scholarly journals B and T Lymphocyte Attenuator Mediates Inhibition of Tumor-Reactive CD8+ T Cells in Patients After Allogeneic Stem Cell Transplantation

2012 ◽  
Vol 189 (1) ◽  
pp. 39-49 ◽  
Author(s):  
Willemijn Hobo ◽  
Wieger J. Norde ◽  
Nicolaas Schaap ◽  
Hanny Fredrix ◽  
Frans Maas ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
T Lymphocyte ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation

Automated Generation of Antigen-Specific T Cells for Adoptive T Cell Therapy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1177-1177
Author(s):  
Melanie Fahrendorff ◽  
Nanette von Oppen ◽  
Georg Rauser ◽  
Mario Assenmacher ◽  
Juergen Schmitz ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
Closed System ◽  
Isolated Cells ◽  
Ifn Gamma ◽  
Cell Processing

Abstract Abstract 1177 The adoptive transfer of antigen-specific T cells can be a powerful tool for immunotherapy of malignant diseases or infectious complications after allogeneic stem cell transplantation (Riddell et al., 1992; Heslop et al. 2010). Human adenovirus (AdV), Epstein-Barr virus (EBV) or cytomegalovirus (HCMV) infections are frequent and often life-threatening complications post allogeneic stem cell transplantation. To reduce the time required to isolate antigen-specific T cells for adoptive transfer we have developed a method to isolate IFN-gamma-secreting CD4+ as well as CD8+ T cells after antigen-specific restimulation, the Cytokine Capture System IFN-gamma (CCS). Several preclinical studies demonstrate the efficient enrichment of functional CD4+ and CD8+ T cells specific for HCMV (Rauser et al., 2004), EBV (Hammer et al., 2007) or AdV (Feuchtinger et al. 2008) using the CCS. First clinical data of adoptively transferred HCMV-, EBV- or AdV-specific T cells into patients post allogeneic stem cell transplantation are very encouraging (Feuchtinger et al., 2010; Moosmann et al., 2010; Feuchtinger et al., 2006) with low T cell doses infused varying from 1–97×10e3 cells/kg. We have now developed a cell processing device for the automation of the CCS procedure. Antigen-specific stimulation, labeling with the CCS reagents, washing steps, cytokine capture, magnetic enrichment and potentially expansion of the isolated cells are performed fully automated in a closed system. At the beginning of the procedure all components including the cellular starting product, antigen(s), reagents, buffer, and media are connected to a sterile single-use closed system processing set in the device. Due to usage of sterile filters and sterile docking the whole process runs under sterile conditions. The cellular end product can be obtained in the medium/buffer of choice, with the desired cell concentration and volume. The cellular starting product can be leukapheresis or bone marrow and the yield of antigen-specific T cells depends on the frequency of IFN-gamma producing cells. When starting with 1×10e9 cells 1–20×10e5 HCMV-specific T cells could be isolated. Cell processing is possible overnight and the isolated cells might be used directly after enrichment or after a phase of in vitro expansion. Using this cell processing device, IFN-gamma secreting HCMV-specific T cells were enriched to the same purity (>80% IFN-gamma secreting CD4+ and CD8+ T cells) as with the semi-automated procedure. Cell loss during the procedure is markedly reduced, leading to an increased yield of IFN-gamma positive cells. An improved viability was observed resulting in better expansion rates. In conclusion, the automation in a closed system enables the fast and robust generation of antigen-specific T cells for adoptive therapy and will reduce clean room requirements. Disclosures: Fahrendorff: Miltenyi Biotec GmbH: Employment. von Oppen:Miltenyi Biotec GmbH: Employment. Rauser:Miltenyi Biotec GmbH: Employment. Assenmacher:Miltenyi Biotec GmbH: Employment. Schmitz:Miltenyi Biotec GmbH: Employment. Biehl:Miltenyi Biotec GmbH: Employment. Miltenyi:Miltenyi Biotec GmbH: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Cytomegalovirus-specific CD8+ T-cells are associated with a reduced incidence of early relapse after allogeneic stem cell transplantation

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0213739 ◽  
Author(s):  
Pavankumar Reddy Varanasi ◽  
Justyna Ogonek ◽  
Susanne Luther ◽  
Elke Dammann ◽  
Michael Stadler ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
Early Relapse

CMV Reactivation after Allogeneic Stem Cell Transplantation Is Associated with a Preponderance of Circulating Late-Stage CMV-Specific CD8+ T Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3250-3250
Author(s):  
Krishna V. Komanduri ◽  
Lisa S. St. John ◽  
Elizabeth J. Shpall ◽  
Richard E. Champlin ◽  
Jeffrey J. Molldrem ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
Late Stage ◽  
Viral Reactivation ◽  
Tetramer Staining ◽  
Cmv Reactivation

Abstract CMV reactivation remains a major cause of morbidity after after allogeneic stem cell transplantation. Using HLA-peptide tetramer staining and cytokine flow cytometry, we previously demonstrated that higher CD4+ and CD8+ T cells specific for CMV were found in the peripheral circulation of individuals who experienced CMV reactivation, but that more of these cells were dysfunctional in subjects experiencing viral reactivation. Recent studies have examined the role of maturation status of virus-specific T cells in the setting of of cleared, persistent and progressive viral infections. CD57 is a marker of replicative senescence that is expressed on a subset of human CD8+ memory T cells that generally lacks CD28 expression, and that is characterized by downregulation of the naïve and central memory T cell markers CD45RA and CCR7. To examine whether CMV reactivation after SCT was associated with late-stage differentiation of CMV-specific CD8+ T cells specific for viral proteins, we first examined the fraction of CD57-expressing CD8+ T cells in patients stratified by the occurrence of post-SCT viral reactivation. In 87 patients examined with HLA-peptide tetramer staining at approximately 3 months after allogeneic SCT, we found that individuals experiencing CMV reactivation within the first 100 days after SCT had significantly higher absolute numbers of circulating CD57+ tetramer-stained CD8+ T cells specific for CMV than those who did not experience viral reactivation (mean 11.8 vs. 1.6 CD57+ tetramer-stained cells/μl, median 3.3 vs. 0.08 cells/μl, p<0.0001). In individuals in whom >75% of tetramer-stained CD8+ T cells were CD57+, the incidence of CMV reactivation was 83%, in contrast to 52% of others. In other experiments, we found that CD57+ tetramerstained CD8+ T cells failed to expand following co-culture with autologous monocyte-derived dendritic cells pulsed with CMV peptide pools, confirming that CD57+ CMV-specific CD8+ T cells may have impaired proliferative capacity. Taken together, these results suggest that late-stage differentiation of memory CD8+ T cells may be indicative of an exhausted antigen-specific immune response, and that optimal post-SCT immune restoration should consider the differentiation status and not simply the numbers of antigen-specific T cells targeted. Figure Figure

Human Cytomegalovirus: Degranulation Is a Prominent Feature of Functionally Impaired pp65- and IE-1-Specific T-Cells in Patients after Allogeneic Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2572-2572
Author(s):  
Stephan Fuhrmann ◽  
Susanne Ganepola ◽  
Lutz Uharek ◽  
Eckhard Thiel ◽  
Wolf-Dieter Ludwig ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Human Cytomegalovirus ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
Cmv Reactivation

Abstract Human cytomegalovirus (CMV) reactivation and disease is still a frequent complication after allogeneic stem cell transplantation (allo SCT). It is well accepted that T-cell immunity is mandatory to control CMV infection and disease and much effort has been put into the development of cell-based monitoring assays. Nevertheless, no reliable marker for protective immunity has been established to date. Most studies use one CMV model antigen (pp65) to compare the frequencies of cytokine producers (mainly IFNg) or multimer-specific T-cells. Methods: In total, we recruited 16 patients after allo SCT, (7 high risk, 9 standard risk pts.). We used 8-colour flow cytometry to detect degranulation (mobilized CD107a/b), intracellular IFNg, TNFa, IL-2 production and CD28-expression in peptide pool stimulated pp65 and IE-1 specific CD8 T-cells. Results were compared to 7 healthy CMV exposed donors. Results: Degranulation identifies the highest percentage of CMV-specific T-cells in allo-transplanted patients (pp65: 0,94% degranulation and 0,31% IFNg; IE-1: 1,44% degranulation and 0,87% IFNg, mean frequency). These T-cells are relatively cytokine deficient compared to those in healthy donors (cytokine-production/degranulation ratio: SCT=0,42, healthy=0,72 for pp65, p=0,048; SCT=0,61, healthy= 1,00 for IE-1, p=0,133, U-test). The cytokine expression pattern differs between antigens used for stimulation, for example more IL-2-producers could be detected in the pp65 specific compartment (12,5% for pp65 and 4,5% for IE-1 of all activated CD8 T-cells, p=0,015). Conclusion: This study demonstrates that degranulation is the most prominent marker of CMV-specific T-cells (pp65 and IE-1) in allo SCT patients. Looking at IFN-g producers only may underestimate the frequencies of CMV specific T-cells in this setting. Furthermore, these subsets have a divergent functionality in transplant recipients compared to healthy individuals. Our data challenge the concept of enumerating CMV specific T-cells to estimate immunity. We rather propose measuring functional differences in the T-cell response may help to identify patients with a high risk of CMV reactivation. A careful dissection of these differences is a prerequisite for the development of monitoring tools and adoptive T-cell transfer.

scholarly journals miR-625-3p is upregulated in CD8+ T cells during early immune reconstitution after allogeneic stem cell transplantation

PLoS ONE ◽  
2017 ◽  
Vol 12 (8) ◽  
pp. e0183828 ◽  
Author(s):  
Kriti Verma ◽  
Nidhi Jyotsana ◽  
Ivonne Buenting ◽  
Susanne Luther ◽  
Angelika Pfanne ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cd8 T Cells ◽  
Allogeneic Stem Cell Transplantation ◽  
Immune Reconstitution
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