MAY 12, 2020 8:00 AM PDT

Deep phenotyping of Tregs in health and disease - lessons from Bone Marrow Failure Syndromes

Speaker
  • Senior Lecturer in Cancer Immunopathology King's College London
    Biography
      Following graduation from medical school and clinical training in Internal Medicine/ Haematology, Dr Kordasti received his MSc in Medical Immunology and PhD in Cancer Immunology from King's College London. He established the role of Tregs in Myelodysplastic Syndrome (MDS) and their effects on disease progression and response to treatment. He continued his work at King's College London and developed an interest in the immunobiology of aplastic anaemia (AA) during this time. He has been senior lecturer at King's College London and senior physician at Guy's Hospital since May 2018 and continues to study the immunobiology of Myeloid Malignancies and Neoplasms. His main research interest is the plasticity of CD4+ T cells, their interaction with inflammatory microenvironment and their role in the immunobiology of myeloid malignancies. Computational biology, multidimensional cytometry as well as multiomics data integration for patient stratification is another focus of his research group. His clinical interests are AA, MDS and MPN.

    Abstract

    DATE: May 12, 2020

    TIME:  8:00am PT

     

    Idiopathic aplastic anemia (AA) has two key characteristics: an autoimmune response against hematopoietic stem/progenitor cells and regulatory T cells (Tregs) deficiency. Using Mass Cytometry (CyTOF) and multidimensional data analysis, we have previously demonstrated reduction in a specific subpopulation of Treg in AA, which predict response to immunosuppression. We have identified two mechanisms that lead to skewed Treg composition in AA.  Firstly, FasL mediated apoptosis on ligand interaction and, secondly, relative IL-2 deprivation. We have shown that IL-2 augmentation can overcome these mechanisms. Interestingly, when high concentrations of IL-2 were used for in vitro Treg expansion cultures, AA Tregs were able to expand. The expanded populations expressed high level of p-BCL-2, which makes them resistant to apoptosis. Using a xenograft mouse model, the function and stability of expanded AA Tregs were tested. We have shown that these Tregs were able to suppress the macroscopic clinical features and tissue manifestations of T cell-mediated graft-versus-host disease. These Tregs maintained their suppressive properties as well as their phenotype in a highly inflammatory environment. Our findings provide an insight into the mechanisms of Treg reduction in AA. We have identified novel targets with potential for therapeutic interventions.  This work highlights the importance of systems immunology and “big data” in clinical translational research and how it may lead to novel therapeutic approaches.  

     

    Learning Objectives:

    • Describe the importance of OMICs data and systems immunology in clinical practice (Bone marrow failure as an example)
    • Decide how can we better define Tregs in human
    • Discuss the clinical importance of novel subpopulations of Tregs in bone marrow failure

     

     

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