NextGen 2024: Bone Marrow Transplantation (BMT) Session Part 3

    NextGen 2024: Bone Marrow Transplantation (BMT) Session Part 3

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    @SJIA_Foundation
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    7 months ago 318

    AIAI Summary

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    Key Insights

    Immune Reconstitution 
after Bone Marrow 
Transplant
NextGen Therapies in SJIA, Still’s & MAS Conference
November 14, 2024
Jim Connelly, MD
Vanderbilt University Medical Center
    1/10
    Immune 
Recovery 
after BMT
Stern et al. Frontiers in Immunology 2018; 9:1672
    2/10
    Measures of Immune Reconstitution (IR)
• Immune cell phenotyping
o Focus in BMT has been on T (transplanter) cells and mostly on CD4+ recovery
o Advantages: Basic flow cytometry available at most centers; sorted cells can be 
used to evaluate split chimerism
o Disadvantages: Limited ability to look at early (<D+30) IR; Advanced phenotyping 
(high dimensional flow cytometry, mass cytometry) expensive and less available; 
Quantitative recovery does not always equal functional reconstitution
• Immune cell function
o Advantages: Can evaluate memory response to specific antigens for decisions 
on viral monitoring/prophylaxis
o Disadvantages: Less available at many centers; Response depends on exposure 
to antigen of interest
    3/10
    Measures of Immune Reconstitution (IR)
•Transcriptome (gene expression through RNA analysis)
o Advantages: Provides large amount of gene expression data at the 
single cell level; identify donor versus recipient at the single cell level
o Disadvantages: Expensive (difficult to do across multiple time points); 
Not all inflammation is bad
•Secretome (cytokines, chemokines)
o Advantages: Inexpensive; Can be conducted before cellular recovery 
(<D+30); Certain cytokines/chemokines may be valuable for identifying 
primary disease activity
o Disadvantages: Not all cytokines/chemokine measurements are 
sensitive (IL1); Certain cytokines/chemokines may be applicable to only 
particular diseases (IL18, CXCL9)
    4/10
    Measures of Immune Reconstitution (IR)
• Chimerism (donor versus recipient)
o Advantages: Predictive of relapse in malignancy and disease remission in 
some non-malignant disorders
o Disadvantages: May not be as predictive of disease remission in immune 
dysregulatory disorders; Usually limited to myeloid (CD33) and T (CD3) cells
• Limitations on studies to date: 
o Almost all analyses have been done on recipient peripheral blood with focus 
on T-(transplanter)-cell
o Static analyses for dynamic recovery
o Inability to measure donor versus recipient IR via non-genetic means
o Studies conducted on large cohorts with variable disease and transplant 
approaches
o Large IR variability complicates analysis in rare diseases with small patient 
numbers
    5/10
    Importance of T-cell (CD4+), 
B-cell Recovery
Non-Relapse Mortality (NRM) and chronic (c)GVHD based on 
CD4+ T-cell (>57 cells/µL), B-cell (>35 cells/µL) Recovery at D+100
Troullioud Lucas et al. Cytotherapy 2023;
    6/10
    Immune Recovery in JIA
Early IR (D+0-D+100): Antigen driven and 
homeostatic proliferation
Late IR (D+100-D+365): Homeostatic proliferation 
(off IST) and thymic production
T-cell Recovery after Pediatric BMT 
Segregated by Conditioning Serotherapy
Lymphocyte Recovery 
after BMT for JIA 
Willemsen et al. BBMT 2015; 21:473-482 Silva et al. Blood Advances 2018; 2:7
    7/10
    Impact of Chimerism on BMT Outcomes in 
JIA
Silva et al. Blood Advances 2018; 2:7
    8/10
    Macrophage (rheuMatologist) Cell
Murine Alveolar Macrophage (AM) Recovery after 
Congenic BMT with Different Conditioning Regimens
Hubbard et al. ExpLungRes 2008; 34(5):263-275
    9/10
    Summary of BMT and JIA BMT IR
• Multiple ways to evaluate immune recovery and reconstitution 
and combining modalities can maximize success and minimize 
deficiencies of each strategy
• For rare diseases, it is imperative to harmonize IR evaluation
post-BMT amongst a variable patient population to assess therapeutic 
efficacy
• Poor outcomes in patients with JIA post-BMT are highlighted by 
significant infectious disease, macrophage activation syndrome, and 
relapsed disease, all potential consequences of poor IR
• For JIA BMT we need to develop novel ways to look at IR given that 
current methods (peripheral blood, chimerism, flow cytometry) are 
inadequate
o Evaluation should focus on innate activity (secretome, 
monocyte/macrophage*), regulatory and effector T cells, thymic function, B 
cells and plasma cells*, and impact of donor HLA-haplotype and phenotype on 
outcomes *Higher resistance to conditioning therapy
    10/10

    NextGen 2024: Bone Marrow Transplantation (BMT) Session Part 3

    • 1. Immune Reconstitution after Bone Marrow Transplant NextGen Therapies in SJIA, Still’s & MAS Conference November 14, 2024 Jim Connelly, MD Vanderbilt University Medical Center
    • 2. Immune Recovery after BMT Stern et al. Frontiers in Immunology 2018; 9:1672
    • 3. Measures of Immune Reconstitution (IR) • Immune cell phenotyping o Focus in BMT has been on T (transplanter) cells and mostly on CD4+ recovery o Advantages: Basic flow cytometry available at most centers; sorted cells can be used to evaluate split chimerism o Disadvantages: Limited ability to look at early (<D+30) IR; Advanced phenotyping (high dimensional flow cytometry, mass cytometry) expensive and less available; Quantitative recovery does not always equal functional reconstitution • Immune cell function o Advantages: Can evaluate memory response to specific antigens for decisions on viral monitoring/prophylaxis o Disadvantages: Less available at many centers; Response depends on exposure to antigen of interest
    • 4. Measures of Immune Reconstitution (IR) •Transcriptome (gene expression through RNA analysis) o Advantages: Provides large amount of gene expression data at the single cell level; identify donor versus recipient at the single cell level o Disadvantages: Expensive (difficult to do across multiple time points); Not all inflammation is bad •Secretome (cytokines, chemokines) o Advantages: Inexpensive; Can be conducted before cellular recovery (<D+30); Certain cytokines/chemokines may be valuable for identifying primary disease activity o Disadvantages: Not all cytokines/chemokine measurements are sensitive (IL1); Certain cytokines/chemokines may be applicable to only particular diseases (IL18, CXCL9)
    • 5. Measures of Immune Reconstitution (IR) • Chimerism (donor versus recipient) o Advantages: Predictive of relapse in malignancy and disease remission in some non-malignant disorders o Disadvantages: May not be as predictive of disease remission in immune dysregulatory disorders; Usually limited to myeloid (CD33) and T (CD3) cells • Limitations on studies to date: o Almost all analyses have been done on recipient peripheral blood with focus on T-(transplanter)-cell o Static analyses for dynamic recovery o Inability to measure donor versus recipient IR via non-genetic means o Studies conducted on large cohorts with variable disease and transplant approaches o Large IR variability complicates analysis in rare diseases with small patient numbers
    • 6. Importance of T-cell (CD4+), B-cell Recovery Non-Relapse Mortality (NRM) and chronic (c)GVHD based on CD4+ T-cell (>57 cells/µL), B-cell (>35 cells/µL) Recovery at D+100 Troullioud Lucas et al. Cytotherapy 2023;
    • 7. Immune Recovery in JIA Early IR (D+0-D+100): Antigen driven and homeostatic proliferation Late IR (D+100-D+365): Homeostatic proliferation (off IST) and thymic production T-cell Recovery after Pediatric BMT Segregated by Conditioning Serotherapy Lymphocyte Recovery after BMT for JIA Willemsen et al. BBMT 2015; 21:473-482 Silva et al. Blood Advances 2018; 2:7
    • 8. Impact of Chimerism on BMT Outcomes in JIA Silva et al. Blood Advances 2018; 2:7
    • 9. Macrophage (rheuMatologist) Cell Murine Alveolar Macrophage (AM) Recovery after Congenic BMT with Different Conditioning Regimens Hubbard et al. ExpLungRes 2008; 34(5):263-275
    • 10. Summary of BMT and JIA BMT IR • Multiple ways to evaluate immune recovery and reconstitution and combining modalities can maximize success and minimize deficiencies of each strategy • For rare diseases, it is imperative to harmonize IR evaluation post-BMT amongst a variable patient population to assess therapeutic efficacy • Poor outcomes in patients with JIA post-BMT are highlighted by significant infectious disease, macrophage activation syndrome, and relapsed disease, all potential consequences of poor IR • For JIA BMT we need to develop novel ways to look at IR given that current methods (peripheral blood, chimerism, flow cytometry) are inadequate o Evaluation should focus on innate activity (secretome, monocyte/macrophage*), regulatory and effector T cells, thymic function, B cells and plasma cells*, and impact of donor HLA-haplotype and phenotype on outcomes *Higher resistance to conditioning therapy


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