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Gamma delta T cell reconstitution is associated with fewer infections and improved event-free survival after hematopoietic stem cell transplantation for pediatric leukemia.

ABSTRACT: After hematopoietic stem cell transplantation (HSCT), successful engraftment and immune recovery is necessary to protect the patient from relapse and infection. Many studies highlight the importance of conventional ?? T cell recovery after HSCT, but the impact of ?? T cell recovery has not been well described. Here, we investigate the recovery of ?? T cells in 102 pediatric patients with acute leukemia in first clinical remission who underwent allogeneic HSCT at St. Jude Children's Research Hospital from 1996 to 2011. Mean patient age was 10.5 ± 5.9 years (range, .6 to 25.2), and mean survivor follow-up was 2.7 ± 1.8 years (range, .12 to 6.0). Diagnoses included 59% patients with acute lymphoblastic leukemia and 41% patients with acute myelogenous leukemia. Multivariate analysis demonstrated significant impact of the maximum number of CD3(+), CD4(+), and CD8(+) T cells and donor source on the ?? T cell recovery (P < .0001, P < .0001, P < .0001, and P < .004, respectively). Univariate and multivariate models found the number of ?? T cells after HSCT to be associated with infections (P = .026 and P = .02, respectively). We found the probability of infections for patients with an elevated number of ?? T cells was significantly lower compared with patients with low or normal ?? T cells after HSCT (18% versus 54%; P = .025). Bacterial infections were not observed in patients with elevated ?? T cells. Finally, event-free survival was significantly higher in patients with enhanced ?? T cell reconstitution compared with patients with low/normal ?? T cell reconstitution after HSCT (91% versus 55%; P = .04). Thus, ?? T cells may play an important role in immune reconstitution after HSCT.

SUBMITTER: Perko R

PROVIDER: S-EPMC4288038 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Gamma delta T cell reconstitution is associated with fewer infections and improved event-free survival after hematopoietic stem cell transplantation for pediatric leukemia.

Perko Ross R Kang Guolian G Sunkara Anusha A Leung Wing W Thomas Paul G PG Dallas Mari H MH

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20141016 1

After hematopoietic stem cell transplantation (HSCT), successful engraftment and immune recovery is necessary to protect the patient from relapse and infection. Many studies highlight the importance of conventional αβ T cell recovery after HSCT, but the impact of γδ T cell recovery has not been well described. Here, we investigate the recovery of γδ T cells in 102 pediatric patients with acute leukemia in first clinical remission who underwent allogeneic HSCT at St. Jude Children's Research Hosp ...[more]

PMID: 25445640

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Project description:Background and objectivesAutologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat aggressive forms of multiple sclerosis (MS). This procedure is believed to result in an immune reset and restoration of a self-tolerant immune system. Immune reconstitution has been extensively studied for T cells, but only to a limited extent for B cells. As increasing evidence suggests an important role of B cells in MS pathogenesis, we sought here to better understand reconstitution and the extent of renewal of the B-cell system after aHSCT in MS.MethodsUsing longitudinal multidimensional flow cytometry and immunoglobulin heavy chain (IgH) repertoire sequencing following aHSCT with BCNU + Etoposide + Ara-C + Melphalan anti-thymocyte globulin, we analyzed the B-cell compartment in a cohort of 20 patients with MS in defined intervals before and up to 1 year after aHSCT and compared these findings with data from healthy controls.ResultsTotal B-cell numbers recovered within 3 months and increased above normal levels 1 year after transplantation, successively shifting from a predominantly transitional to a naive immune phenotype. Memory subpopulations recovered slowly and remained below normal levels with reduced repertoire diversity 1 year after transplantation. Isotype subclass analysis revealed a proportional shift toward IgG1-expressing cells and a reduction in IgG2 cells. Mutation analysis of IgH sequences showed that highly mutated memory B cells and plasma cells may transiently survive conditioning while the analysis of sequence cluster overlap, variable (IGHV) and joining (IGHJ) gene usage and repertoire diversity suggested a renewal of the late posttransplant repertoire. In patients with early cytomegalovirus reactivation, reconstitution of naive and memory B cells was delayed.DiscussionOur detailed characterization of B-cell reconstitution after aHSCT in MS indicates a reduced reactivation potential of memory B cells up to 1 year after transplantation, which may leave patients susceptible to infection, but may also be an important aspect of its mechanism of action.

Project description:T-cell receptor (TCR) ?? cells are perceived as innate-like effector cells with the possibility of mediating graft-vs. -tumor (GVT) without causing graft-vs.-host disease (GVHD) in the setting of hematopoietic allogeneic stem cell transplantation (HSCT). We conducted a prospective study to assess the clinical impact of TCR ?? cell immune reconstitution on overall survival, relapse-free-survival, relapse and GVHD. The impact of CD3, CD4, and CD8 T cells together with NK cells including subtypes were analyzed in parallel. A total of 108 patients with hematological malignancies transplanted with HLA-matched, T cell replete stem cell grafts were included for analyses of absolute concentrations of CD3, CD4, and CD8 positive T cells and NK cells together with a multi-color flow cytometry panel with staining for TCR??, TCR??, V?1, V?2, CD3, CD4, CD8, HLA-DR, CD196, CD45RO, CD45RA, CD16, CD56, CD337, and CD314 at 28, 56, 91, 180, and 365 days after transplantation. Immune reconstitution data including subsets and differentiation markers of T and NK cells during the first year after transplantation was provided. Patients with TCR ?? cell concentrations above the median value of 21 (0-416) × 106 cells/L 56 days after transplantation had significantly improved overall survival (p = 0.001) and relapse-free survival (p = 0.007) compared to patients with concentrations below this value. When day 56 cell subset concentrations were included as continuous variables, TCR ?? cells were the only T cell subsets with a significant impact on OS and RFS; the impact of TCR ?? cells remained statistically significant in multivariate analyses adjusted for pre-transplant risk factors. The risk of death from relapse was significantly decreased in patients with high concentrations of TCR ?? cells 56 days after transplantation (p = 0.003). Also, the risk of acute GVHD was significantly lower in patients with day 28 TCR ?? cell concentrations above the median of 18 × 106 cells/L compared to patients with low concentrations (p = 0.01). These results suggest a protective role of TCR ?? cells in relapse and GVHD and encourage further research in developing adaptive TCR ?? cell therapy for improving outcomes after HSCT.

Dataset Information

Gamma delta T cell reconstitution is associated with fewer infections and improved event-free survival after hematopoietic stem cell transplantation for pediatric leukemia.

Publications

Gamma delta T cell reconstitution is associated with fewer infections and improved event-free survival after hematopoietic stem cell transplantation for pediatric leukemia.

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