| 1. |
- Al Agrafi, Faisal, et al.
(författare)
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Selective lysis of acute myeloid leukemia cells by CD34/CD3 bispecific antibody through the activation of γδ T-cells
- 2024
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Ingår i: Oncoimmunology. - : Taylor and Francis Ltd.. - 2162-4011 .- 2162-402X. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite the considerable progress in acute myeloid leukemia (AML) treatment, relapse after allogeneic hematopoietic stem cell transplantation (HSCT) is still frequent and associated with a poor prognosis. Relapse has been shown to be correlated with an incomplete eradication of CD34+ leukemic stem cells prior to HSCT. Previously, we have shown that a novel CD34-directed, bispecific T-cell engager (BTE) can efficiently redirect the T-cell effector function toward cancer cells, thus eliminating leukemic cells in vitro and in vivo. However, its impact on γδ T-cells is still unclear. In this study, we tested the efficacy of the CD34-specific BTE using in vitro expanded γδ T-cells as effectors. We showed that the BTEs bind to γδ T-cells and CD34+ leukemic cell lines and induce target cell killing in a dose-dependent manner. Additionally, γδ T-cell mediated killing was found to be superior to αβ T-cell mediated cytotoxicity. Furthermore, we observed that only in the presence of BTE the γδ T-cells induced primary AML blast killing in vitro. Importantly, our results show that γδ T-cells did not target the healthy CD34intermediate endothelial blood–brain barrier cell line (hCMEC/D3) nor lysed CD34+ HSCs from healthy bone marrow samples.
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| 2. |
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| 3. |
- Arruda, Lucas C. M., et al.
(författare)
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Impact of gamma delta T cells on clinical outcome of hematopoietic stem cell transplantation : systematic review and meta-analysis
- 2019
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 3:21, s. 3436-3448
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Forskningsöversikt (refereegranskat)abstract
- Allogeneic hematopoietic stem cell transplantation (HSCT) using alpha beta T-/B-cell-depleted grafts recently emerged as a transplant strategy and highlighted the potential role of gamma delta T cells on HSCT outcomes. Our aim was to scrutinize available evidence of gamma delta T-cell impact on relapse, infections, survival, and acute graft-versus-host disease (aGVHD). We performed a systematic review and meta-analysis of studies assessing gamma delta T cells in HSCT. We searched PubMed, Web of Science, Scopus, and conference abstracts from inception to March 2019 for relevant studies. We included all studies that assessed gamma delta T cells associated with HSCT. Data were extracted independently by 2 investigators based on strict selection criteria. A random-effects model was used to pool outcomes across studies. Primary outcome was disease relapse. We also assessed infections, survival, and aGVHD incidence. The review was registered with PROSPERO (CRD42019133344). Our search returned 2412 studies, of which 11 (919 patients) were eligible for meta-analysis. Median follow-up was 30 months (interquartile range, 22-32). High gamma delta T-cell values after HSCT were associated with less disease relapse (risk ratio [RR], 0.58; 95% confidence interval [95% CI], 0.40-0.84; P = .004; I-2 = 0%), fewer viral infections (RR, 0.59; 95% CI, 0.43-0.82; P < .002; I-2 = 0%) and higher overall (HR, 0.28; 95% CI, 0.18-0.44; P < .00001; I-2 = 0%) and disease-free survivals (HR 0.29; 95% CI, 0.18-0.48; P < .00001; I-2 = 0%). We found no association between high gd T-cell values and aGVHD incidence (RR, 0.72; 95% CI, 0.41-1.27; P = .26; I-2 = 0%). In conclusion, high gd T cells after HSCT is associated with a favorable clinical outcome but not with aGVHD development, suggesting that gd T cells have a significant effect on the success of HSCT. This study was registered with PROSPERO as #CRD42019133344.
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| 4. |
- Berglund, Sofia, et al.
(författare)
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Expansion of Gammadelta T Cells from Cord Blood : A Therapeutical Possibility
- 2018
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Ingår i: STEM CELLS INTERNATIONAL. - : HINDAWI LTD. - 1687-966X .- 1687-9678.
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Tidskriftsartikel (refereegranskat)abstract
- Gammadelta (gamma delta) T cells are found in both blood and tissues and have antiviral and antitumor properties. The frequency of gamma delta T cells in umbilical cord blood (UCB) is low, and the majority express delta 1, in contrast to blood, whereas the main subset is delta 2 gamma 9 T cells. UCB gamma delta T cells are functionally immature, which together with their scarcity complicates the development of UCB gamma delta T cell therapies. We aimed to develop an effective expansion protocol for UCB gamma delta T cells based on zoledronate and IL-2. We found that culture with 5 mu M zoledronate and 200 IU IL-2/ml medium for 14 days promoted extensive proliferation. The majority of the cultured cells were gamma 9 delta 2 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 gamma delta 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 gamma delta T cell therapies is feasible. It could prove a valuable treatment modality for patients after umbilical cord blood transplantation.
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| 5. |
- Casulo, Carla, et al.
(författare)
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Autologous Transplantation in Follicular Lymphoma with Early Therapy Failure : A National LymphoCare Study and Center for International Blood and Marrow Transplant Research Analysis
- 2018
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 24:6, s. 1163-1171
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Tidskriftsartikel (refereegranskat)abstract
- Patients with follicular lymphoma (FL) experiencing early therapy failure (ETF) within 2 years of frontline chemoimmunotherapy have poor overall survival (OS). We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National LymphoCare Study (NLCS) to determine whether autologous hematopoietic cell transplant (autoHCT) can improve outcomes in this high-risk FL subgroup. ETF was defined as failure to achieve at least partial response after frontline chemoimmunotherapy or lymphoma progression within 2 years of frontline chemoimmunotherapy. We identified 2 groups: the non-autoHCT cohort (patients from the NLCS with ETF not undergoing autoHCT) and the autoHCT cohort (CIBMTR patients with ETF undergoing autoHCT). All patients received rituximab-based chemotherapy as frontline treatment; 174 non-autoHCT patients and 175 autoHCT patients were identified and analyzed. There was no difference in 5-year OS between the 2 groups (60% versus 67%, respectively; P = .16). A planned subgroup analysis showed that patients with ETF receiving autoHCT soon after treatment failure (≤1 year of ETF; n = 123) had higher 5-year OS than those without autoHCT (73% versus 60%, P = .05). On multivariate analysis, early use of autoHCT was associated with significantly reduced mortality (hazard ratio, .63; 95% confidence interval, .42 to .94; P = .02). Patients with FL experiencing ETF after frontline chemoimmunotherapy lack optimal therapy. We demonstrate improved OS when receiving autoHCT within 1 year of treatment failure. Results from this unique collaboration between the NLCS and CIBMTR support consideration of early consolidation with autoHCT in select FL patients experiencing ETF.
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| 6. |
- Foord, Emelie, et al.
(författare)
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Characterization of ascites- and tumor-infiltrating gamma delta T cells reveals distinct repertoires and a beneficial role in ovarian cancer
- 2021
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 13:577
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Tidskriftsartikel (refereegranskat)abstract
- The role of gamma delta T cells in antitumor immunity has been under investigation for the past two decades, but little is known about their contribution to clinical outcomes in patients. Here, we set out to define the clonotypic, phenotypic, and functional features of gamma delta T cells in peripheral blood, ascites, and metastatic tumor tissue from patients with advanced epithelial ovarian cancer. T cell receptor (TCR) sequencing of the gamma chain revealed that tumor-infiltrating gamma delta T cells have a unique and skewed repertoire with high TCR diversity and low clonality. In contrast, ascites-derived gamma delta T cells presented a lower TCR diversity and higher clonality, suggesting a TCR-dependent clonal focusing at this site. Further investigation showed that tumor samples had abundant gamma delta T cells with a tissue-resident, activation-associated phenotype, less usage of V gamma 9 and an impaired response to adaptive-associated stimuli, implying an innate-like activation pathway, rather than an adaptive TCR-engaging pathway, at these tumor sites. Furthermore, high gamma delta T cell cytokine responsiveness upon stimulation was associated with a favorable outcome for patients in terms of both overall survival and reduced residual tumor burden after primary surgery. Last, the functionality of gamma delta T cells and patient survival were negatively affected by the proportions of CD39-expressing T cells, highlighting the potential of CD39 as a target to improve gamma delta T cell responses and unleash their antitumor capabilities.
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| 7. |
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| 8. |
- Gaballa, Ahmed, et al.
(författare)
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CD8(+)gamma delta T Cells Are More Frequent in CMV Seropositive Bone Marrow Grafts and Display Phenotype of an Adaptive Immune Response
- 2019
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Ingår i: STEM CELLS INTERNATIONAL. - : HINDAWI LTD. - 1687-966X .- 1687-9678. ; 2019
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Tidskriftsartikel (refereegranskat)abstract
- The role of gamma delta (gamma delta) T cells in human cytomegalovirus (HCMV) immune surveillance has been the focus of research interest for years. Recent reports have shown a substantial clonal proliferation of gamma delta T cells in response to HCMV, shedding light on the adaptive immune response of gamma delta T cells. Nevertheless, most efforts have focused on V delta 2(neg)gamma delta T cell subset while less attention has been given to investigate other less common gamma delta T cell subsets. In this regard, a distinct subpopulation of gamma delta T cells that expresses the CD8 coreceptor (CD8(+)gamma delta T cells) has not been thoroughly explored. Whether it is implicated in HCMV response and its ability to generate adaptive response has not been thoroughly investigated. In this study, we combined flow cytometry and immune sequencing of the TCR gamma-chain (TRG) to analyze in-depth bone marrow (BM) graft gamma delta T cells from CMV seropositive (CMV+) and CMV seronegative (CMV-) donors. We showed that the frequency of CD8(+)gamma delta T cells was significantly higher in CMV+ grafts compared to CMV- grafts (P<0.001). Further characterization revealed that CD8(+)gamma delta T cells from CMV+ grafts express V gamma 9(-) and preferentially differentiated from a naive to terminal effector memory phenotype (CD27(low/-)CD45RO(-)). In line with these findings, TRG immune sequencing revealed clonal focusing and reduced usage of the V gamma 9/JP gene segment in a CMV+ graft. Furthermore, CD8(+)gamma delta T cells showed an enhanced response to TCR/CD3 and cytokine stimulation in contrast to CD8(-)gamma delta T cells. We conclude that gamma delta T cells in BM grafts are reshaped by donor CMV serostatus and highlight the potential adaptive role of CD8(+)gamma delta T cells in HCMV immune response.
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| 9. |
- Gaballa, Ahmed
(författare)
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Characterization of human gamma delta T cells in allogeneic hematopoietic stem cell transplantation
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Over the last five decades, allogeneic hematopoietic stem cell transplantation (HSCT) has evolved rapidly, continuing to offer a cure for several hematological diseases. Nevertheless, associated life-threatening complications remain an obstacle against exploiting its full therapeutic benefit. Among these complications, infection, relapse, and graft-versus-host disease (GVHD) represent not only the most common but also the most serious ones. Though commonly regarded as distinct clinical events, their underlying pathophysiology is firmly related from an immunological perspective. T lymphocytes are key players in HSCT complications and their proper reconstitution following allogeneic HSCT is central for beneficial clinical outcome. The last two decades have witnessed a growing interest in a subset of T cells known as gamma delta (γδ) T cells. The immunological capabilities of these unconventional cells have been intensively explored. However, more efforts aimed at unraveling the immunobiological features of different γδ subsets are warranted to effectively exploit their full immunotherapeutic potential. In the present work, I tried to tackle several immune-related aspects that directly influence allogeneic HSCT outcome with a special focus on γδ T cells. In paper I, the main objective was to address the impact of different GVHD prophylaxis regimens on de novo generation of T and B lymphocytes. Using PCR methods, T cell receptor recombination excision circle (TREC), kappa deleting recombination excision circle (KREC), and telomere length (TL) were quantified in the peripheral blood (PB) of transplanted patients at several time intervals. Although there was no significant difference between the two GVHD prophylaxis groups, we identified other transplant related factors that were associated with reduced TREC and/or KREC levels after HSCT. Furthermore, we showed that high levels of these excision circles correlated with favorable outcome post HSCT. In paper II-IV, more attention was paid to explore the role of γδ T cells in donor grafts. Using multicolor flow cytometry together with other molecular and functional assays, we found a significant association between graft frequencies of CD8+γδ T cells and acute GVHD (aGVHD) grade II-III in Paper II. Additionally, we showed that higher frequencies of CD27+ γδ T cells in the stem cell grafts were correlated with both less relapse and CMV incidences. The results from paper II highlighting a potential role of CD8+γδ T cells in donor grafts raised our interest to further investigate this subset to elucidate their immunological characteristics. In paper III we thoroughly analysed γδ T cells in BM grafts using multicolor flow cytometry and TCR repertoire analysis using next generation sequencing (NGS). We showed that grafts from CMV+ donors contained higher proportions of CD8+γδ T that preferentially expressed Vγ9- and differentiated towards terminal effector memory phenotype. Additionally, analysis of TCRγ chain revealed a clonally focused repertoire in CMV+ donor grafts. We also showed that CD8+γδ T cells differentially respond to TCR stimuli suggesting adaptive-like phenotype. In paper IV, we sought to address whether allogeneic HSCT outcome is influenced by γδ TCR repertoire composition in donor grafts. Immunosequencing of TCRγ chain by NGS revealed a more public repertoire and increased presence of long sequence clonotypes in graft given to non-relapsed patients. Further analysis of the amino acid sequences identified 12 public and 4 private sequences that were exclusively found in high frequencies in grafts given to nonrelapsed patients. Finally, in paper V we aimed to optimize a protocol for efficient in-vitro expansion of Vγ9Vδ2 T cells from umbilical cord blood (UCB). Phenotypical and functional characterization of expanded cells was comparable to PB and suggests that UCB can be a reliable source for Vγ9Vδ2 T cell expansion.
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| 10. |
- Gaballa, Ahmed, et al.
(författare)
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Evaluating Thymic Function After Human Hematopoietic Stem Cell Transplantation in the Personalized Medicine Era
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Forskningsöversikt (refereegranskat)abstract
- Hematopoietic stem cell transplantation (HSCT) is an effective treatment option for several malignant and non-malignant hematological diseases. The clinical outcome of this procedure relies to a large extent on optimal recovery of adaptive immunity. In this regard, the thymus plays a central role as the primary site forde novogeneration of functional, diverse, and immunocompetent T-lymphocytes. The thymus is exquisitely sensitive to several insults during HSCT, including conditioning drugs, corticosteroids, infections, and graft-vs.-host disease. Impaired thymic recovery has been clearly associated with increased risk of opportunistic infections and poor clinical outcomes in HSCT recipients. Therefore, better understanding of thymic function can provide valuable information for improving HSCT outcomes. Recent data have shown that, besides gender and age, a specific single-nucleotide polymorphism affects thymopoiesis and may also influence thymic output post-HSCT, suggesting that the time of precision medicine of thymic function has arrived. Here, we review the current knowledge about thymic role in HSCT and the recent work of genetic control of human thymopoiesis. We also discuss different transplant-related factors that have been associated with impaired thymic recovery and the use of T-cell receptor excision circles (TREC) to assess thymic output, including its clinical significance. Finally, we present therapeutic strategies that could boost thymic recovery post-HSCT.
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