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Gretchen A Hoff, Johannes C Fischer, Katharine Hsu, Sarah Cooley, Jeffrey S Miller, Tao Wang, Michael Haagenson, Stephen Spellman, Stephanie J Lee, Markus Uhrberg, Jeffrey M Venstrom, Michael R Verneris
Natural Killer (NK) cells are important in graft versus leukemia responses following hematopoietic cell transplantation (HCT). A variety of surface receptors dictate NK cell function, including killer immunoglobulin receptor (KIR) recognition of HLA-C. Previous single center studies show that HLA-C epitopes, designated C1 and C2, were associated with allogeneic-HCT outcomes; specifically recipients homozygous for the C1 epitope (C1/C1) experienced a survival benefit. Additionally, mismatching at HLA-C was beneficial in recipients possessing at least one C2 allele, while the opposite was true for homozygous C1 (C1/C1) recipients where HLA-C mismatching resulted in worse outcomes...
October 13, 2016: Biology of Blood and Marrow Transplantation
Ahmed Gaballa, Mikael Sundin, Arwen Stikvoort, Muhamed Abumaree, Mehmet Uzunel, Darius Sairafi, Michael Uhlin
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...
October 11, 2016: International Journal of Molecular Sciences
Jessica Heinrichs, David Bastian, Anandharaman Veerapathran, Claudio Anasetti, Brain Betts, Xue-Zhong Yu
Graft-versus-host disease (GVHD) is a significant cause of non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Existing strategies to prevent and treat GVHD are incomplete, where a significant portion of allo-HCT recipients developed this complication. Despite this, one such therapy has emerged involving the use of regulatory T cells (Tregs) to control GVHD. The use of natural Tregs (nTregs) yielded positive pre-clinical results and are actively under investigation to reduce GVHD...
2016: J Immunol Res Ther
Suelen Martins Perobelli, Ana Carolina Terra Mercadante, Rômulo Gonçalves Galvani, Triciana Gonçalves-Silva, Ana Paula Gregório Alves, Antonio Pereira-Neves, Marlene Benchimol, Alberto Nóbrega, Adriana Bonomo
Acute graft-versus-host disease (aGVHD) is the main complication of allogeneic hematopoietic stem cell transplantation, and many efforts have been made to overcome this important limitation. We showed previously that G-CSF treatment generates low-density splenic granulocytes that inhibit experimental aGVHD. In this article, we show that aGVHD protection relies on incoming IL-10(+) neutrophils from G-CSF-treated donor spleen (G-Neutrophils). These G-Neutrophils have high phagocytic capacity, high peroxide production, low myeloperoxidase activity, and low cytoplasmic granule content, which accounts for their low density...
October 5, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Jian-Ming Li, Christopher T Petersen, Jingxia Li, Reema Panjwani, Daniel J Chandra, Cynthia R Giver, Bruce R Blazar, Edmund K Waller
The goal of allogeneic bone marrow transplantation (allo-BMT) is elimination of leukemia cells through the graft-versus-leukemia (GvL) activity of donor cells, while limiting graft-versus-host disease (GvHD). Immune checkpoint pathways regulate GvL and GvHD activities, but blocking antibodies or genetic inactivation of these pathways can cause lethal GVHD. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide that regulates co-inhibitory pathways; its role in allo-BMT has not been studied...
September 26, 2016: Cancer Research
Nirali N Shah, David M Loeb, Hahn Khuu, David Stroncek, Tolu Ariyo, Mark Raffeld, Cindy Delbrook, Crystal L Mackall, Alan S Wayne, Terry J Fry
Relapse of hematologic malignancies is the primary cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HCT). Treatment for post-HCT relapse using donor lymphocyte infusion (DLI) has limited utility, particularly in the setting of acute leukemia, and can result in the development of graft-versus-host disease (GVHD). The Wilms' tumor 1 (WT1) gene product is a tumor-associated antigen that is expressed in acute leukemia and other hematologic malignancies, with limited expression in normal tissues...
September 12, 2016: Biology of Blood and Marrow Transplantation
Daniela Renzi, Francesco Marchesi, Gottardo De Angelis, Loredana Elia, Emanuela Salvatorelli, Svitlana Gumenyuk, Francesca Palombi, Francesco Pisani, Atelda Romano, Antonio Spadea, Elena Papa, Marco Canfora, William Arcese, Andrea Mengarelli
We describe the case of a patient with a Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with dasatinib plus steroids as the first-line therapy who achieved a molecular complete remission and then underwent a matched, unrelated donor allogeneic transplant. Five months after the transplant, he experienced a disease relapse with an T315I mutation, which was resistant to salvage chemotherapy. Once the details of the T315I mutation were acquired, we initiated ponatinib treatment at a standard dosage and observed a rapid decrease of minimal residual disease (MRD) at molecular assessment...
September 10, 2016: Chemotherapy
Raphael Carapito, Nicolas Jung, Marius Kwemou, Meiggie Untrau, Sandra Michel, Angélique Pichot, Gaëlle Giacometti, Cécile Macquin, Wassila Ilias, Aurore Morlon, Irina Kotova, Petya Apostolova, Annette Schmitt-Graeff, Anne Cesbron, Katia Gagne, Machteld Oudshoorn, Bronno van der Holt, Myriam Labalette, Eric Spierings, Christophe Picard, Pascale Loiseau, Ryad Tamouza, Antoine Toubert, Anne Parissiadis, Valérie Dubois, Xavier Lafarge, Myriam Maumy-Bertrand, Frédéric Bertrand, Luca Vago, Fabio Ciceri, Catherine Paillard, Sergi Querol, Jorge Sierra, Katharina Fleischhauer, Arnon Nagler, Myriam Labopin, Hidetoshi Inoko, Peter A von dem Borne, Jürgen Kuball, Masao Ota, Yoshihiko Katsuyama, Mauricette Michallet, Bruno Lioure, Régis Peffault de Latour, Didier Blaise, Jan J Cornelissen, Ibrahim Yakoub-Agha, Frans Claas, Philippe Moreau, Noël Milpied, Dominique Charron, Mohamad Mohty, Robert Zeiser, Gérard Socié, Seiamak Bahram
Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs...
October 13, 2016: Blood
Cor H J Lamers, Rebecca Wijers, Cornelis A M van Bergen, Judith A E Somers, Eric Braakman, Jan Willem Gratama, Reno Debets, J H Frederik Falkenburg, Jan J Cornelissen
While double umbilical cord blood transplantation (dUCBT) in adult patients may be associated with less graft failure as compared to single UCBT, hematopoietic recovery generally originates from a single cord blood unit (CBU). CBU predominance is still incompletely understood. We recently showed that blood CD4+ T-cell numbers rapidly increase after dUCBT and early CD4+ T-cell chimerism predicts for graft predominance. Given the frequent HLA-class II allele mismatches between CBUs in dUCBT, we hypothesized that alloreactive HLA-class II-specific CD4+ T-cells from the 'winning' CBU may contribute to rejection of the 'loser' CBU...
August 16, 2016: Blood
Muhammad Waqas Khan, Zartash Gul
Blinatumomab, a bispecific T-cell engager monoclonal antibody used to manage Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) can be used to treat patients by inducing graft versus leukemia reaction post allogeneic hematopoietic stem cell transplantation, a feature which it was post allogeneic bone marrow transplantation, a feature which this drug was not aimed to do.
August 2016: Clinical Case Reports
Elke Rücker-Braun, Cornelia S Link, Maria Schmiedgen, Antje Tunger, Petra Vizjak, Raphael Teipel, Rebekka Wehner, Denise Kuehn, Yannik F Fuchs, Uta Oelschlaegel, Lothar Germeroth, Marc Schmitz, Martin Bornhäuser, Johannes Schetelig, Falk Heidenreich
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Graft versus leukemia (GvL) effects which are exerted by donor T cells directed against leukemic-associated antigens (LAA) are considered to play a crucial role in disease eradication. While the expansion of cytotoxic T lymphocytes (CTL) specific for cytomegalovirus (CMV) in response to an infection has been shown in multiple studies, data about CTLs mediating GvL effects are limited...
July 26, 2016: Experimental Hematology
Jessica Heinrichs, Jun Li, Hung Nguyen, Yongxia Wu, David Bastian, Anusara Daethanasanmak, M-Hanief Sofi, Steven Schutt, Chen Liu, Junfei Jin, Brian Betts, Claudio Anasetti, Xue-Zhong Yu
Adoptive natural regulatory T cell (nTreg) therapy has improved the outcome for patients suffering from graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (Allo-HCT). However, fear of broad immune suppression and subsequent dampening of beneficial graft-versus-leukemia (GVL) responses remains a challenge. To address this concern, we generated alloreactive induced Tregs (iTregs) from resting CD4(+) or CD8(+) T cells and tested their ability to suppress GVH and maintain GVL responses...
June 2016: Oncoimmunology
R-G Mihăilă
Graft versus host disease (GVHD) is the main complication of allogeneic hematopoietic cell transplantation and is more frequent after peripheral stem cell transplants. Graft versus leukemia or lymphoma component of them is beneficial to eradicate residual tumor mass after previous treatment and conditioning regimen. A severe GVHD may endanger the patient's life. The most important liver manifestations of GVHD are increased serum alkaline phosphatase and bilirubin values. The last allows to estimate the GVHD severity...
April 2016: Romanian Journal of Internal Medicine, Revue Roumaine de Médecine Interne
Koen van Besien, Nebu Koshy, Usama Gergis, Sebastian Mayer, Melissa Cushing, Hannah Rennert, Ronit Reich-Slotky, Tomer Mark, Roger Pearse, Adriana Rossi, Adrienne Phillips, Liljana Vasovic, Rosanna Ferrante, Yen-Michael Hsu, Tsiporah Shore
Haplo-cord stem cell transplantation combines the infusion of CD34 selected hematopoietic progenitors from a haplo-identical donor with an umbilical cord blood (UCB) graft from an unrelated donor and allows faster count recovery, with low rates of disease recurrence and chronic graft-versus-host disease (GVHD). But the contribution of the umbilical cord blood graft to long-term transplant outcome remains unclear. We analyzed 39 recipients of haplo-cord transplants with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), engrafted and in remission at 2 months...
June 23, 2016: Leukemia & Lymphoma
P Tsirigotis, M Byrne, C Schmid, F Baron, F Ciceri, J Esteve, N C Gorin, S Giebel, M Mohty, B N Savani, A Nagler
Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the therapeutic method with the most potent anti-leukemic activity mediated by the graft versus leukemia effect. However, a significant proportion of patients with AML will relapse after allo-SCT. The prognosis for these patients is dismal, with a probability of long-term survival of <20%. Data from previous studies have shown that disease-specific prognostic factors, are in general, the same as those in patients treated with conventional chemotherapy...
June 13, 2016: Bone Marrow Transplantation
Asim Saha, Roddy S O'Connor, Govindarajan Thangavelu, Scott B Lovitch, Durga Bhavani Dandamudi, Caleph B Wilson, Benjamin G Vincent, Victor Tkachev, Jan M Pawlicki, Scott N Furlan, Leslie S Kean, Kazutoshi Aoyama, Patricia A Taylor, Angela Panoskaltsis-Mortari, Rocio Foncea, Parvathi Ranganathan, Steven M Devine, Joel S Burrill, Lili Guo, Catarina Sacristan, Nathaniel W Snyder, Ian A Blair, Michael C Milone, Michael L Dustin, James L Riley, David A Bernlohr, William J Murphy, Brian T Fife, David H Munn, Jeffrey S Miller, Jonathan S Serody, Gordon J Freeman, Arlene H Sharpe, Laurence A Turka, Bruce R Blazar
Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD...
July 1, 2016: Journal of Clinical Investigation
Gaurav Goyal, Krishna Gundabolu, Saraschandra Vallabhajosyula, Peter T Silberstein, Vijaya Raj Bhatt
Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft-versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis...
June 2016: Therapeutic Advances in Hematology
Shuting Zhao, Lingling Zhang, Jianfeng Han, Jianhong Chu, Hai Wang, Xilin Chen, Youwei Wang, Norm Tun, Lanchun Lu, Xue-Feng Bai, Martha Yearsley, Steven Devine, Xiaoming He, Jianhua Yu
Allogeneic transplantation of hematopoietic stem cells (HSC) in combination with T cells has a curative potential for hematopoietic malignancies through graft-versus-leukemia (GVL) effects, but is often compromised by the notorious side effect of graft-versus-host disease (GVHD) resulting from alloreactivity of the donor T cells. Here, we tested if temporary immunoisolation achieved by conformally encapsulating the donor T cells within a biocompatible and biodegradable porous film (∼450 nm in thickness) of chitosan and alginate could attenuate GVHD without compromising GVL...
June 28, 2016: ACS Nano
Rupert Handgretinger, Peter Lang, Maya C André
Natural killer (NK) cells play an important role in surveillance and elimination of malignant cells. Their spontaneous cytotoxicity was first demonstrated in vitro against leukemia cell lines, and NK cells might play a crucial role in the therapy of leukemia. NK cell activity is controlled by an array of germ line-encoded activating and inhibitory receptors, as well as modulating coreceptors. This biologic feature can be exploited in allogeneic cell therapy, and the recognition of "missing-self" on target cells is crucial for promoting NK cell-mediated graft-versus-leukemia effects...
June 30, 2016: Blood
Xiebing Bao, Qian Zhu, Shengli Xue, Xiaohui Hu, Xiao Ma, Feng Chen, Suning Chen, Aining Sun, Depei Wu, Jianhua Yu, Xiaojin Wu, Huiying Qiu
A considerable number of studies have demonstrated that cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) could enforce graft-versus leukemia (GVL) effect in acute myeloid leukemia (AML) patients. However, the use of antithymocyte globulin (ATG) as part of graft-versus-host disease (GVHD) prophylaxis may dampen this beneficial effect of CMV replication. In this context, we retrospectively analyzed the effect of CMV reactivation on relapse, survival and prognosis in a total of 227 AML patients who received a myeloablative (MA) conditioning regimen at a single research center between January 2010 and April 2013...
2016: American Journal of Translational Research
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