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T-cells, hematopoietic cell transplant

L T Rahmat, A C Logan
Chronic graft-versus-host disease (cGvHD) is a grave complication of allogeneic hematopoietic cell transplantation (alloHCT). Despite the use of prophylactic regimens for cGvHD, a significant proportion of patients develop cGvHD following alloHCT. The standard first-line therapy for cGvHD is high-dose corticosteroids. However, roughly 50% of patients will exhibit steroid-refractory or steroid-dependent cGvHD, which increases the risk of non-relapse mortality. Ibrutinib was approved by the U.S. Food and Drug Administration (FDA) in August 2017 for the treatment of cGvHD after failure of one or more lines of systemic therapy...
May 2018: Drugs of Today
Vera Buchele, Benjamin Abendroth, Maike Büttner-Herold, Tina Vogler, Johanna Rothamer, Sakhila Ghimire, Evelyn Ullrich, Ernst Holler, Markus F Neurath, Kai Hildner
Intestinal graft-versus-host disease (GvHD) is a life-threatening, inflammatory donor T cell-mediated complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the light of the reported efficacy of interleukin-23 (IL-23)-blockade to mitigate syngeneic intestinal inflammation in inflammatory bowel disease patients, targeting IL-23 and thereby interleukin-17a (IL-17a) producing T helper (Th17) cells as the T cell subset assumed to be mostly regulated by IL-23, has emerged as a putatively general concept to harness immune-mediated mucosal inflammation irrespective of the underlying trigger...
2018: Frontiers in Immunology
Emmanuel Katsanis, Lauren N Sapp, Nicole Varner, Shannon Koza, Baldassarre Stea, Yi Zeng
More than half of patients undergoing hematopoietic cell transplantation at our institution are ethnic or racial minorities, making the search for matched unrelated donors more challenging. Since the introduction of haploidentical bone marrow transplant (haplo-BMT) into our pediatric BMT program in 2015, 69.2% of the recipients have been minorities. Herein, we describe our experience with the first thirteen pediatric and young adult patients with hematologic malignancies who have undergone T-cell replete haplo-BMT following myeloablative conditioning (MAC) at our institution...
June 13, 2018: Biology of Blood and Marrow Transplantation
Jaap van Doorn, Brigitte T A van den Broek, Ans J Geboers, Gé-Ann Kuiper, J J Boelens, Peter M van Hasselt
Although disease progression in Mucopolysaccharidosis I (MPS-1) can be attenuated by hematopoietic cell transplantation (HCT), it is increasingly recognized that residual disease is substantial. Biomarkers that would allow us to evaluate the efficacy of HCT (and upcoming new therapies) in non-hematological tissues are needed. Current biomarkers, including the iduronidase (IDUA) activity in leukocytes, are not suitable for this purpose as they are assessed in tissues of hematological origin and may not reflect enzyme availability in non-hematologic tissues...
June 12, 2018: Biology of Blood and Marrow Transplantation
Aurélie Berland, Jérémie Rosain, Sophie Kaltenbach, Vincent Allain, Nizar Mahlaoui, Isabelle Melki, Alice Fievet, Catherine Dubois d'Enghien, Marie Ouachée-Chardin, Laurence Perrin, Nathalie Auger, Funda Erol Cipe, Andrea Finocchi, Figen Dogu, Felipe Suarez, Despina Moshous, Thierry Leblanc, Alexandre Belot, Claire Fieschi, David Boutboul, Marion Malphettes, Lionel Galicier, Eric Oksenhendler, Stéphane Blanche, Alain Fischer, Patrick Revy, Dominique Stoppa-Lyonnet, Capucine Picard, Jean-Pierre de Villartay
- BACKGROUND: V(D)J recombination ensures the diversity of the adaptive immune system. While its complete defect causes Severe Combined Immunodeficiency (T-B-SCID), its suboptimal activity, is associated with a broad spectrum of immune manifestations such as late onset combined immunodeficiency and autoimmunity. The earliest molecular diagnosis of these patients is required to adopt the best therapy strategy, in particular when it involves myelo-ablative conditioning regimen for hematopoietic stem cell transplantation (HSCT)...
June 12, 2018: Journal of Allergy and Clinical Immunology
Nour M Moukalled, Fuad A El Rassi, Sally N Temraz, Ali T Taher
Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by a broad clinical spectrum related to ineffective hematopoiesis leading to unilineage or multilineage cytopenias, with a high propensity for transformation to acute myeloid leukemia. Iron overload has been recently identified as one of the important conditions complicating the management of these diverse disorders. The accumulation of iron is mainly related to chronic transfusions; however, evidence suggests a possible role for ineffective erythropoiesis and increased intestinal absorption of iron, related to altered hepcidin and growth differentiation factor-15 levels in the development of hemosiderosis in patients with MDS...
June 15, 2018: Cancer
Ofrat Beyar-Katz, Saar Gill
Acute myeloid leukemia (AML) is a rapidly progressive, poor-prognosis malignancy arising from hematopoietic stem/progenitor cells. The long history of successful use of allogeneic hematopoietic cell transplantation (alloHCT) in AML indicates that this disease is immunoresponsive, leading to optimism that novel immunotherapies such as bispecific antibodies, chimeric antigen receptor T cells, and immune checkpoint inhibitors will generate meaningful disease control. However, emerging data on the immunoevasive tactics employed by AML blasts at diagnosis and at relapse indicate that optimism must be tempered by an understanding of this essential paradox...
June 14, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Tetsushi Yoshikawa
Two of the four betaherpesviruses, Cytomegalovirus (CMV) and human herpesvirus 6B (HHV-6B), play an important role in opportunistic infections in hematopoietic stem cell transplant (HSCT) recipients. These viruses are ubiquitous in humans and can latently infect mononuclear lymphocytes, complicating the diagnosis of the diseases they cause. Although the detection of viral DNA in a patient's peripheral blood by real-time PCR is widely used for monitoring viral infection, it is insufficient for the diagnosis of virus-associated disease...
2018: Advances in Experimental Medicine and Biology
Christos Demosthenous, Chrysavgi Lalayanni, Michalis Iskas, Vassiliki Douka, Nikoleta Pastelli, Achilles Anagnostopoulos
Blinatumomab, a bispecific T-cell engager antibody construct targeting CD19, has been shown to improve the outcome in patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia. Treatment with blinatumomab demonstrated significant survival benefit over chemotherapy, supporting its use as a bridge therapy to allogeneic hematopoietic stem cell transplantation. Unfortunately, following initial response, approximately 50% of responding patients eventually relapse. At the time of failure, the majority of patients have CD19-positive blasts, yet a concerning number of CD19-negative relapses has been reported...
May 7, 2018: Current Problems in Cancer
Brian T Fisher, Craig L K Boge, Hans Petersen, Alix E Seif, Matthew Bryan, Richard L Hodinka, Ana Maria Cardenas, Dale R Purdy, Brandon Loudon, Adriana E Kajon
Background: Human adenoviruses (HAdVs) are associated with significant morbidity and death after hematopoietic cell transplantation (HCT). In this study, we sought to determine the incidence of HAdV infection among pediatric HCT recipients in the polymerase chain reaction (PCR) testing era, identify risk factors for viremia among patients undergoing HAdV surveillance, and assess the effectiveness of preemptive cidofovir. Methods: A single-center retrospective cohort of patients who underwent a transplant within a 10-year period was assembled...
June 8, 2018: Journal of the Pediatric Infectious Diseases Society
Ryutaro Iwabuchi, Shota Ikeno, Mie Kobayashi-Ishihara, Haruko Takeyama, Manabu Ato, Yasuko Tsunetsugu-Yokota, Kazutaka Terahara
Two cytokines, fms-related tyrosine kinase 3 ligand (Flt3-L) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are considered to be the essential regulators of dendritic cell (DC) development in vivo . However, the combined effect of Flt3-L and GM-CSF on human DCs has not been evaluated in vivo . In this study, we, therefore, aimed at evaluating this using a humanized mouse model. Humanized non-obese diabetic/SCID/Jak3null (hNOJ) mice were constructed by transplanting hematopoietic stem cells from human umbilical cord blood into newborn NOJ mice, and in vivo transfection (IVT) was performed by hydrodynamic injection-mediated gene delivery using plasmids encoding human Flt3-L and GM-CSF...
2018: Frontiers in Immunology
Hanna Leins, Medhanie Mulaw, Karina Eiwen, Vadim Sakk, Ying Liang, Michael Denkinger, Hartmut Geiger, Reinhold Schirmbeck
Aging-associated remodeling of the immune system impairs its functional integrity and contributes to increased morbidity and mortality in the elderly. Aging of hematopoietic stem cells (HSCs), from which all cells of the adaptive immune system ultimately originate, might play a crucial role in the remodeling of the aged immune system. We recently reported that aging of HSCs is, in part, driven by elevated activity of the small RhoGTPase Cdc42 and that aged HSCs can be rejuvenated in vitro by inhibition of the elevated Cdc42 activity in aged HSCs with the pharmacological compound CASIN...
June 11, 2018: Blood
Sarah K Tasian, Jessica A Casas, David Posocco, Shilpa Gandre-Babbe, Alyssa L Gagne, Ge Liang, Mignon L Loh, Mitchell J Weiss, Deborah L French, Stella T Chou
Juvenile myelomonocytic leukemia (JMML) is an uncommon myeloproliferative neoplasm driven by Ras pathway mutations and hyperactive Ras/MAPK signaling. Outcomes for many children with JMML remain dismal with current standard-of-care cytoreductive chemotherapy and hematopoietic stem cell transplantation. We used patient-derived induced pluripotent stem cells (iPSCs) to characterize the signaling profiles and potential therapeutic vulnerabilities of PTPN11-mutant and CBL-mutant JMML. We assessed whether MEK, JAK, and PI3K/mTOR kinase inhibitors (i) could inhibit myeloproliferation and aberrant signaling in iPSC-derived hematopoietic progenitors with PTPN11 E76K or CBL Y371H mutations...
June 8, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Xiubo Fan, Dianyang Guo, Alice M S Cheung, Zhi Yong Poon, Chui Sun Yap, Shane Goh Ee, Dianyan Guo, Huihua Li, Sudipto Bari, Shang Li, Kiat Hon Lim, William Hwang Ying Khee
The immunosuppressive properties of mesenchymal stromal cells (MSCs) have been clinically proven to be effective in treating graft-versus-host disease (GVHD). However, MSC therapy is limited by the need for laborious and expensive manufacturing processes that are fraught with batch-to-batch variability. Substitution of MSC therapy with key MSC-mediated immunomodulatory factors could be an option for GVHD treatment. Using a simulated in vitro model of the immunosuppressive effects of MSC on allogeneic graft reactions, a synergistic two-factor combination (2FC) of CXCL5 and anti-CCL24 was identified from a panel of over 100 immunomodulatory factors as being superior to MSC in the modulation of mixed lymphocyte reactions...
June 5, 2018: Biology of Blood and Marrow Transplantation
F Ekşi, T Karslıgil, I Gündeş, M Sağlam, M P Kırık, M S Büdeyri, H Haydaroğlu Şahin, M Pehlivan
INTRODUCTION: BK virus (BKV) is a common human polyomavirus and causes latent infection. Especially in immunosuppressive patients, early diagnosis and treatment are very important in reducing the high mortality rate. In this study, we investigated BKV DNA in serum and plasma and urine specimens by real-time polymerase chain reaction (PCR) method in allogeneic hematopoietic stem cell transplantation patients. MATERIALS AND METHODS: BKV DNA was isolated in QIAsymphony SP/AS (Hilden, Germany) equipment using QIAsymphony DSP Virus/Pathogen Midi Kit, Version 1 (QIAGEN, Hilden, Germany) in urine and serum samples collected from 100 patients post-transplantation...
June 2018: Transplantation Proceedings
Yoshihiro Inamoto
Chronic graft-versus-host disease (cGVHD) occurs in approximately 40% of patients who undergo allogeneic hematopoietic cell transplantation. It affects various organs and causes significant morbidity and mortality. The manifestations of cGVHD resemble those of autoimmune diseases. Inflammation, cellular immunity, humoral immunity, and fibrosis are implicated in cGVHD pathogenesis. The 2005 NIH consensus criteria for cGVHD have set standards for designing and reporting clinical trials, and the criteria were revised in 2014 to incorporate accumulated evidence and questions...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Nancy A Kernan, Paul G Richardson, Angela R Smith, Brandon M Triplett, Joseph H Antin, Leslie Lehmann, Yoav Messinger, Wei Liang, Robin Hume, William Tappe, Robert J Soiffer, Stephan A Grupp
BACKGROUND: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant-associated chemotherapy. Following HSCT, VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States...
June 6, 2018: Pediatric Blood & Cancer
Wenjing Yu, Yu Wang, Depei Wu, Qifa Liu, Lanping Xu, Xiaohui Zhang, Kaiyan Liu, Xiaojun Huang
To compare the efficacy of HLA6/6-matched haploidentical hematopoietic stem cell transplant (haplo-HSCT) with that of HLA3/6-matched HSCT in T-cell-replete transplants, we recruited 27 consecutive recipients from multiple centers who received HLA6/6-matched haplo-HSCT from a parent or child donor between February 2010 and May 2016. A matched-pair analysis was designed. For each recipient from the study cohort, two recipients were randomly selected from the control cohort and matched (according to patient age, patient sex, disease type, disease status, donor age, donor sex, and recipient-donor relationship)...
May 30, 2018: Science China. Life Sciences
Meghan Rothenberger, John E Wagner, Ashley Haase, Douglas Richman, Bartosz Grzywacz, Matthew Strain, Steven Lada, Jacob Estes, Courtney V Fletcher, Anthony T Podany, Jodi Anderson, Thomas Schmidt, Steve Wietgrefe, Timothy Schacker, Michael R Verneris
Background: Allogeneic hematopoietic cell transplantation (allo-HCT) in a CCR5∆32 homozygous donor resulted in HIV cure. Understanding how allo-HCT impacts the HIV reservoir will inform cure strategies. Methods: A 12-year-old with perinatally acquired, CCR5-tropic HIV and acute lymphoblastic leukemia underwent myeloablative conditioning and umbilical cord blood (UCB) transplantation from a CCR5∆32 homozygous donor. Peripheral blood mononuclear cells (PBMCs) and the rectum were sampled pre- and post-transplant...
May 2018: Open Forum Infectious Diseases
Lingling Zhang, Jianhua Yu, Wei Wei
Graft-versus-host disease (GVHD) is a serious and deadly complication of patients, who undergo hematopoietic stem cell transplantation (HSCT). Despite prophylactic treatment with immunosuppressive agents, 20-80% of recipients develop acute GVHD after HSCT. And the incidence rates of chronic GVHD range from 6 to 80%. Standard therapeutic strategies are still lacking, although considerable advances have been gained in knowing of the predisposing factors, pathology, and diagnosis of GVHD. Targeting immune cells, such as regulatory T cells, as well as tolerogenic dendritic cells or mesenchymal stromal cells (MSCs) display considerable benefit in the relief of GVHD through the deletion of alloactivated T cells...
2018: Frontiers in Immunology
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