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T-cells, hematopoietic cell transplant

Karla Gálvez, Paula Muñoz, Valentina Vera, Claudio Arce
INTRODUCTION: Graft-versus-host disease (GVHD) is caused by a pathologic and destructive response of the organism as a result of the interaction between donor immunocompetent T lymphocytes and the recipient tisular antigens. It's considered the most serious complication of hematopoietic stem cell transplantation, most frequently described after bone marrow transplantation (BMT). The skin is usually the first and most commonly affected organ, in both acute and chronic, with a variable clinical spectrum of presentation...
February 2018: Revista Chilena de Pediatría
Fatih Erbey, Arzu Akçay, Didem Atay, Ercüment Ovalı, Gülyüz Öztürk
T-cell-depleted HAPLO HSCT is an option to treat children with high-risk acute leukemia lacking an HLA-identical donor. We reviewed the outcome of children with acute leukemia after HAPLO (n = 21) and HLA-MUD (n = 32) transplantation. The proportion of patients with ≥CR2 was significantly higher in HAPLO transplantation than MUD transplantation. Patients with MUD transplantation were significantly higher ABO incompatible than patients with HAPLO transplantation. There was no difference between the 2 groups in terms of engraftment, aGvHD and cGvHD, VOD, hemorrhagic cystitis, infections, and relapse...
April 16, 2018: Pediatric Transplantation
Tiberiu Tat, Huming Li, Catalin-Sorin Constantinescu, Anca Onaciu, Sergiu Chira, Ciprian Osan, Sergiu Pasca, Bobe Petrushev, Vlad Moisoiu, Wilhelm-Thomas Micu, Cristian Berce, Sebastian Tranca, Delia Dima, Ioana Berindan-Neagoe, Jianliang Shen, Ciprian Tomuleasa, Liren Qian
Chimeric antigen receptor-modified T cells (CAR-T cells) and donor lymphocyte infusion (DLI) are important protocols in lymphocyte engineering. CAR-T cells have emerged as a new modality for cancer immunotherapy due to their potential efficacy against hematological malignancies. These genetically modified receptors contain an antigen-binding moiety, a hinge region, a transmembrane domain, and an intracellular costimulatory domain resulting in lymphocyte T cell activation subsequent to antigen binding. In present-day medicine, four generations of CAR-T cells are described depending on the intracellular signaling domain number of T cell receptors...
March 27, 2018: Oncotarget
Jeannine S McCune, Barry Storer, Sushma Thomas, Jožefa McKiernan, Rohan Gupta, Brenda M Sandmaier
We evaluated inosine monophosphate dehydrogenase (IMPDH) 1 and IMPDH2 pharmacogenetics in 247 recipient-donor pairs after nonmyeloablative hematopoietic cell transplant (HCT) recipients. Patients were conditioned with total body irradiation + fludarabine, received grafts from related or unrelated donors (10% HLA mismatch), with post-graft immunosuppression of mycophenolate mofetil (MMF) with a calcineurin inhibitor. Recipient and donor IMPDH genotype (rs11706052, rs2278294, rs2278293) were not associated with day 28 T-cell chimerism, acute graft versus host disease, disease relapse, cytomegalovirus reactivation, non-relapse mortality, or overall survival...
April 12, 2018: Biology of Blood and Marrow Transplantation
Eo Toriyama, Yoshitaka Imaizumi, Hiroaki Taniguchi, Jun Taguchi, Jun Nakashima, Hidehiro Itonaga, Shinya Sato, Koji Ando, Yasushi Sawayama, Tomoko Hata, Takuya Fukushima, Yasushi Miyazaki
Adult T-cell leukemia-lymphoma (ATL) is an intractable hematopoietic malignancy with a very poor prognosis. Although improved responses have been achieved through intensive chemotherapy in newly diagnosed patients with aggressive ATL, most patients suffer from relapse or disease recurrence, and an effective salvage therapy, especially for candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT), is yet to be established. The efficacy of the EPOCH regimen has been reported for several lymphoid malignancies; however, its efficacy for ATL has not been sufficiently evaluated...
April 12, 2018: International Journal of Hematology
Corina Schneidawind, Johan Jeong, Dominik Schneidawind, In-Suk Kim, Jesús Duque-Afonso, Stephen Hon Kit Wong, Masayuki Iwasaki, Erin H Breese, James L Zehnder, Matthew Porteus, Michael L Cleary
Genome editing provides a potential approach to model de novo leukemogenesis in primary human hematopoietic stem and progenitor cells (HSPCs) through induction of chromosomal translocations by targeted DNA double-strand breaks. However, very low efficiency of translocations and lack of markers for translocated cells serve as barriers to their characterization and model development. Here, we used transcription activator-like effector nucleases to generate t(9;11) chromosomal translocations encoding MLL-AF9 and reciprocal AF9-MLL fusion products in CD34+ human cord blood cells...
April 24, 2018: Blood Advances
Maximilian Stahl, Michelle DeVeaux, Pau Montesinos Fernández, Raphaël Itzykson, Ellen K Ritchie, Mikkael A Sekeres, Navneet Majhail, John Barnard, Nikolai A Podoltsev, Andrew Brunner, Rami S Komrokji, Vijaya R Bhatt, Aref Al-Kali, Thomas Cluzeau, Valeria Santini, Gail J Roboz, Pierre Fenaux, Mark Litzow, Amir T Fathi, Sarah Perreault, Tae Kon Kim, Thomas Prebet, Norbert Vey, Vivek Verma, Guido Kobbe, Juan Bergua, Josefina Serrano, Steven D Gore, Amer M Zeidan
No abstract text is available yet for this article.
April 9, 2018: Biology of Blood and Marrow Transplantation
Long Liu, Ying-Jun Chang, Lan-Ping Xu, Xiao-Hui Zhang, Yu Wang, Kai-Yan Liu, Xiao-Jun Huang
Donor lymphocyte infusion is an effective approach to treat acute myeloid leukemia (AML) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) that significantly improves the survival of relapsed patients. However, the mechanism of an effective anti-leukemic response following DLI in AML relapse remains elusive. Here, we investigated the role of T cell exhaustion in AML relapse after allo-HSCT in prospective cohorts of 41 patients with the first AML relapse and 41 non-relapsed AML controls after allo-HSCT and determined whether DLI exerts effective anti-leukemic effects by reversing T cell exhaustion in the relapsed cohorts by detecting the phenotypes and functions of T cells using flow cytometry...
April 9, 2018: Biology of Blood and Marrow Transplantation
Tina Baake, Katharina Jörß, Jennifer Suennemann, Laura Roßmann, Hanibal Bohnenberger, Jan P Tuckermann, Holger M Reichardt, Henrike J Fischer, Sybille D Reichardt
Graft-versus-host disease (GvHD) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT), which is caused by allogeneic T cells recognizing molecules of the recipient as foreign. Endogenous glucocorticoids (GC) released from the adrenal gland are crucial in regulating such inflammatory diseases. Here we demonstrate that genetically engineered mice, that are largely unresponsive to GC, suffer from aggravated clinical symptoms and increased mortality after HSCT, effects that could be tempered by neutralization of IL-6...
March 20, 2018: Oncotarget
Yasuyuki Arai, Uimook Choi, Cristina I Corsino, Sherry M Koontz, Masaki Tajima, Colin L Sweeney, Mary A Black, Steven A Feldman, Mary C Dinauer, Harry L Malech
We report a novel approach to bone marrow (BM) conditioning using c-kit-targeted chimeric antigen receptor T (c-kit CAR-T) cells in mice. Previous reports using anti-c-kit or anti-CD45 antibody linked to a toxin such as saporin have been promising. We developed a distinctly different approach using c-kit CAR-T cells. Initial studies demonstrated in vitro killing of hematopoietic stem cells by c-kit CAR-T cells but poor expansion in vivo and poor migration of CAR-T cells into BM. Pre-treatment of recipient mice with low-dose cyclophosphamide (125 mg/kg) together with CXCR4 transduction in the CAR-T cells enhanced trafficking to and expansion in BM (<1%-13...
March 10, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Eileen Danaher Hacker, Tara Peters, Pritesh Patel, Damiano Rondelli
AIMS: This pilot study tested and refined a free-living physical activity intervention. The investigators evaluated the acceptability and feasibility of the intervention after hematopoietic stem cell transplantation and determined preliminary effects on physical activity, fatigue, muscle strength, functional ability, and quality of life. DESIGN: This pilot study used a 1-group, pretest-posttest design. METHODS: The free-living physical activity intervention consisted of an education component and 6 weeks of gradually increasing physical activity after discharge from the hospital...
May 2018: Clinical Nurse Specialist CNS
Mitra Bhattacharyya, Pablo Penaloza-MacMaster
Bone marrow transplantation is a treatment for various cancers and genetic diseases, and the only case of cured a HIV infection involved the use of this clinical procedure, highlighting the potential use of this therapy for curing many chronic diseases. However, little is known about how chronic viral infection influences lymphocyte reconstitution after bone marrow transplantation. To address this, we infected mice with chronic lymphocytic choriomeningitis virus (LCMV), and performed bone marrow transplantation to assess lymphocyte reconstitution...
March 18, 2018: AIDS Research and Human Retroviruses
Kathryn T Maples, Roy T Sabo, John M McCarty, Amir A Toor, Kelly G Hawks
Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but carries a high risk of relapse. This retrospective review evaluates the effectiveness of maintenance azacitidine in high-risk AML and MDS patients to reduce the probability of relapse. Twenty-five patients who received maintenance azacitidine were matched to historical controls in a two-to-one ratio based on diagnosis, donor type, conditioning regimen intensity, and age...
April 4, 2018: Leukemia & Lymphoma
Tara M Robinson, Gabrielle T Prince, Chris Thoburn, Erica Warlick, Anna Ferguson, Yvette L Kasamon, Ivan M Borrello, Allan Hess, B Douglas Smith
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies. Currently, approved drugs are given with non-curative intent as the only known cure is allogeneic bone marrow transplantation, which relies on the donor's immune system driving an allogeneic effect. Previous efforts to harness the endogenous immune system have been less successful. We present the results of a pilot study of K562/GM-CSF (GVAX) whole-cell vaccination in MDS patients. The primary objective of safety was met as there were no serious adverse events...
April 4, 2018: Leukemia & Lymphoma
J Mascarenhas, E Virtgaym, M Stal, H Blacklock, A T Gerds, R Mesa, P Ganly, D Snyder, I Tabbara, D Tremblay, E Moshier
Myelofibrosis (MF) is a chronic yet progressive myeloid neoplasm in which only a minority of patients undergo curative therapy, hematopoietic stem cell transplantation. Ruxolitinib, a JAK1/2 inhibitor, is the lone therapy approved for MF, offering a clear symptom and spleen benefit at the expense of treatment-related cytopenias. Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression. Due to an FDA-mandated full clinical hold, the randomized phase 3 PERSIST trials were abruptly stopped and PAC was immediately discontinued for all patients...
April 3, 2018: Annals of Hematology
Lauren P McLaughlin, Catherine M Bollard, Michael D Keller
Patients with primary immunodeficiency disorders (PID) have an increased risk from acute and chronic Epstein-Barr Virus (EBV) viral infections and EBV-associated malignancies. Hematopoietic stem cell transplantation (HSCT) is a curative strategy for many patients with PID, but EBV-related complications are common in the immediate post-transplant period due to delayed reconstitution of T cell immunity. Adoptive T cell therapy with EBV-specific T cells is a promising therapeutic strategy for patients with PID both before and after HSCT...
2018: Frontiers in Immunology
Takafumi Hiramoto, Li B Li, Sarah E Funk, Roli K Hirata, David W Russell
X-linked severe combined immunodeficiency (X-SCID) has been successfully treated by hematopoietic stem cell (HSC) transduction with retroviral vectors expressing the interleukin-2 receptor subunit gamma gene (IL2RG), but several patients developed malignancies due to vector integration near cellular oncogenes. This adverse side effect could in principle be avoided by accurate IL2RG gene editing with a vector that does not contain a functional promoter or IL2RG gene. Here, we show that adeno-associated virus (AAV) gene editing vectors can insert a partial Il2rg cDNA at the endogenous Il2rg locus in X-SCID murine bone marrow cells and that these ex vivo-edited cells repopulate transplant recipients and produce CD4+ and CD8+ T cells...
March 6, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Jacek Nowak, Klaudia Nestorowicz, Elżbieta Graczyk-Pol, Renata Mika-Witkowska, Marta Rogatko-Koros, Emilia Jaskula, Katarzyna Koscinska, Sylwia Madej, Agnieszka Tomaszewska, Barbara Nasilowska-Adamska, Andrzej Szczepinski, Kazimierz Halaburda, Jaroslaw Dybko, Kazimierz Kuliczkowski, Tomasz Czerw, Sebastian Giebel, Jerzy Holowiecki, Malgorzata Baranska, Anna Pieczonka, Jacek Wachowiak, Anna Czyz, Lidia Gil, Anna Lojko-Dankowska, Mieczyslaw Komarnicki, Maria Bieniaszewska, Agnieszka Kucharska, Andrzej Hellmann, Anna Gronkowska, Wieslaw W Jedrzejczak, Miroslaw Markiewicz, Anna Koclega, Slawomira Kyrcz-Krzemien, Monika Mielcarek, Krzysztof Kalwak, Jan Styczynski, Mariusz Wysocki, Katarzyna Drabko, Beata Wójcik, Jerzy Kowalczyk, Jolanta Gozdzik, Daria Pawliczak, Sławomir Gwozdowicz, Joanna Dziopa, Urszula Szlendak, Agnieszka Witkowska, Marta Zubala, Agnieszka Gawron, Krzysztof Warzocha, Andrzej Lange
Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N=889 patients by the population-based detection of HLA allele phase mismatch...
March 29, 2018: Human Immunology
Junichi Hashiguchi, Masahiro Onozawa, Tomoaki Naka, Kanako C Hatanaka, Souichi Shiratori, Junichi Sugita, Katsuya Fujimoto, Yoshihiro Matsuno, Takanori Teshima
Toxoplasma gondii (T. gondii) reactivation is one of the fatal complications after hematopoietic stem cell transplantation (HSCT); however, re-infection has not been reported. Here we report a case of mycosis fungoides in which cervical lymphadenopathy developed after HSCT. Initially, recurrent lymphoma was suspected. However, biopsy of the lymph node showed typical histology of toxoplasmosis and serology showed re-infection of T. gondii. Toxoplasmosis needs to be differentiated for cases with lymphoadenopthy after HSCT...
March 30, 2018: Transplant Infectious Disease: An Official Journal of the Transplantation Society
Motoko Yamaguchi, Ritsuro Suzuki, Masahiko Oguchi
Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a subtype of mature T- and NK-cell lymphomas characterized by its association with Epstein-Barr virus and extranodal involvement. Although there is geographic variance in the frequency of ENKL, its clinical features are similar between Western countries and endemic areas, such as East Asia. Anthracycline-containing chemotherapy is not recommended to treat ENKL. No standard treatment has been established based on the results of randomized controlled trials...
March 30, 2018: Blood
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