Session Name: Biomarkers, Immune Assessment and Clinical Outcomes III
Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:45pm
Presentation Time: 4:15pm-4:27pm
*Purpose: Post-transplant lymphoproliferative disorder (PTLD) remains a serious problem in the pediatric transplant population. The Clinical Trials of Organ Transplantation in Children (CTOT-C)-06 is a prospective NIAID-sponsored multi-institutional study intended to identify viral and immune biomarkers of Epstein-Barr virus (EBV)-associated PTLD. We are evaluating high-throughput DNA sequencing (HTS) of immunoglobulin heavy chain (IGH) genes to track B cell clones for potential early detection of PTLD, and for monitoring immunosuppression and graft rejection.
*Methods: Enrollment ended in August, 2018 with sample collection completed in August, 2019. Of 944 pediatric patients enrolled, 872 were transplanted (219 kidney, 421 liver, 180 heart, 52 small intestine) at seven US centers. Mean age at transplant was 6.7 yrs (range <1-21 yr); 54% male and 46% female. Immunosuppression and anti-viral therapy were per each center's standard protocol. EBV serostatus was collected at the time of transplant. EBV PCR data was collected during each 3 month period up to 24 months post-transplant and every 6 months thereafter. Longitudinal blood samples from patients who developed PTLD (n=13), and matched controls (n=20), were analyzed by IGH HTS for clonal expansions, clonal persistence and changes in clonal populations, including Ig somatic hypermutation (SHM), isotype usage, and complementarity-determining region 3.
*Results: There were 34 documented cases of biopsy-proven EBV+ PTLD (overall incidence=3.9%). The prospectively observed incidence was 13.5% in small intestine, 4.4% in heart, 3.2% in kidney and 2.9% in liver. From ~14-million IGH reads and 1.7-million clones detected, we inferred strong effects of pediatric patient age, immunosuppressive medications, time from transplant, and EBV infection date on patient B cell repertoires, particularly in SHM frequencies in class-switched and non-switched isotypes. B cell clonal expansions were also traced.
*Conclusions: In evaluating IGH HTS for PTLD detection and transplant monitoring in pediatric organ transplantation, we demonstrate the importance of accounting for the effects on patient B cell repertoires of major clinical variables such as age, immunosuppression, transplant timing and EBV infection, in efforts to predict PTLD development and monitor patient immunity.
To cite this abstract in AMA style:Jackson K, Martinez O, Krams S, Robien M, Lapasaran M, Armstrong B, Twist C, Weinberg K, Gratzinger D, Tam B, Sever M, Brown M, Bernstein D, Esquivel C, Boyd SD. Transplant Monitoring and PTLD Detection with B Cell Receptor Repertoire Analysis in a Large Prospective Pediatric Cohort [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/transplant-monitoring-and-ptld-detection-with-b-cell-receptor-repertoire-analysis-in-a-large-prospective-pediatric-cohort/. Accessed January 19, 2022.
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