening a library of 739 overlapping peptides representing the sequences of 20 different Bp antigens, we aimed to define immune correlates of protection at the level of immunoprevalent T-cell epitopes. Responses to a large number of epitopes were common in healthy seropositive individuals: we found remarkably broad responsiveness to Bp epitopes, with 235 of 739 peptides recognized by ≥80% of all tested donors. The cumulative response to Bp epitopes in healthy, seropositive, donors from this endemic region were of the order of thousands of spot forming cells per million cells, making Bp recognition a significant component of the T-cell repertoire. Noteworthy among our findings, analysis revealed 10 highly immunoprevalent T-cell epitopes, able to induce Bp-specific IFNγ responses that were high in responding T-cell frequency within the repertoire, and also common across individuals with different human leukocyte antigen types. Acute melioidosis patients showed poor T-cell responses to the immunoprevalent epitopes, but acquired responsiveness following recovery from infection. Our findings suggest
Altmann D, 2018, Don't let peer review panels for grant awards turn into a wolf pack., Nature, Vol: 555, Pages: 311-311
Reynolds CJ, Suleyman OM, Ortega-Prieto AM, et al., 2018, T cell immunity to Zika virus targets immunodominant epitopes that show cross-reactivity with other Flaviviruses, Scientific Reports, Vol: 8, ISSN: 2045-2322
Zika virus (ZIKV) Infection has several outcomes from asymptomatic exposure to rash, conjunctivitis, Guillain-Barré syndrome or congenital Zika syndrome. Analysis of ZIKV immunity is confounded by the fact that several related Flaviviruses infect humans, including Dengue virus 1–4, West Nile virus and Yellow Fever virus. HLA class II restricted T cell cross-reactivity between ZIKV and other Flaviviruses infection(s) or vaccination may contribute to protection or to enhanced immunopathology. We mapped immunodominant, HLA class II restricted, CD4 epitopes from ZIKV Envelope (Env), and Non-structural (NS) NS1, NS3 and NS5 antigens in HLA class II transgenic mice. In several cases, ZIKV primed CD4 cells responded to homologous sequences from other viruses, including DENV1–4, WNV or YFV. However, cross-reactive responses could confer immune deviation - the response to the Env DENV4 p1 epitope in HLA-DR1 resulted in IL-17A immunity, often associated with exacerbated immunopathogenesis. This conservation of recognition across Flaviviruses, may encompass protective and/or pathogenic components and poses challenges to characterization of ZIKV protective immunity.
Dunachie SJ, Jenjaroen K, Reynolds CJ, et al., 2017, Infection with Burkholderia pseudomallei - immune correlates of survival in acute melioidosis, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322
Melioidosis, caused by Burkholderia pseudomallei, is a potentially lethal infection with no licensed vaccine. There is little understanding of why some exposed individuals have no symptoms, while others rapidly progress to sepsis and death, or why diabetes confers increased susceptibility. We prospectively recruited a cohort of 183 acute melioidosis patients and 21 control subjects from Northeast Thailand and studied immune parameters in the context of survival status and the presence or absence of diabetes. HLA-B*46 (one of the commonest HLA class I alleles in SE Asia) and HLA-C*01 were associated with an increased risk of death (odds ratio 2.8 and 3.1 respectively). Transcriptomic analysis during acute infection in diabetics indicated the importance of interplay between immune pathways including those involved in antigen presentation, chemotaxis, innate and adaptive immunity and their regulation. Survival was associated with enhanced T cell immunity to nine of fifteen immunodominant antigens analysed including AhpC (BPSL2096), BopE (BPSS1525), PilO (BPSS1599), ATP binding protein (BPSS1385) and an uncharacterised protein (BPSL2520). T cell immunity to GroEL (BPSL2697) was specifically impaired in diabetic individuals. This characterization of immunity associated with survival during acute infection offers insights into correlates of protection and a foundation for design of an effective multivalent vaccine.
Lima Keesen TS, de Almeida RP, Gois BM, et al., 2017, Guillain-Barre syndrome and arboviral infection in Brazil, Lancet Infectious Diseases, Vol: 17, Pages: 693-694, ISSN: 1473-3099
Sim MJW, Malaker SA, Khan A, et al., 2017, Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C, Immunology Meeting, Publisher: AMER ASSOC IMMUNOLOGISTS, ISSN: 0022-1767
SIM M, Malaker S, Khan A, et al., 2017, Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C, Frontiers in Immunology, Vol: 8, ISSN: 1664-3224
Background.Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys80). KIR2DL2 and KIR2DL 3 bind HLA-C alleles of group C1 (Asn80). However, this model cannot explain HLA-C allelic effects in disease or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes.Results.The impact of HLA-C bound peptide on inhibit ory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2, C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL 2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL 2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides or HIV Gag peptides by HLA-C can promote KIR cross-reactive binding.Conclusions.KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1binding to C2, providing an explanation for KIR2DL3–C1 interactions appearing weaker than KIR2DL1–C2. In addition, cros
Boelen LP, O'Neill PK, Quigley KJ, et al., 2016, BIITE: A Tool to Determine HLA Class II Epitopes from T Cell ELISpot Data, PLOS Computational Biology, Vol: 12, ISSN: 1553-734X
Activation of CD4+ T cells requires the recognition of peptides that are presented by HLA class II molecules and can be assessed experimentally using the ELISpot assay. However, even given an individual’s HLA class II genotype, identifying which class II molecule is responsible for a positive ELISpot response to a given peptide is not trivial. The two main difficulties are the number of HLA class II molecules that can potentially be formed in a single individual (3–14) and the lack of clear peptide binding motifs for class II molecules. Here, we present a Bayesian framework to interpret ELISpot data (BIITE: Bayesian Immunogenicity Inference Tool for ELISpot); specifically BIITE identifies which HLA-II:peptide combination(s) are immunogenic based on cohort ELISpot data. We apply BIITE to two ELISpot datasets and explore the expected performance using simulations. We show this method can reach high accuracies, depending on the cohort size and the success rate of the ELISpot assay within the cohort.
Boyton RJ, Altmann D, 2016, Bronchiectasis: Current Concepts in Pathogenesis, Immunology, and Microbiology, Annual Review of Pathology-Mechanisms of Disease, Vol: 11, Pages: 523-554, ISSN: 1553-4014
Bronchiectasis is a disorder of persistent lung inflammation and recurrent infection, defined by a common pathological end point: irreversible bronchial dilatation arrived at through diverse etiologies. This suggests an interplay between immunogenetic susceptibility, immune dysregulation, bacterial infection, and lung damage. The damaged epithelium impairs mucus removal and facilitates bacterial infection with increased cough, sputum production, and airflow obstruction. Lung infection is caused by respiratory bacterial and fungal pathogens, including Pseudomonas aeruginosa, Haemophilus, Aspergillus fumigatus, and nontuberculous mycobacteria. Recent studies have highlighted the relationship between the lung microbiota and microbial-pathogen niches. Disease may result from environments favoring interleukin-17-driven neutrophilia. Bronchiectasis may present in autoimmune disease, as well as conditions of immune dysregulation, such as combined variable immune deficiency, transporter associated with antigen processing–deficiency syndrome, and hyperimmunoglobulin E syndrome. Differences in prevalence across geography and ethnicity implicate an etiological mix of genetics and environment underpinning susceptibility.
Ascough S, Ingram RJ, Chu KK, et al., 2016, CD4+ T Cells Targeting Dominant and Cryptic Epitopes from Bacillus anthracis Lethal Factor., Frontiers in Microbiology, Vol: 6, ISSN: 1664-302X
Anthrax is an endemic infection in many countries, particularly in the developing world. The causative agent, Bacillus anthracis, mediates disease through the secretion of binary exotoxins. Until recently, research into adaptive immunity targeting this bacterial pathogen has largely focused on the humoral response to these toxins. There is, however, growing recognition that cellular immune responses involving IFNγ producing CD4+ T cells also contribute significantly to a protective memory response. An established concept in adaptive immunity to infection is that during infection of host cells, new microbial epitopes may be revealed, leading to immune recognition of so called 'cryptic' or 'subdominant' epitopes. We analyzed the response to both cryptic and immunodominant T cell epitopes derived from the toxin component lethal factor and presented by a range of HLA-DR alleles. Using IFNγ-ELISpot assays we characterized epitopes that elicited a response following immunization with synthetic peptide and the whole protein and tested their capacities to bind purified HLA-DR molecules in vitro. We found that DR1 transgenics demonstrated T cell responses to a greater number of domain III cryptic epitopes than other HLA-DR transgenics, and that this pattern was repeated with the immunodominant epitopes, as a greater proportion of these epitopes induced a T cell response when presented within the context of the whole protein. Immunodominant epitopes LF457-476 and LF467-487 were found to induce a T cell response to the peptide, as well as to the whole native LF protein in DR1 and DR15, but not in DR4 transgenics. The analysis of Domain I revealed the presence of several unique cryptic epitopes all of which showed a strong to moderate relative binding affinity to HLA-DR4 molecules. However, none of the cryptic epitopes from either domain III or I displayed notably high binding affinities across all HLA-DR alleles assayed. These responses were influenced by the speci
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.