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1.
HLA ; 100(1): 52-58, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1816658

ABSTRACT

The effects of COVID-19 vaccination on alloimmunization and clinical impact in transplant candidates remain largely unknown. In a 61-year-old man who had no donor-specific antibodies (DSA) and was planned to undergo ABO-incompatible kidney transplantation (ABOi KT), DSAs (anti-A24, anti-B51, and anti-Cw14) developed after COVID-19 vaccination. After desensitization therapy, antibody level was further increased, leading to flow cytometric crossmatch-positive status. Donor-specific T cell immunity using interferon-gamma ELISPOT was continuously negative, whereas SARS-CoV-2 specific T cell immunity was intact. After confirming the C1q-negative status of DSA, the patient received ABOi KT. The patient had stable graft function and suppressed alloimmunity up to 2 months after KT. COVID-19 vaccination might relate to alloimmunization in transplant candidates, and desensitization through immune monitoring can help guide transplantation.


Subject(s)
COVID-19 , Kidney Transplantation , Alleles , Antibodies , COVID-19 Vaccines , Flow Cytometry , Graft Rejection , Graft Survival , HLA Antigens , Humans , Living Donors , Male , Middle Aged , SARS-CoV-2 , Vaccination
2.
Elife ; 102021 08 05.
Article in English | MEDLINE | ID: covidwho-1513039

ABSTRACT

For an emerging disease like COVID-19, systems immunology tools may quickly identify and quantitatively characterize cells associated with disease progression or clinical response. With repeated sampling, immune monitoring creates a real-time portrait of the cells reacting to a novel virus before disease-specific knowledge and tools are established. However, single cell analysis tools can struggle to reveal rare cells that are under 0.1% of the population. Here, the machine learning workflow Tracking Responders EXpanding (T-REX) was created to identify changes in both rare and common cells across human immune monitoring settings. T-REX identified cells with highly similar phenotypes that localized to hotspots of significant change during rhinovirus and SARS-CoV-2 infections. Specialized MHCII tetramer reagents that mark rhinovirus-specific CD4+ cells were left out during analysis and then used to test whether T-REX identified biologically significant cells. T-REX identified rhinovirus-specific CD4+ T cells based on phenotypically homogeneous cells expanding by ≥95% following infection. T-REX successfully identified hotspots of virus-specific T cells by comparing infection (day 7) to either pre-infection (day 0) or post-infection (day 28) samples. Plotting the direction and degree of change for each individual donor provided a useful summary view and revealed patterns of immune system behavior across immune monitoring settings. For example, the magnitude and direction of change in some COVID-19 patients was comparable to blast crisis acute myeloid leukemia patients undergoing a complete response to chemotherapy. Other COVID-19 patients instead displayed an immune trajectory like that seen in rhinovirus infection or checkpoint inhibitor therapy for melanoma. The T-REX algorithm thus rapidly identifies and characterizes mechanistically significant cells and places emerging diseases into a systems immunology context for comparison to well-studied immune changes.


Subject(s)
COVID-19/immunology , Leukemia, Myeloid, Acute/immunology , Melanoma/immunology , Picornaviridae Infections/immunology , Unsupervised Machine Learning , Adolescent , Adult , Algorithms , CD4-Positive T-Lymphocytes/immunology , Humans , Leukemia, Myeloid, Acute/drug therapy , Melanoma/drug therapy , Neoplasms , Rhinovirus/isolation & purification , SARS-CoV-2/isolation & purification , Young Adult
3.
Front Immunol ; 12: 635942, 2021.
Article in English | MEDLINE | ID: covidwho-1389176

ABSTRACT

SARS-CoV-2 infection takes a mild or clinically inapparent course in the majority of humans who contract this virus. After such individuals have cleared the virus, only the detection of SARS-CoV-2-specific immunological memory can reveal the exposure, and hopefully the establishment of immune protection. With most viral infections, the presence of specific serum antibodies has provided a reliable biomarker for the exposure to the virus of interest. SARS-CoV-2 infection, however, does not reliably induce a durable antibody response, especially in sub-clinically infected individuals. Consequently, it is plausible for a recently infected individual to yield a false negative result within only a few months after exposure. Immunodiagnostic attention has therefore shifted to studies of specific T cell memory to SARS-CoV-2. Most reports published so far agree that a T cell response is engaged during SARS-CoV-2 infection, but they also state that in 20-81% of SARS-CoV-2-unexposed individuals, T cells respond to SARS-CoV-2 antigens (mega peptide pools), allegedly due to T cell cross-reactivity with Common Cold coronaviruses (CCC), or other antigens. Here we show that, by introducing irrelevant mega peptide pools as negative controls to account for chance cross-reactivity, and by establishing the antigen dose-response characteristic of the T cells, one can clearly discern between cognate T cell memory induced by SARS-CoV-2 infection vs. cross-reactive T cell responses in individuals who have not been infected with SARS-CoV-2.


Subject(s)
COVID-19/immunology , COVID-19/virology , Host-Pathogen Interactions/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Antigens, Viral/immunology , Biomarkers , COVID-19/metabolism , Cross Reactions/immunology , Cytokines/metabolism , Epitopes, T-Lymphocyte/immunology , Humans , Immunodominant Epitopes/immunology , Immunologic Memory , Peptides/immunology , Protein Binding , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/metabolism
4.
Cells ; 10(8)2021 07 21.
Article in English | MEDLINE | ID: covidwho-1325606

ABSTRACT

Assessment of humoral immunity to SARS-CoV-2 and other infectious agents is typically restricted to detecting antigen-specific antibodies in the serum. Rarely does immune monitoring entail assessment of the memory B-cell compartment itself, although it is these cells that engage in secondary antibody responses capable of mediating immune protection when pre-existing antibodies fail to prevent re-infection. There are few techniques that are capable of detecting rare antigen-specific B cells while also providing information regarding their relative abundance, class/subclass usage and functional affinity. In theory, the ELISPOT/FluoroSpot (collectively ImmunoSpot) assay platform is ideally suited for antigen-specific B-cell assessments since it provides this information at single-cell resolution for individual antibody-secreting cells (ASC). Here, we tested the hypothesis that antigen-coating efficiency could be universally improved across a diverse set of viral antigens if the standard direct (non-specific, low affinity) antigen absorption to the membrane was substituted by high-affinity capture. Specifically, we report an enhancement in assay sensitivity and a reduction in required protein concentrations through the capture of recombinant proteins via their encoded hexahistidine (6XHis) affinity tag. Affinity tag antigen coating enabled detection of SARS-CoV-2 Spike receptor binding domain (RBD)-reactive ASC, and also significantly improved assay performance using additional control antigens. Collectively, establishment of a universal antigen-coating approach streamlines characterization of the memory B-cell compartment after SARS-CoV-2 infection or COVID-19 vaccinations, and facilitates high-throughput immune-monitoring efforts of large donor cohorts in general.


Subject(s)
Antigens, Viral/analysis , B-Lymphocytes/immunology , Enzyme-Linked Immunospot Assay/methods , Immunologic Memory , SARS-CoV-2/immunology , Viral Proteins/immunology , Animals , COVID-19 , Histidine , Humans , Mice , Oligopeptides , SARS-CoV-2/metabolism
5.
J Immunol Methods ; 492: 112994, 2021 05.
Article in English | MEDLINE | ID: covidwho-1099182

ABSTRACT

The annual meeting of the Association of Medical Laboratory Immunologists (AMLI) was convened virtually over the month of August. Prior to the emergence of the COVID-19 pandemic, AMLI's scientific committee had chosen the following topics as the focus of its 2020 meeting: Histocompatibility Testing and Transplant Immunology; Secondary Immunodeficiency and Immunotherapy Monitoring; ANA Update; and Emerging Infectious Diseases and New Algorithms for Testing. Given the central role of the discipline in the evaluation of the host response to infection, it was apt to add a separate session on antibody testing for SARS-CoV-2 infections to the original program. The current report provides an overview of the subjects discussed in the course of this meeting.


Subject(s)
Allergy and Immunology , COVID-19/immunology , Immunotherapy/methods , SARS-CoV-2/physiology , Societies, Medical , Algorithms , Animals , Group Processes , Histocompatibility Testing , Host-Pathogen Interactions , Humans , Laboratories , Pandemics , SARS-CoV-2/chemistry , Transplantation Immunology , Virtual Reality
6.
Cytometry A ; 99(1): 11-18, 2021 01.
Article in English | MEDLINE | ID: covidwho-1086332

ABSTRACT

Cytometry is playing a crucial role in addressing the COVID-19 pandemic. In this commentary-written by a variety of stakeholders in the cytometry, immunology, and infectious disease communities-we review cytometry's role in the COVID-19 response and discuss workflow issues critical to planning and executing effective research in this emerging field. We discuss sample procurement and processing, biosafety, technology options, data sharing, and the translation of research findings into clinical environments. © 2020 International Society for Advancement of Cytometry.


Subject(s)
COVID-19/prevention & control , Containment of Biohazards/trends , Flow Cytometry/trends , SARS-CoV-2/isolation & purification , Translational Research, Biomedical/trends , Biomedical Research/methods , Biomedical Research/trends , COVID-19/epidemiology , Containment of Biohazards/methods , Flow Cytometry/methods , Humans , Information Dissemination/methods , Translational Research, Biomedical/methods
7.
Cells ; 10(2)2021 01 27.
Article in English | MEDLINE | ID: covidwho-1055022

ABSTRACT

Monitoring antigen-specific T cell immunity relies on functional tests that require T cells and antigen presenting cells to be uncompromised. Drawing of blood, its storage and shipment from the clinical site to the test laboratory, and the subsequent isolation, cryopreservation and thawing of peripheral blood mononuclear cells (PBMCs) before the actual test is performed can introduce numerous variables that may jeopardize the results. Therefore, no T cell test is valid without assessing the functional fitness of the PBMC being utilized. This can only be accomplished through the inclusion of positive controls that actually evaluate the performance of the antigen-specific T cell and antigen presenting cell (APC) compartments. For Caucasians, CEF peptides have been commonly used to this extent. Moreover, CEF peptides only measure CD8 cell functionality. We introduce here universal CD8+ T cell positive controls without any racial bias, as well as positive controls for the CD4+ T cell and APC compartments. In summary, we offer new tools and strategies for the assessment of PBMC functional fitness required for reliable T cell immune monitoring.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Leukocytes, Mononuclear/immunology , Antigen-Presenting Cells/immunology , Antigens/immunology , Humans , Immunologic Tests/methods , Peptides/immunology
8.
Cytometry B Clin Cytom ; 100(1): 33-41, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1006421

ABSTRACT

Over a remarkably short period of time, a great deal of knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection has been acquired, through the focused and cooperative effort of the international scientific community. Much has become known about how the immune response is coordinated to fight infection, and how it becomes dysregulated in severe disease. In this review, we take an in-depth look at the many immune features associated with the host response to SARS-CoV2, as well as those that appear to mark severe disease.


Subject(s)
COVID-19/diagnostic imaging , COVID-19/immunology , Flow Cytometry/methods , Fluorescent Antibody Technique/methods , SARS-CoV-2/immunology , Biomarkers/analysis , COVID-19/pathology , COVID-19/therapy , Chemokines/analysis , Chemokines/metabolism , Cytokines/analysis , Cytokines/metabolism , Fluorescent Antibody Technique/trends , Host-Pathogen Interactions/immunology , Humans , Immunity/physiology , Metabolomics/methods , Metabolomics/trends , Risk Assessment , Severity of Illness Index
9.
Semin Immunol ; 50: 101428, 2020 08.
Article in English | MEDLINE | ID: covidwho-947460

ABSTRACT

The vaccine field is pursuing diverse approaches to translate the molecular insights from analyses of effective antibodies and their targeted epitopes into immunogens capable of eliciting protective immune responses. Here we review current antibody-guided strategies including conformation-based, epitope-based, and lineage-based vaccine approaches, which are yielding promising vaccine candidates now being evaluated in clinical trials. We summarize directions being employed by the field, including the use of sequencing technologies to monitor and track developing immune responses for understanding and improving antibody-based immunity. We review opportunities and challenges to transform powerful new discoveries into safe and effective vaccines, which are encapsulated by vaccine efforts against a variety of pathogens including HIV-1, influenza A virus, malaria parasites, respiratory syncytial virus, and SARS-CoV-2. Overall, this review summarizes the extensive progress that has been made to realize antibody-guided structure-based vaccines, the considerable challenges faced, and the opportunities afforded by recently developed molecular approaches to vaccine development.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Vaccinology/methods , COVID-19 Vaccines/therapeutic use , Humans , Primary Prevention/methods , SARS-CoV-2/immunology
10.
bioRxiv ; 2020 Nov 04.
Article in English | MEDLINE | ID: covidwho-900745

ABSTRACT

For an emerging disease like COVID-19, systems immunology tools may quickly identify and quantitatively characterize cells associated with disease progression or clinical response. With repeated sampling, immune monitoring creates a real-time portrait of the cells reacting to a novel virus before disease specific knowledge and tools are established. However, single cell analysis tools can struggle to reveal rare cells that are under 0.1% of the population. Here, the machine learning workflow Tracking Responders Expanding (T-REX) was created to identify changes in both very rare and common cells in diverse human immune monitoring settings. T-REX identified cells that were highly similar in phenotype and localized to hotspots of significant change during rhinovirus and SARS-CoV-2 infections. Specialized reagents used to detect the rhinovirus-specific CD4+ cells, MHCII tetramers, were not used during unsupervised analysis and instead 'left out' to serve as a test of whether T-REX identified biologically significant cells. In the rhinovirus challenge study, T-REX identified virus-specific CD4+ T cells based on these cells being a distinct phenotype that expanded by ≥95% following infection. T-REX successfully identified hotspots containing virus-specific T cells using pairs of samples comparing Day 7 of infection to samples taken either prior to infection (Day 0) or after clearing the infection (Day 28). Mapping pairwise comparisons in samples according to both the direction and degree of change provided a framework to compare systems level immune changes during infectious disease or therapy response. This revealed that the magnitude and direction of systemic immune change in some COVID-19 patients was comparable to that of blast crisis acute myeloid leukemia patients undergoing induction chemotherapy and characterized the identity of the immune cells that changed the most. Other COVID-19 patients instead matched an immune trajectory like that of individuals with rhinovirus infection or melanoma patients receiving checkpoint inhibitor therapy. T-REX analysis of paired blood samples provides an approach to rapidly identify and characterize mechanistically significant cells and to place emerging diseases into a systems immunology context.

11.
J Reprod Immunol ; 143: 103243, 2021 02.
Article in English | MEDLINE | ID: covidwho-894079

ABSTRACT

A primigravid woman with Covid-19 related respiratory insufficiency was admitted into a tertiary Intensive Care Unit at 23 3/7 weeks' gestation. Highly sensitive flow cytometry of peripheral leukocytes indicated significantly suppressed naïve T- and B-cell compartments. The suppressed immune cell responses led us keep the initially started administration of corticosteroids for fetal and maternal indication at a low dose. After three weeks her B-cell response peaked, SARS-CoV-2 was cleared and clinical improvement ensued a week later. At 28 weeks' gestation, a son of 1570 g was born by cesarean section. She was extubated two days postpartum and discharged from hospital 5.5 weeks postpartum.


Subject(s)
B-Lymphocytes/immunology , COVID-19/diagnosis , Pregnancy Complications, Infectious/diagnosis , Pregnancy/immunology , Respiratory Insufficiency/diagnosis , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Adult , COVID-19/immunology , Cesarean Section , Critical Care , Female , Flow Cytometry , Gravidity , Humans
12.
Cancer Immunol Immunother ; 70(4): 1127-1142, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-841222

ABSTRACT

Cytokine storm can result from cancer immunotherapy or certain infections, including COVID-19. Though short-term immune-related adverse events are routinely described, longer-term immune consequences and sequential immune monitoring are not as well defined. In 2006, six healthy volunteers received TGN1412, a CD28 superagonist antibody, in a first-in-man clinical trial and suffered from cytokine storm. After the initial cytokine release, antibody effect-specific immune monitoring started on Day + 10 and consisted mainly of evaluation of dendritic cell and T-cell subsets and 15 serum cytokines at 21 time-points over 2 years. All patients developed problems with concentration and memory; three patients were diagnosed with mild-to-moderate depression. Mild neutropenia and autoantibody production was observed intermittently. One patient suffered from peripheral dry gangrene, required amputations, and had persistent Raynaud's phenomenon. Gastrointestinal irritability was noted in three patients and coincided with elevated γδT-cells. One had pruritus associated with elevated IgE levels, also found in three other asymptomatic patients. Dendritic cells, initially undetectable, rose to normal within a month. Naïve CD8+ T-cells were maintained at high levels, whereas naïve CD4+ and memory CD4+ and CD8+ T-cells started high but declined over 2 years. T-regulatory cells cycled circannually and were normal in number. Cytokine dysregulation was especially noted in one patient with systemic symptoms. Over a 2-year follow-up, cognitive deficits were observed in all patients following TGN1412 infusion. Some also had signs or symptoms of psychological, mucosal or immune dysregulation. These observations may discern immunopathology, treatment targets, and long-term monitoring strategies for other patients undergoing immunotherapy or with cytokine storm.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , CD28 Antigens/agonists , COVID-19/immunology , Cognitive Dysfunction/immunology , Cytokine Release Syndrome/immunology , Drug-Related Side Effects and Adverse Reactions/immunology , Immunotherapy/adverse effects , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Adult , Antibodies, Monoclonal, Humanized/pharmacology , Cognitive Dysfunction/etiology , Cohort Studies , Cytokine Release Syndrome/etiology , Follow-Up Studies , Humans , Male , Young Adult
13.
Int Immunopharmacol ; 89(Pt A): 107034, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-796273

ABSTRACT

BACKGROUND: COVID-19 is threating human health worldwide. We aim to investigate the dynamic changes of immune status in COVID-19 patients with clinical evolution. METHODS: Sixty-one COVID-19 patients (42 mild cases and 19 severe cases, 51 cases without secondary infection as non-infection group and 10 cases with secondary bacterial/fungal infection as infection group) and 52 healthy controls (HCs) were enrolled from our hospital. Leucocyte classification, lymphocyte subsets and cytokines were detected by full-automatic blood cell analyzer and flow cytometer, respectively. RESULTS: Upon admission, eosinophils and lymphocyte subsets decreased significantly, while neutrophils, monocytes, basophils, IL-2, IL-6, IL-10 and IFN-γ increased significantly in COVID-19 patients compared to HCs. CD3+ T and DN (CD3+CD4-CD8-) cells appeared sustained decline, leucocytes, neutrophils and IL-10 showed sustained increase in severe group compared to mild group. Compared with the non-infection group, we observed a depletion of eosinophils, CD3+ T and CD4+ T cells, but leucocytes, neutrophils, IL-6 and IL-10 on the contrary in the infection group. Besides, in severe group of COVID-19 patients, DN cells were negatively correlated with IL-10, and DP (CD3+CD4+CD8+) cells were negatively correlated with IL-6. Lymphocytes, eosinophils, CD3+ T cells, CD4+ T cells, IL-6 and IL-10 all had great diagnostic efficacy (AUC, 0.905-0.975) for COVID-19. The laboratory indicators of COVID-19 patients with improved condition also showed a recovery trend with time. CONCLUSIONS: The immune status of COVID-19 patients is different in each stage, and dynamic monitoring of related indicators can help predict the disease and may avoid cytokine storms.


Subject(s)
COVID-19/immunology , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , Cytokines/analysis , Female , Humans , Lymphocyte Subsets/immunology , Male , Middle Aged
14.
J Transl Med ; 18(1): 291, 2020 07 31.
Article in English | MEDLINE | ID: covidwho-691020

ABSTRACT

BACKGROUND: Covid-19 morbidity and mortality are associated with a dysregulated immune response. Tools are needed to enhance existing immune profiling capabilities in affected patients. Here we aimed to develop an approach to support the design of targeted blood transcriptome panels for profiling the immune response to SARS-CoV-2 infection. METHODS: We designed a pool of candidates based on a pre-existing and well-characterized repertoire of blood transcriptional modules. Available Covid-19 blood transcriptome data was also used to guide this process. Further selection steps relied on expert curation. Additionally, we developed several custom web applications to support the evaluation of candidates. RESULTS: As a proof of principle, we designed three targeted blood transcript panels, each with a different translational connotation: immunological relevance, therapeutic development relevance and SARS biology relevance. CONCLUSION: Altogether the work presented here may contribute to the future expansion of immune profiling capabilities via targeted profiling of blood transcript abundance in Covid-19 patients.


Subject(s)
Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Transcriptome , Adult , Antibodies, Viral/blood , Betacoronavirus , COVID-19 , Coronavirus Infections/immunology , Gene Expression Profiling , Humans , Immune System , Internet , Pandemics , Pneumonia, Viral/immunology , RNA-Seq , SARS-CoV-2 , Software
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