scholarly journals The role of the thymus in T-cell immune reconstitution after umbilical cord blood transplantation

Blood ◽  
2014 ◽  
Vol 124 (22) ◽  
pp. 3201-3211 ◽  
Author(s):  
Ioannis Politikos ◽  
Vassiliki A. Boussiotis
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
T Cell Receptor ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
T Cell Reconstitution

Abstract Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cells for patients without HLA-matched adult donors. UCB contains a low number of nucleated cells and mostly naive T cells, resulting in prolonged time to engraftment and lack of transferred T-cell memory. Although the first phase of T-cell reconstitution after UCB transplantation (UCBT) depends on peripheral expansion of transferred T cells, permanent T-cell reconstitution is mediated via a central mechanism, which depends on de novo production of naive T lymphocytes by the recipient’s thymus from donor-derived lymphoid-myeloid progenitors (LMPs). Thymopoiesis can be assessed by quantification of recent thymic emigrants, T-cell receptor excision circle levels, and T-cell receptor repertoire diversity. These assays are valuable tools for monitoring posttransplantation thymic recovery, but more importantly they have shown the significant prognostic value of thymic reconstitution for clinical outcomes after UCBT, including opportunistic infections, disease relapse, and overall survival. Strategies to improve thymic entry and differentiation of LMPs and to accelerate recovery of the thymic stromal microenvironment may improve thymic lymphopoiesis. Here, we discuss the mechanisms and clinical implications of thymic recovery and new approaches to improve reconstitution of the T-cell repertoire after UCBT.

scholarly journals Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy

Blood ◽  
2006 ◽  
Vol 107 (7) ◽  
pp. 2643-2652 ◽  
Author(s):  
Lisa Marie Serrano ◽  
Timothy Pfeiffer ◽  
Simon Olivares ◽  
Tontanai Numbenjapon ◽  
Jennifer Bennitt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Adoptive Immunotherapy ◽  
Lymphoblastic Leukemia ◽  
Cord Blood Transplantation ◽  
Hematopoietic Stem ◽  
B Lineage

AbstractDisease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)–derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19+ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19+ tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19+ B-ALL relapse.

scholarly journals Clearance of CMV viremia and survival after double umbilical cord blood transplantation in adults depends on reconstitution of thymopoiesis

Blood ◽  
2010 ◽  
Vol 115 (20) ◽  
pp. 4111-4119 ◽  
Author(s):  
Julia A. Brown ◽  
Kristen Stevenson ◽  
Haesook T. Kim ◽  
Corey Cutler ◽  
Karen Ballen ◽  
...  
Keyword(s):  
T Cells ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Immune Reconstitution ◽  
Cord Blood Transplantation ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Hematopoietic Stem ◽  
Blood Transplantation

Umbilical cord blood grafts are increasingly used as sources of hematopoietic stem cells in adults. Data regarding the outcome of this approach in adults are consistent with delayed and insufficient immune reconstitution resulting in high infection-related morbidity and mortality. Using cytomegalovirus (CMV)–specific immunity as a paradigm, we evaluated the status, mechanism, and clinical implications of immune reconstitution in adults with hematologic malignancies undergoing unrelated double unit cord blood transplantation. Our data indicate that CD8+ T cells capable of secreting interferon-γ (IFN-γ) in a CMV-specific enzyme-linked immunosorbent spot (ELISpot) assay are detectable at 8 weeks after transplantation, before reconstitution of thymopoiesis, but fail to clear CMV viremia. Clearance of CMV viremia occurs later and depends on the recovery of CD4+CD45RA+ T cells, reconstitution of thymopoiesis, and attainment of T-cell receptor rearrangement excision circle (TREC) levels of 2000 or more copies/μg DNA. In addition, overall survival was significantly higher in patients who displayed thymic regeneration and attainment of TREC levels of 2000 or more copies/μg DNA (P = .005). These results indicate that reconstitution of thymopoiesis is critical for long-term clinical outcome in adult recipients of umbilical cord blood transplant. The trial was prospectively registered at http://www.clinicaltrials.gov (NCT00133367).

Prediction of T-cell reconstitution by assessment of T-cell receptor excision circle before allogeneic hematopoietic stem cell transplantation in pediatric patients

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 886-893 ◽  
Author(s):  
Xiaohua Chen ◽  
Raymond Barfield ◽  
Ely Benaim ◽  
Wing Leung ◽  
James Knowles ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Thymic Function ◽  
T Cell Reconstitution

Abstract The extent and rapidity with which T cells are regenerated from graft-derived precursor cells directly influences the incidence of infection and the T-cell–based graft-versus-tumor effect. Measurement of T-cell receptor excision circles (TRECs) in peripheral blood is a means of quantifying recent thymic T-cell production and has been used after transplantation in many studies to estimate thymus-dependent T-cell reconstitution. We hypothesized that the quality of thymic function before transplantation affects thymus-dependent T-cell reconstitution after transplantation. We used real-time polymerase chain reaction (PCR) to quantify signal-joint TRECs (sjTRECs) before and after transplantation. T-cell reconstitution was evaluated by T-cell receptor β (TCRβ) CDR3 size spectratyping. We tested 77 healthy sibling donors and 244 samples from 26 pediatric recipients of allogeneic hematopoietic stem cell transplantation (AHSCT). Blood from the healthy donors contained 1200 to 155 000 sjTREC copies/mL blood. Patients who had greater than 1200 copies/mL blood before transplantation showed early recovery of sjTREC numbers and TCRβ repertoire diversity. In contrast, patients who had fewer than 1200 copies/mL blood before transplantation demonstrated significantly slower restoration of thymus-dependent T cells. We conclude that the rate of reconstitution of thymus-dependent T cells is dependent on the competence of thymic function in the recipients before transplantation. Therefore, pretransplantation measurement of sjTREC may provide an important tool for predicting thymus-dependent T-cell reconstitution after transplantation.

scholarly journals Expansion of Gammadelta T Cells from Cord Blood: A Therapeutical Possibility

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Sofia Berglund ◽  
Ahmed Gaballa ◽  
Piamsiri Sawaisorn ◽  
Berit Sundberg ◽  
Michael Uhlin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cultured Cells ◽  
Cord Blood Transplantation ◽  
Γδ T Cells ◽  
Main Memory ◽  
Cell Therapies

Gammadelta (γδ) T cells are found in both blood and tissues and have antiviral and antitumor properties. The frequency of γδ T cells in umbilical cord blood (UCB) is low, and the majority express δ1, in contrast to blood, whereas the main subset is δ2γ9 T cells. UCB γδ T cells are functionally immature, which together with their scarcity complicates the development of UCB γδ T cell therapies. We aimed to develop an effective expansion protocol for UCB γδ T cells based on zoledronate and IL-2. We found that culture with 5 μM zoledronate and 200 IU IL-2/ml medium for 14 days promoted extensive proliferation. The majority of the cultured cells were γ9δ2 T cells. The fold expansion of this, originally infrequent, subset was impressive (median and maximum fold change 253 and 1085, resp.). After culture, the cells had a polyclonal γδ T cell repertoire and the main memory subset was central memory (CD45RO+ CD27+). The cells produced cytokines such as IL-1B, IL-2, and IL-8 and displayed significant tumor-killing capacity. These results show that development of in vitro expanded UCB γδ T cell therapies is feasible. It could prove a valuable treatment modality for patients after umbilical cord blood transplantation.

CD8+ T-cell reconstitution in recipients of umbilical cord blood transplantation and characteristics associated with leukemic relapse

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4480-4488 ◽  
Author(s):  
Natacha Merindol ◽  
Martin A. Champagne ◽  
Michel Duval ◽  
Hugo Soudeyns
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Cd8 T Cells ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
Leukemic Relapse

Abstract Recipients of umbilical cord blood (UCB) transplantation (UCBT) face a high risk of morbidity and mortality related to opportunistic infections (OI) and leukemic relapse. To understand the molecular basis of these UCBT-related complications, the characteristics of UCB-derived antigen-specific CD8+ T cells were examined in a group of pediatric UCBT recipients. Compared with the UCB graft inoculum and the late post-UCBT period (12-36 months), declining clonal diversity of UCB-derived CD8+ T cells specific for the Melan-A26-35 A27L peptide and high frequencies of PD-1-expressing CD8+ T cells were observed in the first 3 months after UCBT, a period during which OIs are most frequent. The CD8+ T-cell compartment predominantly comprised CD45RA+ CCR7− terminally differentiated effector-memory T cells until 6 months after UCBT, at which time the polyfunctionality of antigen-specific CD8+ T cells was reestablished. Finally, the frequency of PD-1+ CD8+ T cells was significantly higher in subjects who subsequently experienced leukemic relapse. This study informs the biologic properties of UCB-derived CD8+ T cells and provides a rationale for the characteristics of UCBT in terms of immune reconstitution and OI. These results also suggest that the elevated frequency of PD-1+ CD8+ T cells could be associated with leukemic relapse in pediatric UCBT recipients.

Rapid T-cell Receptor CD4+ Repertoire Reconstitution and Immune Recovery in Unrelated Umbilical Cord Blood Transplanted Pediatric Leukemia Patients

2006 ◽  
Vol 28 (7) ◽  
pp. 403-411 ◽  
Author(s):  
Andrea Finocchi ◽  
Maria Luisa Romiti ◽  
Silvia Di Cesare ◽  
Pamela Puliafito ◽  
Simone Pensieroso ◽  
...  
Keyword(s):  
T Cell ◽  
Cord Blood ◽  
T Cell Receptor ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cell Receptor ◽  
Immune Recovery ◽  
Pediatric Leukemia

A Single Center Experience with Allogeneic Sibling Umbilical-Cord-Blood Transplantation in Children with Malignant and Non-Malignant Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2042-2042
Author(s):  
Yongping Song ◽  
Yanli Zhang ◽  
Baijun Fang ◽  
Xudong Wei ◽  
Lulu Lu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Median Time ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cd4 T Cells ◽  
Cord Blood Transplantation ◽  
Umbilical Cord Blood Transplantation ◽  
Blood Transplantation

Abstract To study the outcome of allogeneic sibling umbilical-cord-blood transplantation (CBT) in children in China, we studied the records of 38 recipients of cord blood from HLA-identical siblings from 1998 through 2004. The mean age at transplant was 10.3+/−5.5 years. Diseases of the patients were leukemia (28), neuroblastoma (3), severe aplastic anaemia (3) and inborn errors of metabolism (four). A volume of 76–208 ml of cord blood was collected from sibling infants soon after delivery. HLA antigens were identical in 32 and one to three antigens mismatched in six. The patients received busulphan and cyclophosphamide as conditioning, and antithymocyte globulin was given to prevent graft rejection. The median number of collected nucleated cells was 3.5 x 107/kg nucleated cells (range, 2.0 to 10.2). T-cell reconstitution was evaluated by using combined approaches of phenotyping analysis of lymphocytes and assessment of ex vivo thymic function by measuring T-cell receptor (TCR) rearrangement excision circles (TRECs). The overall survival is 89% at the median observation time of 72 months. The median time for neutrophil engraftment (absolute neutrophil count >500/mm3) was 16 days (range, 10 to 41days). The median time to become transfusion independent after CBT was 27 days for platelets (range, 15 to 54) and was 28 days for packed red blood cells (range, 19 to 128). Acute GVHD (aGVHD)was observed in 20/38 patients and involved only skin in 16 patients, skin and liver or gut in 2 patients and all 3 organs in another 2 patients. Seventeen of 20 patients had grade 1 to 2 aGVHD toxicity, whereas 3 patients experienced grade 3 to 4 aGVHD. Chronic GVHD (cGVHD) developed in 12 patients. Acute transplant related mortality was 5.5%. Cause of death was persisting non-engraftment till day +100 after transplant. Late mortality occurred in 2 patients: one cGVHD associated haemorrhage 22 months after CBT and one cGVHD associated septicaemia 4 years after CBT. Immunologic reconstitution demonstrated that CBT resulted in consistent and stable T-, B- and natural killer (NK) cell development. The kinetics of development was such that T-cell development occurred between 65 to 180 days. Initial T-cell engraftment consisted predominantly of CD45RO+, CD3+, and CD4+ T cells, and at 12 to 24 months changed to CD45RA+, CD3+, and CD4+ T cells, indicating de novo maturation of T cells. During the first 5 months after transplantation, TCR repertoires were highly abnormal and TREC values low. However, in a longer follow-up (one years or more after transplantation) TREC values and TCR diversity increased and became normal. This data confirms that CBT still should be the first treatment choice if an HLA-identical sibling is available.

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