Immune Reconstitution after Bone Marrow Transplant

NextGen Therapies in SJIA, Still's & MAS Conference

November 14, 2024 Jim Connelly, MD

Vanderbilt University Medical Center

Immune Recovery after BMT


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 (

· 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
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 (
• o Disadvantages: Not all cytokines/chemokine measurements are sensitive (IL1); Certain cytokines/chemokines may be applicable to only particular diseases (IL18, CXCL9)
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
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


Immune Recovery in JIA

T-cell Recovery after Pediatric BMT Segregated by Conditioning Serotherapy

Lymphocyte Recovery after BMT for JIA


Impact of Chimerism on BMT Outcomes in JIA


Macrophage (rheuMatologist) Cell

Murine Alveolar Macrophage (AM) Recovery after Congenic BMT with Different Conditioning Regimens


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