Tracking T-cell immune reconstitution after TCRαβ/CD19-depleted hematopoietic cells transplantation in children

• Published in: Leukemia Vol. 31; no. 5; pp. 1145 - 1153
• Main Authors: Zvyagin, I V, Mamedov, I Z, Tatarinova, O V, Komech, E A, Kurnikova, E E, Boyakova, E V, Brilliantova, V, Shelikhova, L N, Balashov, D N, Shugay, M, Sycheva, A L, Kasatskaya, S A, Lebedev, Y B, Maschan, A A, Maschan, M A, Chudakov, D M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-05-2017; Nature Publishing Group
• Subjects: 45; 45/23; 692/308; Abdomen; Adolescent; Anemia; Antigens, CD19; Apheresis; Bar codes; Bone marrow; Cancer Research; CD19 antigen; Child; Child, Preschool; Children; Cloning; Confidence intervals; Critical Care Medicine; Depletion; Disease prevention; Graft Survival; Graft versus host disease; Hematologic Diseases - therapy; Hematological diseases; Hematology; Hematopoietic Stem Cell Transplantation - methods; Hemopoiesis; Humans; Immune reconstitution; Immune system; Immunology; Infant; Intensive; Internal Medicine; Leukemia; Lymphocyte Depletion - methods; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Oncology; Optimization; original-article; Pediatrics; Progenitor cells; Receptors, Antigen, T-Cell, alpha-beta; Software; Stem cells; T cell receptors; T-Lymphocytes - immunology; Thymus; Time Factors; Transplantation; Transplants & implants; Young Adult
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2016.321

αβT-cell-depleted allogeneic hematopoietic cell transplantation holds promise for the safe and accessible therapy of both malignant and non-malignant blood disorders. Here we employed molecular barcoding normalized T-cell receptor (TCR) profiling to quantitatively track T-cell immune reconstitution after TCRαβ-/CD19-depleted transplantation in children. We demonstrate that seemingly early reconstitution of αβT-cell counts 2 months after transplantation is based on only several hundred rapidly expanded clones originating from non-depleted graft cells. In further months, frequency of these hyperexpanded clones declines, and after 1 year the observed T-cell counts and TCRβ diversity are mostly provided by the newly produced T cells. We also demonstrate that high TCRβ diversity at day 60 observed for some of the patients is determined by recipient T cells and intrathymic progenitors that survived conditioning regimen. Our results indicate that further efforts on optimization of TCRαβ-/CD19-depleted transplantation protocols should be directed toward providing more efficient T-cell defense in the first months after transplantation.