High-dimensional profiling of pediatric immune responses to solid organ transplantation

Rao, Mahil; Amouzgar, Meelad; Harden, James T.; Lapasaran, Mary Gay; Trickey, Amber W.; Odim, Jonah; Debnam, Tracia; Esquivel, Carlos O.; Bendall, Sean C.; Martinez, Olivia M.; Krams, Sheri M.

doi:10.1016/j.xcrm.2023.101147

Cited by 3 publications

References 48 publications

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Application of Mass Cytometry Platforms to Solid Organ Transplantation

Zhang,

Sen,

Pena

et al. 2024

Transplantation

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Transplantation serves as the cornerstone of treatment for patients with end-stage organ disease. The prevalence of complications, such as allograft rejection, infection, and malignancies, underscores the need to dissect the complex interactions of the immune system at the single-cell level. In this review, we discuss studies using mass cytometry or cytometry by time-of-flight, a cutting-edge technology enabling the characterization of immune populations and cell-to-cell interactions in granular detail. We review the application of mass cytometry in human and experimental animal studies in the context of transplantation, uncovering invaluable contributions of the tool to understanding rejection and other transplant-related complications. We discuss recent innovations that have the potential to streamline and standardize mass cytometry workflows for application to multisite clinical trials. Additionally, we introduce imaging mass cytometry, a technique that couples the power of mass cytometry with spatial context, thereby mapping cellular interactions within tissue microenvironments. The synergistic integration of mass cytometry and imaging mass cytometry data with other omics data sets and high-dimensional data platforms to further define immune dynamics is discussed. In conclusion, mass cytometry technologies, when integrated with other tools and data, shed light on the intricate landscape of the immune response in transplantation. This approach holds significant potential for enhancing patient outcomes by advancing our understanding and facilitating the development of new diagnostics and therapeutics.

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Application of Mass Cytometry Platforms to Solid Organ Transplantation

Zhang,

Sen,

Pena

et al. 2024

Transplantation

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Defining the T cell transcriptional landscape in pediatric liver transplant rejection at single cell resolution

Peters,

DePasquale,

Begum

et al. 2024

Preprint

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Acute cellular rejection (ACR) affects >80% of pediatric liver transplant recipients within 5 years, and late ACR is associated with graft failure. Traditional anti-rejection therapy for late ACR is ineffective and has remained unchanged for six decades. Although CD8+ T cells promote late ACR, little has been done to define their specificity and gene expression. Here, we used single-cell sequencing and immune repertoire profiling (10X Genomics) on 30 cryopreserved 16G liver biopsies from 14 patients (5 pre-transplant or with no ACR, 9 with ACR). We identified expanded intragraft CD8+ T cell clonotypes (CD8EXP) and their gene expression profiles in response to anti-rejection treatment. Notably, we found that expanded CD8+ clonotypes (CD8EXP) bore markers of effector and CD56hiCD161- 'NK-like' T cells, retaining their clonotype identity and phenotype in subsequent biopsies from the same patients despite histologic ACR resolution. CD8EXP clonotypes localized to portal infiltrates during active ACR, and persisted in the lobule after histologic ACR resolution. CellPhoneDB analysis revealed differential crosstalk between KC and CD8EXP during late ACR, with activation of the LTB-LTBR pathway and downregulation of TGFβ signaling. Therefore, persistently-detected intragraft CD8EXP clones remain active despite ACR treatment and may contribute to long-term allograft fibrosis and failure of operational tolerance.

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Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorders in pediatric transplantation: A prospective multicenter study in the United States

Tajima,

Martinez,

Bernstein

et al. 2024

Pediatric Transplantation

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BackgroundEpstein–Barr virus (EBV)‐associated post‐transplant lymphoproliferative disorders (PTLD) is the most common malignancy in children after transplant; however, difficulties for early detection may worsen the prognosis.MethodsThe prospective, multicenter, study enrolled 944 children (≤21 years of age). Of these, 872 received liver, heart, kidney, intestinal, or multivisceral transplants in seven US centers between 2014 and 2019 (NCT02182986). In total, 34 pediatric EBV+ PTLD (3.9%) were identified by biopsy. Variables included sex, age, race, ethnicity, transplanted organ, EBV viral load, pre‐transplant EBV serology, immunosuppression, response to chemotherapy and rituximab, and histopathological diagnosis.ResultsThe uni−/multivariable competing risk analyses revealed the combination of EBV‐seropositive donor and EBV‐naïve recipient (D+R−) was a significant risk factor for PTLD development (sub‐hazard ratio: 2.79 [1.34–5.78], p = .006) and EBV DNAemia (2.65 [1.72–4.09], p < .001). Patients with D+R− were significantly more associated with monomorphic/polymorphic PTLD than those with the other combinations (p = .02). Patients with monomorphic/polymorphic PTLD (n = 21) had significantly more EBV DNAemia than non‐PTLD patients (p < .001) and an earlier clinical presentation of PTLD than patients with hyperplasias (p < .001), within 6‐month post‐transplant. Among non‐liver transplant recipients, monomorphic/polymorphic PTLD were significantly more frequent than hyperplasias in patients ≥5 years of age at transplant (p = .01).ConclusionsD+R− is a risk factor for PTLD and EBV DNAemia and associated with the incidence of monomorphic/polymorphic PTLD. Intensive follow‐up of EBV viral load within 6‐month post‐transplant, especially for patients with D+R− and/or non‐liver transplant recipients ≥5 years of age at transplant, may help detect monomorphic/polymorphic PTLD early in pediatric transplant.

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High-dimensional profiling of pediatric immune responses to solid organ transplantation

Cited by 3 publications

References 48 publications

Application of Mass Cytometry Platforms to Solid Organ Transplantation

Application of Mass Cytometry Platforms to Solid Organ Transplantation

Defining the T cell transcriptional landscape in pediatric liver transplant rejection at single cell resolution

Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorders in pediatric transplantation: A prospective multicenter study in the United States

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