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Dr. Ahmed Gaballa
Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

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0 Immune System
0 GvHD
0 transplantation
0 gamma delta t cells

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Review
Published: 29 May 2021 in Viruses
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Gamma delta (γδ) T cells form an unconventional subset of T lymphocytes that express a T cell receptor (TCR) consisting of γ and δ chains. Unlike conventional αβ T cells, γδ T cells share the immune signature of both the innate and the adaptive immunity. These features allow γδ T cells to act in front-line defense against infections and tumors, rendering them an attractive target for immunotherapy. The role of γδ T cells in the immune response to cytomegalovirus (CMV) has been the focus of intense research for several years, particularly in the context of transplantation, as CMV reactivation remains a major cause of transplant-related morbidity and mortality. Therefore, a better understanding of the mechanisms that underlie CMV immune responses could enable the design of novel γδ T cell-based therapeutic approaches. In this regard, the advent of next-generation sequencing (NGS) and single-cell TCR sequencing have allowed in-depth characterization of CMV-induced TCR repertoire changes. In this review, we try to shed light on recent findings addressing the adaptive role of γδ T cells in CMV immunosurveillance and revisit CMV-induced TCR reshaping in the era of NGS. Finally, we will demonstrate the favorable and unfavorable effects of CMV reactive γδ T cells post-transplantation.

ACS Style

Ahmed Gaballa; Faisal Alagrafi; Michael Uhlin; Arwen Stikvoort. Revisiting the Role of γδ T Cells in Anti-CMV Immune Response after Transplantation. Viruses 2021, 13, 1031 .

AMA Style

Ahmed Gaballa, Faisal Alagrafi, Michael Uhlin, Arwen Stikvoort. Revisiting the Role of γδ T Cells in Anti-CMV Immune Response after Transplantation. Viruses. 2021; 13 (6):1031.

Chicago/Turabian Style

Ahmed Gaballa; Faisal Alagrafi; Michael Uhlin; Arwen Stikvoort. 2021. "Revisiting the Role of γδ T Cells in Anti-CMV Immune Response after Transplantation." Viruses 13, no. 6: 1031.

Research article
Published: 20 January 2021 in Science Translational Medicine
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The role of γδ 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 γδ T cells in peripheral blood, ascites, and metastatic tumor tissue from patients with advanced epithelial ovarian cancer. T cell receptor (TCR) sequencing of the γ chain revealed that tumor-infiltrating γδ T cells have a unique and skewed repertoire with high TCR diversity and low clonality. In contrast, ascites-derived γδ 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 γδ T cells with a tissue-resident, activation-associated phenotype, less usage of Vγ9 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 γδ 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 γδ 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 γδ T cell responses and unleash their antitumor capabilities.

ACS Style

Emelie Foord; Lucas C. M. Arruda; Ahmed Gaballa; Charlotte Klynning; Michael Uhlin. Characterization of ascites- and tumor-infiltrating γδ T cells reveals distinct repertoires and a beneficial role in ovarian cancer. Science Translational Medicine 2021, 13, eabb0192 .

AMA Style

Emelie Foord, Lucas C. M. Arruda, Ahmed Gaballa, Charlotte Klynning, Michael Uhlin. Characterization of ascites- and tumor-infiltrating γδ T cells reveals distinct repertoires and a beneficial role in ovarian cancer. Science Translational Medicine. 2021; 13 (577):eabb0192.

Chicago/Turabian Style

Emelie Foord; Lucas C. M. Arruda; Ahmed Gaballa; Charlotte Klynning; Michael Uhlin. 2021. "Characterization of ascites- and tumor-infiltrating γδ T cells reveals distinct repertoires and a beneficial role in ovarian cancer." Science Translational Medicine 13, no. 577: eabb0192.

Mini review article
Published: 31 July 2020 in Frontiers in Immunology
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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 for de novo generation 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.

ACS Style

Ahmed Gaballa; Emmanuel Clave; Michael Uhlin; Antoine Toubert; Lucas C. M. Arruda. Evaluating Thymic Function After Human Hematopoietic Stem Cell Transplantation in the Personalized Medicine Era. Frontiers in Immunology 2020, 11, 1341 .

AMA Style

Ahmed Gaballa, Emmanuel Clave, Michael Uhlin, Antoine Toubert, Lucas C. M. Arruda. Evaluating Thymic Function After Human Hematopoietic Stem Cell Transplantation in the Personalized Medicine Era. Frontiers in Immunology. 2020; 11 ():1341.

Chicago/Turabian Style

Ahmed Gaballa; Emmanuel Clave; Michael Uhlin; Antoine Toubert; Lucas C. M. Arruda. 2020. "Evaluating Thymic Function After Human Hematopoietic Stem Cell Transplantation in the Personalized Medicine Era." Frontiers in Immunology 11, no. : 1341.

Research article
Published: 03 July 2020 in Science Immunology
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CD8+ T cell exhaustion is a hallmark of many cancers and chronic infections. In mice, T cell factor 1 (TCF-1) maintains exhausted CD8+ T cell responses, whereas thymocyte selection-associated HMG box (TOX) is required for the epigenetic remodeling and survival of exhausted CD8+ T cells. However, it has remained unclear to what extent these transcription factors play analogous roles in humans. In this study, we mapped the expression of TOX and TCF-1 as a function of differentiation and specificity in the human CD8+ T cell landscape. Here, we demonstrate that circulating TOX+ CD8+ T cells exist in most humans, but that TOX is not exclusively associated with exhaustion. Effector memory CD8+ T cells generally expressed TOX, whereas naive and early-differentiated memory CD8+ T cells generally expressed TCF-1. Cytolytic gene and protein expression signatures were also defined by the expression of TOX. In the context of a relentless immune challenge, exhausted HIV-specific CD8+ T cells commonly expressed TOX, often in clusters with various activation markers and inhibitory receptors, and expressed less TCF-1. However, polyfunctional memory CD8+ T cells specific for cytomegalovirus (CMV) or Epstein-Barr virus (EBV) also expressed TOX, either with or without TCF-1. A similar phenotype was observed among HIV-specific CD8+ T cells from individuals who maintained exceptional immune control of viral replication. Collectively, these data demonstrate that TOX is expressed by most circulating effector memory CD8+ T cell subsets and not exclusively linked to exhaustion.

ACS Style

Takuya Sekine; André Perez-Potti; Son Nguyen; Jean-Baptiste Gorin; Vincent H. Wu; Emma Gostick; Sian Llewellyn-Lacey; Quirin Hammer; Sara Falck-Jones; Sindhu Vangeti; Meng Yu; Anna Smed-Sörensen; Ahmed Gaballa; Michael Uhlin; Johan K. Sandberg; Christian Brander; Piotr Nowak; Paul A. Goepfert; David A. Price; Michael R. Betts; Marcus Buggert. TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells. Science Immunology 2020, 5, eaba7918 .

AMA Style

Takuya Sekine, André Perez-Potti, Son Nguyen, Jean-Baptiste Gorin, Vincent H. Wu, Emma Gostick, Sian Llewellyn-Lacey, Quirin Hammer, Sara Falck-Jones, Sindhu Vangeti, Meng Yu, Anna Smed-Sörensen, Ahmed Gaballa, Michael Uhlin, Johan K. Sandberg, Christian Brander, Piotr Nowak, Paul A. Goepfert, David A. Price, Michael R. Betts, Marcus Buggert. TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells. Science Immunology. 2020; 5 (49):eaba7918.

Chicago/Turabian Style

Takuya Sekine; André Perez-Potti; Son Nguyen; Jean-Baptiste Gorin; Vincent H. Wu; Emma Gostick; Sian Llewellyn-Lacey; Quirin Hammer; Sara Falck-Jones; Sindhu Vangeti; Meng Yu; Anna Smed-Sörensen; Ahmed Gaballa; Michael Uhlin; Johan K. Sandberg; Christian Brander; Piotr Nowak; Paul A. Goepfert; David A. Price; Michael R. Betts; Marcus Buggert. 2020. "TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells." Science Immunology 5, no. 49: eaba7918.

Research article
Published: 06 December 2019 in Stem Cells International
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The role of gamma delta (γδ) 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 γδ T cells in response to HCMV, shedding light on the adaptive immune response of γδ T cells. Nevertheless, most efforts have focused on Vδ2negγδ T cell subset while less attention has been given to investigate other less common γδ T cell subsets. In this regard, a distinct subpopulation of γδ T cells that expresses the CD8 coreceptor (CD8+γδ 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 γ-chain (TRG) to analyze in-depth bone marrow (BM) graft γδ T cells from CMV seropositive (CMV+) and CMV seronegative (CMV-) donors. We showed that the frequency of CD8+γδ T cells was significantly higher in CMV+ grafts compared to CMV- grafts (P<0.001). Further characterization revealed that CD8+γδ T cells from CMV+ grafts express Vγ9- and preferentially differentiated from a naive to terminal effector memory phenotype (CD27low/-CD45RO-). In line with these findings, TRG immune sequencing revealed clonal focusing and reduced usage of the Vγ9/JP gene segment in a CMV+ graft. Furthermore, CD8+γδ T cells showed an enhanced response to TCR/CD3 and cytokine stimulation in contrast to CD8-γδ T cells. We conclude that γδ T cells in BM grafts are reshaped by donor CMV serostatus and highlight the potential adaptive role of CD8+γδ T cells in HCMV immune response.

ACS Style

Ahmed Gaballa; Lucas C. M. Arruda; Emelie Foord (Former Surname Rådestad); Michael Uhlin. CD8+γδ T Cells Are More Frequent in CMV Seropositive Bone Marrow Grafts and Display Phenotype of an Adaptive Immune Response. Stem Cells International 2019, 2019, 1 -13.

AMA Style

Ahmed Gaballa, Lucas C. M. Arruda, Emelie Foord (Former Surname Rådestad), Michael Uhlin. CD8+γδ T Cells Are More Frequent in CMV Seropositive Bone Marrow Grafts and Display Phenotype of an Adaptive Immune Response. Stem Cells International. 2019; 2019 ():1-13.

Chicago/Turabian Style

Ahmed Gaballa; Lucas C. M. Arruda; Emelie Foord (Former Surname Rådestad); Michael Uhlin. 2019. "CD8+γδ T Cells Are More Frequent in CMV Seropositive Bone Marrow Grafts and Display Phenotype of an Adaptive Immune Response." Stem Cells International 2019, no. : 1-13.

Review
Published: 12 November 2019 in Blood Advances
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Allogeneic hematopoietic stem cell transplantation (HSCT) using αβ T-/B-cell-depleted grafts recently emerged as a transplant strategy and highlighted the potential role of γδ T cells on HSCT outcomes. Our aim was to scrutinize available evidence of γδ 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 γδ 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 γδ 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 γδ 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; I2 = 0%), fewer viral infections (RR, 0.59; 95% CI, 0.43-0.82; P = .002; I2 = 0%) and higher overall (HR, 0.28; 95% CI, 0.18-0.44; P < .00001; I2 = 0%) and disease-free survivals (HR 0.29; 95% CI, 0.18-0.48; P < .00001; I2 = 0%). We found no association between high γδ T-cell values and aGVHD incidence (RR, 0.72; 95% CI, 0.41-1.27; P = .26; I2 = 0%). In conclusion, high γδ T cells after HSCT is associated with a favorable clinical outcome but not with aGVHD development, suggesting that γδ T cells have a significant effect on the success of HSCT. This study was registered with PROSPERO as #CRD42019133344.

ACS Style

Lucas C. M. Arruda; Ahmed Gaballa; Michael Uhlin. Impact of γδ T cells on clinical outcome of hematopoietic stem cell transplantation: systematic review and meta-analysis. Blood Advances 2019, 3, 3436 -3448.

AMA Style

Lucas C. M. Arruda, Ahmed Gaballa, Michael Uhlin. Impact of γδ T cells on clinical outcome of hematopoietic stem cell transplantation: systematic review and meta-analysis. Blood Advances. 2019; 3 (21):3436-3448.

Chicago/Turabian Style

Lucas C. M. Arruda; Ahmed Gaballa; Michael Uhlin. 2019. "Impact of γδ T cells on clinical outcome of hematopoietic stem cell transplantation: systematic review and meta-analysis." Blood Advances 3, no. 21: 3436-3448.

Journal article
Published: 01 June 2019 in Biology of Blood and Marrow Transplantation
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Lymphocyte reconstitution is pivotal for successful long-term outcome after allogeneic hematopoietic stem cell transplantation (HSCT), and conditioning regimen and post-transplantation immunosuppression are risk factors for prolonged immunodeficiency. Nevertheless, the effects of different immunosuppressive protocols on lymphocyte output and replicative capacity have not been investigated. Here we assessed T cell receptor excision circles (TREC), kappa-deleting recombination excision circles (KREC), and T cell telomere length (TL) as proxy markers for immune reconstitution in patients in a prospective randomized trial comparing graft-versus-host disease (GVHD) prophylaxis after transplantation (cyclosporine/methotrexate versus tacrolimus/sirolimus; n = 200). Results showed that medians of TREC, KREC, and TL were not significantly different between the prophylaxis groups at any assessment time point during follow-up (24 months), but the kinetics of TREC, KREC, and TL were significantly influenced by other transplantation-related factors. Older recipient age, the use of antithymocyte globulin before graft infusion, and use of peripheral blood stem cell grafts were associated with lower TREC levels, whereas acute GVHD transiently affected KREC levels. Patients with lymphocyte excision circle levels above the median at ≤6 months post-transplantation had reduced transplantation-related mortality and superior 5-year overall survival (P < .05). We noticed significant T cell telomere shortening in the patient population as a whole during follow-up. Our results suggest that lymphocyte reconstitution after transplantation is not altered by different immunosuppressive protocols. This study has been registered at ClinicalTrials.gov (identifier: NCT00993343).

ACS Style

Johan Törlén; Ahmed Gaballa; Mats Remberger; Lisa-Mari Mörk; Berit Sundberg; Jonas Mattsson; Michael Uhlin. Effect of Graft-versus-Host Disease Prophylaxis Regimens on T and B Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation. Biology of Blood and Marrow Transplantation 2019, 25, 1260 -1268.

AMA Style

Johan Törlén, Ahmed Gaballa, Mats Remberger, Lisa-Mari Mörk, Berit Sundberg, Jonas Mattsson, Michael Uhlin. Effect of Graft-versus-Host Disease Prophylaxis Regimens on T and B Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation. Biology of Blood and Marrow Transplantation. 2019; 25 (6):1260-1268.

Chicago/Turabian Style

Johan Törlén; Ahmed Gaballa; Mats Remberger; Lisa-Mari Mörk; Berit Sundberg; Jonas Mattsson; Michael Uhlin. 2019. "Effect of Graft-versus-Host Disease Prophylaxis Regimens on T and B Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation." Biology of Blood and Marrow Transplantation 25, no. 6: 1260-1268.

Journal article
Published: 05 February 2019 in Bone Marrow Transplantation
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The impact of intra-graft T cells on the clinical outcome after allogeneic hematopoietic cell transplantation has been investigated. Most previous studies have focused on the role of αβ cells while γδ cells have received less attention. It has been an open question whether γδ cells are beneficial or not for patient outcome, especially with regards to graft versus host disease. In this study, graft composition of γδ cell subsets was analyzed and correlated to clinical outcome in 105 recipients who underwent allogeneic hematopoietic cell transplantation between 2013 and 2016. We demonstrate for the first time that grafts containing higher T-cell proportions of CD8+γδ cells were associated with increased cumulative incidence of acute graft versus host disease grade II–III (50% vs 22.6%; P = 0.008). Additionally, graft T-cell frequency of CD27+γδ cells was inversely correlated with relapse (P = 0.006) and CMV reactivation (P = 0.05). We conclude that clinical outcome after allogeneic hematopoietic cell transplantation is influenced by the proportions of distinct γδ cell subsets in the stem cell graft. We also provide evidence that CD8+γδ cells are potentially alloreactive and may play a role in acute graft versus host disease. This study illustrates the importance of better understanding of the role of distinct subsets of γδ cells in allogeneic hematopoietic cell transplantation.

ACS Style

Ahmed Gaballa; Arwen Stikvoort; Björn Önfelt; Jonas Mattsson; Mikael Sundin; Emma Watz; Michael Uhlin. T-cell frequencies of CD8+ γδ and CD27+ γδ cells in the stem cell graft predict the outcome after allogeneic hematopoietic cell transplantation. Bone Marrow Transplantation 2019, 54, 1562 -1574.

AMA Style

Ahmed Gaballa, Arwen Stikvoort, Björn Önfelt, Jonas Mattsson, Mikael Sundin, Emma Watz, Michael Uhlin. T-cell frequencies of CD8+ γδ and CD27+ γδ cells in the stem cell graft predict the outcome after allogeneic hematopoietic cell transplantation. Bone Marrow Transplantation. 2019; 54 (10):1562-1574.

Chicago/Turabian Style

Ahmed Gaballa; Arwen Stikvoort; Björn Önfelt; Jonas Mattsson; Mikael Sundin; Emma Watz; Michael Uhlin. 2019. "T-cell frequencies of CD8+ γδ and CD27+ γδ cells in the stem cell graft predict the outcome after allogeneic hematopoietic cell transplantation." Bone Marrow Transplantation 54, no. 10: 1562-1574.

Journal article
Published: 01 February 2019 in The Journal of Immunology
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Although the impact of donor graft composition on clinical outcomes after hematopoietic stem cell transplantation (HSCT) has been studied, little is known about the role of intragraft γδ TCR repertoire on clinical outcomes following HSCT. Using a high-throughput sequencing platform, we sought to analyze the TCR γ-chain (TRG) repertoire of γδ T cells within donor stem cell grafts and address its potential impact on clinical response in the corresponding patients. A total of 20 peripheral blood stem cell grafts were analyzed, and donors were classified as CMV+/−. The respective acute myeloid leukemia recipients were followed for disease relapse and acute graft-versus-host disease (aGvHD) development post-HSCT. In all samples, TRG repertoire showed a reduced diversity and displayed overrepresented clones. This was more prominent in grafts from CMV+ donors, which presented a more private repertoire, lower diversity, skewed distribution, and reduced usage of the V9-JP pairing. Grafts given to nonrelapse patients presented a more public repertoire and increased presence of long sequence clonotypes. Variable-joining gene segment usage was not associated with aGvHD development, but a higher usage of V2-JP1 pairing and lower usage of V4-J2/V5-J2/V8-JP2 were observed in grafts given to nonrelapse patients. Our work identified five private overrepresented and one public CDR3 sequence (CATWDGPYYKKLF) associated with CMV infection, in addition to 12 highly frequent public sequences present exclusively in grafts given to nonrelapse patients. Our findings show that, despite CMV infection reshaping the TRG repertoire, TRG composition is not associated with aGvHD development, and several public sequences are associated with clinical remission.

ACS Style

Lucas C. M. Arruda; Ahmed Gaballa; Michael Uhlin. Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution. The Journal of Immunology 2019, 202, 1859 -1870.

AMA Style

Lucas C. M. Arruda, Ahmed Gaballa, Michael Uhlin. Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution. The Journal of Immunology. 2019; 202 (6):1859-1870.

Chicago/Turabian Style

Lucas C. M. Arruda; Ahmed Gaballa; Michael Uhlin. 2019. "Graft γδ TCR Sequencing Identifies Public Clonotypes Associated with Hematopoietic Stem Cell Transplantation Efficacy in Acute Myeloid Leukemia Patients and Unravels Cytomegalovirus Impact on Repertoire Distribution." The Journal of Immunology 202, no. 6: 1859-1870.

Journal article
Published: 30 May 2018 in Cytotherapy
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The use of CD19 chimeric antigen receptor (CAR) T cells to treat B-cell malignancies has proven beneficial. Several groups use serum to produce CD19 CAR T cells. Today, ready-to-use serum-free media that require no addition of serum are commercially available. Therefore, it becomes important to evaluate the production of CD19 CAR T cells with and without the addition of serum. T cells from buffy coats were cultured in AIM-V and TexMACS (TM) supplemented with 5% human serum (A5% and TM5%, respectively), and in TM without serum. Cells were activated with OKT3 and expanded in interleukin (IL)-2. Viral transduction was performed in RetroNectin-coated plates using the spinoculation method. CD19 CAR T cells were tested for their viability, expansion, transduction efficacy, phenotype and cytotoxicity. CD19 CAR T cells expanded in A5% and TM5% showed significantly better viability and higher fold expansion than cells expanded in TM. TM promoted the expansion of CD8+ T cells and effector phenotype of CD19 CAR T cells. The transduction efficacy and the cytotoxic function were comparable between the different media. Higher CD107a+ cells were detected in TM and TM5%, whereas higher IL-2+ and IL-17+ cells were detected in A5%. CD19 CAR exhibited co-expression of inhibitory receptors such as TIM-3+LAG-3+ and/or TIM-3+PD-1+. Our results indicate that serum supplementation promotes better CD19 CAR T-cell expansion and viability in vitro. CD19 CAR T cells produced in TM medium showed lower CD4/CD8 ratio, which warrants further evaluation in clinical settings. Overall, the choice of culture medium impacts CD19 CAR T-cell end product.

ACS Style

Rehab Alnabhan; Ahmed Gaballa; Lisa-Mari Mörk; Jonas Mattsson; Michael Uhlin; Isabelle Magalhaes. Media evaluation for production and expansion of anti-CD19 chimeric antigen receptor T cells. Cytotherapy 2018, 20, 941 -951.

AMA Style

Rehab Alnabhan, Ahmed Gaballa, Lisa-Mari Mörk, Jonas Mattsson, Michael Uhlin, Isabelle Magalhaes. Media evaluation for production and expansion of anti-CD19 chimeric antigen receptor T cells. Cytotherapy. 2018; 20 (7):941-951.

Chicago/Turabian Style

Rehab Alnabhan; Ahmed Gaballa; Lisa-Mari Mörk; Jonas Mattsson; Michael Uhlin; Isabelle Magalhaes. 2018. "Media evaluation for production and expansion of anti-CD19 chimeric antigen receptor T cells." Cytotherapy 20, no. 7: 941-951.

Research article
Published: 07 March 2018 in Stem Cells International
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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.

ACS Style

Sofia Berglund; Ahmed Gaballa; Piamsiri Sawaisorn; Berit Sundberg; Michael Uhlin. Expansion of Gammadelta T Cells from Cord Blood: A Therapeutical Possibility. Stem Cells International 2018, 2018, 1 -15.

AMA Style

Sofia Berglund, Ahmed Gaballa, Piamsiri Sawaisorn, Berit Sundberg, Michael Uhlin. Expansion of Gammadelta T Cells from Cord Blood: A Therapeutical Possibility. Stem Cells International. 2018; 2018 ():1-15.

Chicago/Turabian Style

Sofia Berglund; Ahmed Gaballa; Piamsiri Sawaisorn; Berit Sundberg; Michael Uhlin. 2018. "Expansion of Gammadelta T Cells from Cord Blood: A Therapeutical Possibility." Stem Cells International 2018, no. : 1-15.

Clinical trial
Published: 01 March 2018 in Biology of Blood and Marrow Transplantation
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Acute graft-versus-host disease (aGVHD) is one of the main major complications of post hematopoietic stem cell transplantation (HSCT). Identifying patients at risk of severe aGVHD may lead to earlier intervention and treatment, resulting in increased survival and a better quality of life. We aimed to identify biomarkers in donor grafts and patient plasma around the time of transplantation which might be predictive of aGVHD development. We build upon our previously published methods by using multiplex assays and multi-colour flow cytometry. We identified five easily assessable cellular markers in donor grafts that combined could potentially be used to calculate risk for severe aGVHD development. Most noteworthy are the T cell subsets expressing IL-7 receptor-α (CD127) and PD-1. Additionally, we identified a potential role for elevated TNFα levels in both graft and patient before HSCT in development of aGVHD.

ACS Style

Arwen Stikvoort; Ahmed Gaballa; Martin Solders; Iris Nederlof; Björn Önfelt; Berit Sundberg; Mats Remberger; Mikael Sundin; Jonas Mattsson; Michael Uhlin. Risk Factors for Severe Acute Graft-versus-Host Disease in Donor Graft Composition. Biology of Blood and Marrow Transplantation 2018, 24, 467 -477.

AMA Style

Arwen Stikvoort, Ahmed Gaballa, Martin Solders, Iris Nederlof, Björn Önfelt, Berit Sundberg, Mats Remberger, Mikael Sundin, Jonas Mattsson, Michael Uhlin. Risk Factors for Severe Acute Graft-versus-Host Disease in Donor Graft Composition. Biology of Blood and Marrow Transplantation. 2018; 24 (3):467-477.

Chicago/Turabian Style

Arwen Stikvoort; Ahmed Gaballa; Martin Solders; Iris Nederlof; Björn Önfelt; Berit Sundberg; Mats Remberger; Mikael Sundin; Jonas Mattsson; Michael Uhlin. 2018. "Risk Factors for Severe Acute Graft-versus-Host Disease in Donor Graft Composition." Biology of Blood and Marrow Transplantation 24, no. 3: 467-477.

Journal article
Published: 12 December 2017 in Pediatric Allergy and Immunology
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Immunodeficiency associated with mutations in the DNA cross-link repair 1C gene (DCLRE1C) can have variable clinical presentations including severe combined immunodeficiency (SCID), Omenn syndrome, atypical SCID or common variable immunodeficiency (CVID) (1-3). DCLRE1C encodes the protein Artemis, a nuclease with intrinsic 5'-3' exonuclease activity on single-stranded DNA that is involved in non-homologous end joining (NHEJ). Artemis is essential for V(D)J recombination of the immunoglobulin and T-cell receptor genes that occur during B- and T-cell development.

ACS Style

Mikael Sundin; Michael Uhlin; Ahmed Gaballa; Kim Ramme; Antonios Kolios; Per Marits; Jakob Nilsson. Late presenting atypical severe combined immunodeficiency (SCID) associated with a novel missense mutation in DCLRE1C. Pediatric Allergy and Immunology 2017, 29, 108 -111.

AMA Style

Mikael Sundin, Michael Uhlin, Ahmed Gaballa, Kim Ramme, Antonios Kolios, Per Marits, Jakob Nilsson. Late presenting atypical severe combined immunodeficiency (SCID) associated with a novel missense mutation in DCLRE1C. Pediatric Allergy and Immunology. 2017; 29 (1):108-111.

Chicago/Turabian Style

Mikael Sundin; Michael Uhlin; Ahmed Gaballa; Kim Ramme; Antonios Kolios; Per Marits; Jakob Nilsson. 2017. "Late presenting atypical severe combined immunodeficiency (SCID) associated with a novel missense mutation in DCLRE1C." Pediatric Allergy and Immunology 29, no. 1: 108-111.

Journal article
Published: 09 October 2017 in Bone Marrow Transplantation
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Reconstitution of the adaptive immune system following allogeneic hematopoietic stem cell transplantation is crucial for beneficial outcome and is affected by several factors, such as GvHD and graft source. The impact of these factors on immune reconstitution has been thoroughly investigated during the early phase after transplantation. However, little is known about their long-term effect. Similarly, leukocyte telomere length (TL) shortening has been reported shortly after transplantation. Nevertheless, whether TL shortening continues in long-term aspect is still unsettled. Here, we assessed T-cell receptor excision circle (TREC), kappa deleting recombination excision circle (KREC) and leukocyte TL in recipients and donors several years post transplantation (median 17 years). Our analysis showed that, recipients who received bone marrow (BM) as the graft source have higher levels of both TREC and KREC. Also, chronic GvHD affected TREC levels and TL but not KREC levels. Finally, we show that recipient’s TL was longer than respective donors in a group of young age recipients with high KREC levels. Our results suggest that BM can be beneficial for long-term adaptive immune recovery. We also present supporting evidence for recipient telomere homeostasis, especially in young age recipients, rather than telomere shortening.

ACS Style

A Gaballa; A Norberg; A Stikvoort; J Mattsson; B Sundberg; M Uzunel; M Remberger; M Uhlin. Assessment of TREC, KREC and telomere length in long-term survivors after allogeneic HSCT: the role of GvHD and graft source and evidence for telomere homeostasis in young recipients. Bone Marrow Transplantation 2017, 53, 69 -77.

AMA Style

A Gaballa, A Norberg, A Stikvoort, J Mattsson, B Sundberg, M Uzunel, M Remberger, M Uhlin. Assessment of TREC, KREC and telomere length in long-term survivors after allogeneic HSCT: the role of GvHD and graft source and evidence for telomere homeostasis in young recipients. Bone Marrow Transplantation. 2017; 53 (1):69-77.

Chicago/Turabian Style

A Gaballa; A Norberg; A Stikvoort; J Mattsson; B Sundberg; M Uzunel; M Remberger; M Uhlin. 2017. "Assessment of TREC, KREC and telomere length in long-term survivors after allogeneic HSCT: the role of GvHD and graft source and evidence for telomere homeostasis in young recipients." Bone Marrow Transplantation 53, no. 1: 69-77.

Review
Published: 13 April 2017 in Expert Opinion on Biological Therapy
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Introduction: Umbilical cord blood (UCB), previously seen as medical waste, is increasingly recognized as a valuable source of cells for therapeutic use. The best-known application is in hematopoietic stem cell transplantation (HSCT), where UCB has become an increasingly important graft source in the 28 years since the first umbilical cord blood transplantation (UCBT) was performed. Recently, UCB has been increasingly investigated as a putative source for adoptive cell therapy. Areas covered: This review covers the advances in umbilical cord blood transplantation (UCBT) to overcome the limitation regarding cellular dose, immunological naivety and additional cell doses such as DLI. It also provides an overview regarding the progress in adoptive cellular therapy using UCB. Expert opinion: UCB has been established as an important source of stem cells for HSCT. Successful strategies to overcome the limitations of UCBT, such as the limited cell numbers and naivety of the cells, are being developed, including novel methods to perform in vitro expansion of progenitor cells, and to improve their homing to the bone marrow. Promising early clinical trials of adoptive therapies with UCB cells, including non-immunological cells, are currently performed for viral infections, malignant diseases and in regenerative medicine.

ACS Style

Sofia Berglund; Isabelle Magalhaes; Ahmed Gaballa; Bruno Vanherberghen; Michael Uhlin. Advances in umbilical cord blood cell therapy: the present and the future. Expert Opinion on Biological Therapy 2017, 17, 691 -699.

AMA Style

Sofia Berglund, Isabelle Magalhaes, Ahmed Gaballa, Bruno Vanherberghen, Michael Uhlin. Advances in umbilical cord blood cell therapy: the present and the future. Expert Opinion on Biological Therapy. 2017; 17 (6):691-699.

Chicago/Turabian Style

Sofia Berglund; Isabelle Magalhaes; Ahmed Gaballa; Bruno Vanherberghen; Michael Uhlin. 2017. "Advances in umbilical cord blood cell therapy: the present and the future." Expert Opinion on Biological Therapy 17, no. 6: 691-699.

Review
Published: 11 October 2016 in International Journal of Molecular Sciences
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Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established treatment modality for a variety of malignant diseases as well as for inborn errors of the metabolism or immune system. Regardless of disease origin, good clinical effects are dependent on proper immune reconstitution. T cells are responsible for both the beneficial graft-versus-leukemia (GVL) effect against malignant cells and protection against infections. The immune recovery of T cells relies initially on peripheral expansion of mature cells from the graft and later on the differentiation and maturation from donor-derived hematopoietic stem cells. The formation of new T cells occurs in the thymus and as a byproduct, T cell receptor excision circles (TRECs) are released upon rearrangement of the T cell receptor. Detection of TRECs by PCR is a reliable method for estimating the amount of newly formed T cells in the circulation and, indirectly, for estimating thymic function. Here, we discuss the role of TREC analysis in the prediction of clinical outcome after allogeneic HSCT. Due to the pivotal role of T cell reconstitution we propose that TREC analysis should be included as a key indicator in the post-HSCT follow-up.

ACS Style

Ahmed Gaballa; Mikael Sundin; Arwen Stikvoort; Muhamed Abumaree; Mehmet Uzunel; Darius Sairafi; Michael Uhlin. T Cell Receptor Excision Circle (TREC) Monitoring after Allogeneic Stem Cell Transplantation; a Predictive Marker for Complications and Clinical Outcome. International Journal of Molecular Sciences 2016, 17, 1705 .

AMA Style

Ahmed Gaballa, Mikael Sundin, Arwen Stikvoort, Muhamed Abumaree, Mehmet Uzunel, Darius Sairafi, Michael Uhlin. T Cell Receptor Excision Circle (TREC) Monitoring after Allogeneic Stem Cell Transplantation; a Predictive Marker for Complications and Clinical Outcome. International Journal of Molecular Sciences. 2016; 17 (10):1705.

Chicago/Turabian Style

Ahmed Gaballa; Mikael Sundin; Arwen Stikvoort; Muhamed Abumaree; Mehmet Uzunel; Darius Sairafi; Michael Uhlin. 2016. "T Cell Receptor Excision Circle (TREC) Monitoring after Allogeneic Stem Cell Transplantation; a Predictive Marker for Complications and Clinical Outcome." International Journal of Molecular Sciences 17, no. 10: 1705.