scholarly journals Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4543-4551 ◽  
Author(s):  
Krishna V. Komanduri ◽  
Lisa S. St. John ◽  
Marcos de Lima ◽  
John McMannis ◽  
Steven Rosinski ◽  
...  
Keyword(s):  
T Cell ◽  
Cord Blood ◽  
Immune Reconstitution ◽  
Cell Function ◽  
De Novo ◽  
Cord Blood Transplantation ◽  
Immune Recovery ◽  
Transplant Recipients ◽  
Memory T Cell ◽  
Blood Transplantation

Advances in immune assessment, including the development of T-cell receptor excision circle (TREC) assays of thymopoiesis, cytokine-flow cytometry assays of T-cell function, and higher-order phenotyping of T-cell maturation subsets have improved our understanding of T-cell homeostasis. Limited data exist using these methods to characterize immune recovery in adult cord blood (CB) transplant recipients, in whom infection is a leading cause of mortality. We now report the results of a single-center prospective study of T-cell immune recovery after cord blood transplantation (CBT) in a predominantly adult population. Our primary findings include the following: (1) Prolonged T lymphopenia and compensatory expansion of B and natural killer (NK) cells was evident; (2) CB transplant recipients had impaired functional recovery, although we did observe posttransplantation de novo T-cell responses to cytomegalovirus (CMV) in a subset of patients; (3) Thymopoietic failure characterized post-CBT immune reconstitution, in marked contrast to results in other transplant recipients; and (4) Thymopoietic failure was associated with late memory T-cell skewing. Our data suggest that efforts to improve outcomes in adult CB transplant recipients should be aimed at optimizing T-cell immune recovery. Strategies that improve the engraftment of lymphoid precursors, protect the thymus during pretransplant conditioning, and/or augment the recovery of thymopoiesis may improve outcomes after CBT.

scholarly journals Excellent T-cell reconstitution and survival depend on low ATG exposure after pediatric cord blood transplantation

Blood ◽  
2016 ◽  
Vol 128 (23) ◽  
pp. 2734-2741 ◽  
Author(s):  
Rick Admiraal ◽  
Caroline A. Lindemans ◽  
Charlotte van Kesteren ◽  
Marc B. Bierings ◽  
A. Birgitta Versluijs ◽  
...  
Keyword(s):  
T Cell ◽  
Cord Blood ◽  
Immune Reconstitution ◽  
Cord Blood Transplantation ◽  
Blood Transplantation ◽  
T Cell Reconstitution ◽  
Individualized Dosing ◽  
Key Points

Key Points Immune reconstitution after CBT is excellent provided ATG exposure is low or absent. Individualized dosing, or omission of ATG in selected patients, may increase the chance of survival after CBT.

scholarly journals Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes

Blood ◽  
2009 ◽  
Vol 114 (9) ◽  
pp. 1958-1967 ◽  
Author(s):  
Patrick J. Hanley ◽  
Conrad Russell Young Cruz ◽  
Barbara Savoldo ◽  
Ann M. Leen ◽  
Maja Stanojevic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Viral Disease ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Transplant Recipients ◽  
Blood Transplantation ◽  
Related Mortality

The naive phenotype of cord blood (CB) T cells may reduce graft-versus-host disease after umbilical cord blood transplantation, but this naivety and their low absolute numbers also delays immune reconstitution, producing higher infection-related mortality that is predominantly related to CMV, adenovirus (Adv), and EBV. Adoptive immunotherapy with peripheral blood-derived virus-specific cytotoxic T lymphocytes (CTLs) can effectively prevent viral disease after conventional stem cell transplantation, and we now describe the generation of single cultures of CTLs from CB that are specific for multiple viruses. Using EBV-infected B cells transduced with a clinical-grade Ad5f35CMVpp65 adenoviral vector as sources of EBV, Adv, and CMV antigens, we expanded virus-specific T cells even from CB T cells with a naive phenotype. After expansion, each CTL culture contained both CD8+ and CD4+ T-cell subsets, predominantly of effector memory phenotype. Each CTL culture also had HLA-restricted virus-specific cytotoxic effector function against EBV, CMV, and Adv targets. The CB CTLs recognized multiple viral epitopes, including CD4-restricted Adv-hexon epitopes and immunosubdominant CD4- and CD8-restricted CMVpp65 epitopes. Notwithstanding their naive phenotype, it is therefore possible to generate trivirus-specific CTLs in a single culture of CB, which may be of value to prevent or treat viral disease in CB transplant recipients. This study is registered at www.clinicaltrials.gov as NCT00078533.

Low Incidence of Cytomegalovirus Infection Associated with Rapid Cell-Mediated Immune Reconstitution after Cord Blood Transplantation Using Full Conditioning Regimen Containing 12Gy Total Body Irradiation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2926-2926
Author(s):  
Satoshi Takahashi ◽  
Jun Ooi ◽  
Akira Tomonari ◽  
Nobuhiro Tsukada ◽  
Takaaki Konuma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Cd8 T Cells ◽  
Immune Reconstitution ◽  
Cord Blood Transplantation ◽  
Blood Transplantation ◽  
Total Body ◽  
Cmv Reactivation ◽  
Cmv Antigenemia

Abstract The one of crucial questions in cord blood transplantation (CBT) is whether naïvity of cord blood lymphocytes could gain antigen-specific cellular immunity during early phase of transplant. Cytomegalovirus (CMV) infection is serious clinical problem in allogeneic transplant recipients and T cell immunity has known to have an important role in control of virus replication and prevention. During 1998 and 2006, 111 adults has received myeloablative regimens including 12 Gy of total body irradiation followed by CBT and a standard cyclosporine and methotrexate combination as GVHD prophylaxis in our institute. Patients also received intravenous immunoglobulin from day −3 to day 120 if the immunoglobulin level in the serum was less than 500 mg/dl. CMV antigenemia assay was performed twice a week after neutrophil recovery until day 120. Once CMV antigenemia is positive, patients received 5 mg/kg ganciclovir (GCV) once daily for at least 2 weeks as preemptive therapy. Ninety-two patients achieved engraftment with full donor chimerism and survived without disease relapse at the time of 120 days after CBT (82.8%). None of these 92 recipients had CMV disease during first 4 months after CBT. We have investigated the association of CMV reactivation status and their immune reconstitution process for 4 months after CBT in 39 patients who received CBT from 2002 to 2006 in our institute. CMV-specific CD4+ and CD8+ T cell recoveries were assessed by detection of interferon-g (IFN-g) producing cells with CMV antigen stimulation using intracellular cytokine staining. The positive was defined as more than 0.1% IFN-g positive cells among CD4+ or CD8+ T cell population. Six of 39 patients were CMV sero-negative and 33 patients were sero-positive. None of 6 CMV sero-negative receipients and 31 of 33 CMV sero-positive recipients observed CMV reactivation and received GCV therapy within the first 4 months. CMV-specific CD4+ T cells were detected in 30 of 31 recipients with positive CMV antigenemia (% positive: 55% at 1 month and 85% at 2 month), on the other hand, CMV-specific CD8+ T cells were detected in 14 out of 31 cases (% positive: 14% at 1 month and 22% at 2 month), both of which were comparable to post-bone marrow or peripheral blood transplants (CMV-specific CD4+ T cells were detected 18 of 21 recipients with positive CMV antigenemia and CMV-specific CD8+ T cells were detected in 12 out of 21). These data suggest that post-thymic naive T lymphocytes in cord blood might obtain memory and effector function in vivo with antigen-specific manner during early phase of post-transplant.

The Impact Of Thymoglobulin Prior To Pediatric Unrelated Umbilical Cord Blood Transplantation On Immune-Reconstitution and Clinical Outcome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3305-3305 ◽  
Author(s):  
Caroline A Lindemans ◽  
Robert Chiesa ◽  
Persis J Amrolia ◽  
Kanchan Rao ◽  
Olga Nikolajeva ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Outcome ◽  
Cord Blood ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Umbilical Cord Blood Transplantation ◽  
Blood Transplantation ◽  
The Impact

Abstract Introduction In vivo T-cell-depletion generated by the use of Thymoglobulin (ATG) within the conditioning regimen might contribute to the delayed immune-reconstitution observed after unrelated umbilical cord blood transplantation (UCBT). We studied the impact of early, late and no ATG on immune reconstitution and clinical outcome. Methods 127 Children receiving an unrelated UCBT in London or Utrecht between 2006 and 2011 were included and divided in 3 groups: late ATG (day -5 to 0, n=48), early ATG (day -9 to -5, n= 33) and no ATG(n=46). The no ATG group received MMF and CsA as GVHD prophylaxis, while the ATG groups both received CSA and prednison as prohylaxis, Endpoints studied were survival, early and late immune-recovery, infections and GvHD. Subset analysis CD3+, CD4+ and CD4+naïve, B and NK cell numbers were prospectively measured during post-transplant follow-up at 1, 2, 3, 6 and 12 months post-UCBT. Results The probability of survival was not significantly different between the groups: 71% +/- 8% (no ATG), 68% +/- 9% (early ATG) and 61% +/- 7% (late ATG). There were no significant differences in engraftment and primary or secondary graft failure. Immune reconstitution as defined by CD3+, CD4+ and CD4+ naïve T-cell counts were significantly higher (p<0.001) in the no ATG group at 1, 2, 3, 6, and 12 months post-UCBT with a log more T cells than in the ATG groups. The median CD3+ T-cell count in the no ATG group at 1, 2, 3, 6 and 12 months post UCBT was 340 x10e6/L, 720 x 10e6/L, 535 x 10e6/L, 940 ± 194 x 10e6/L, and 1860 x 10e6/L respectively. In the no ATG group significantly less viral reactivations (p=0.021) were noted. A higher probability (p<0,001) of severe acute GvHD (31%+/-9%) was found in the no ATG group compared to 18% +/- 9% for the early ATG and 5% +/-4% for the late ATGgroup. This was not associated with a higher probability of chronic GvHD or non-infectious lung injury in the no ATG group. Conclusion Cord blood transplantation without Thymoglobulin (ATG), in the context of MMF and CsA post-transplant prophylaxis, is associated with higher GVHD risk but with a surprisingly good immune reconstitution and with an engraftment and survival similar to the groups with ATG. The findings of improved immune-reconstitution, associated with lower viral reactivations, albeit at the cost of increased rates of acute GvHD (but not chronic GvHD), suggest that omitting ATG in cord blood transplantation may be important to prevent viral reactivations, especially in those at high risk for these. Disclosures: No relevant conflicts of interest to declare.

Immune-reconstitution after combined haploidentical and umbilical cord blood transplantation.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6535-6535 ◽  
Author(s):  
Koen van Besien ◽  
Nitin Jain ◽  
Viviane Schouten ◽  
Hongtao Liu ◽  
Jodie Ulaszek ◽  
...  
Keyword(s):  
T Cell ◽  
Cord Blood ◽  
Immune Reconstitution ◽  
Cord Blood Transplantation ◽  
Pneumococcal Vaccination ◽  
Serological Response ◽  
T Cell Repertoire ◽  
Normal Range ◽  
Cell Repertoire ◽  
Blood Transplantation

6535^ Background: Umbilical cord blood (UCB) stem cells are frequently employed for allogeneic stem cell transplantation. However, delayed myeloid and lymphoid immune-reconstitution with UCB transplantation leads to increased risk of infections. We recently reported a pilot study combining UCB with a HLA haploidentical donor (Liu et al. Blood. 2011). Here, we report the immune reconstitution after the haploidentical-cord blood transplantation. Methods: Pts received reduced-intensity conditioning with fludarabine/melphalan/rATG and were assessed for lymphocyte subsets, serological response to pneumococcal vaccination, Cylex Immuknow assay which measures amount of ATP secreted by CD4 lymphocytes on stimulation by PHA, and T-cell spectratyping. Results: 45 pts, enrolled between 01/2007 and 04/2011, are included in this analysis. The median absolute lymphocyte subset counts at serial time-points are shown in the Table. The median absolute values of CD3, CD4 and CD8 counts remained below the normal range throughout the 1st year post-transplant. The NK-cells and B-cells reached normal range by day 30 and day 100, respectively. Serological response to pneumococcal vaccination was seen in 7/17 (defined as seroconversion or >3 fold rise in titers of serotype 14, 19F and 23F) evaluable pts at a median 74 days after vaccination. Immuknow assay showed that 6/6 pts tested within first 30 days of transplant had low values whereas 5/8 tested >1yr had normal/high values. Of the 9 pts who were assessed for T-cell receptor repertoire by T-cell spectratyping, 7 had a polyclonal, complex T cell repertoire similar to healthy controls. CMV viremia requiring treatment occurred in 14 patients. EBV reactivation occurred in 18 pts and 5 developed PTLD 68 to 314 days after transplant. Conclusions: Haploidentical cord blood transplantation leads to rapid myeloid recovery and recovery of B-cell and NK cell numbers. T-cell recovery is more delayed, but at 1-year most pts have a polyclonal T cell repertoire and robust T-cell responses. [Table: see text]

scholarly journals Rapid T-cell chimerism switch and memory T-cell expansion are associated with pre-engraftment immune reaction early after cord blood transplantation

2012 ◽  
Vol 160 (2) ◽  
pp. 255-258 ◽  
Author(s):  
Naofumi Matsuno ◽  
Hisashi Yamamoto ◽  
Nobukazu Watanabe ◽  
Naoyuki Uchida ◽  
Hikari Ota ◽  
...  
Keyword(s):  
T Cell ◽  
Cord Blood ◽  
Cell Expansion ◽  
Immune Reaction ◽  
Cord Blood Transplantation ◽  
Memory T Cell ◽  
Blood Transplantation ◽  
T Cell Expansion
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