Browsing by Subject "Allogeneic hematopoietic cell transplantation"

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    Early Th1 immunity promotes immune tolerance and may impair graft-versus-leukemia effect after allogeneic hematopoietic cell transplantation
    (European Hematology Association, 2016-05) Engelhardt, Brian G.; Paczesny, Sophie; Jung, Dae Kwang; Daguindau, Etienne; Jagasia, Madan; Savani, Bipin N.; Chinratanalab, Wichai; Cornell, Robert F.; Goodman, Stacey; Greer, John P.; Kassim, Adetola A.; Sengsayadeth, Salyka; Yoder, Sandra M.; Rock, Michael T.; Crowe Jr., James E.; Department of Pediatrics, IU School of Medicine
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    Graft-Versus-Host Disease-Free Antitumoral Signature After Allogeneic Donor Lymphocyte Injection Identified by Proteomics and Systems Biology
    (American Society of Clinical Oncology, 2019) Liu, Xiaowen; Yue, Zongliang; Cao, Yimou; Taylor, Lauren; Zhang, Qing; Choi, Sung W.; Hanash, Samir; Ito, Sawa; Chen, Jake Yue; Wu, Huanmei; Paczesny, Sophie; Pediatrics, School of Medicine
    PURPOSE: As a tumor immunotherapy, allogeneic hematopoietic cell transplantation with subsequent donor lymphocyte injection (DLI) aims to induce the graft-versus-tumor (GVT) effect but often also leads to acute graft-versus-host disease (GVHD). Plasma tests that can predict the likelihood of GVT without GVHD are still needed. PATIENTS AND METHODS: We first used an intact-protein analysis system to profile the plasma proteome post-DLI of patients who experienced GVT and acute GVHD for comparison with the proteome of patients who experienced GVT without GVHD in a training set. Our novel six-step systems biology analysis involved removing common proteins and GVHD-specific proteins, creating a protein-protein interaction network, calculating relevance and penalty scores, and visualizing candidate biomarkers in gene networks. We then performed a second proteomics experiment in a validation set of patients who experienced GVT without acute GVHD after DLI for comparison with the proteome of patients before DLI. We next combined the two experiments to define a biologically relevant signature of GVT without GVHD. An independent experiment with single-cell profiling in tumor antigen-activated T cells from a patient with post-hematopoietic cell transplantation relapse was performed. RESULTS: The approach provided a list of 46 proteins in the training set, and 30 proteins in the validation set were associated with GVT without GVHD. The combination of the two experiments defined a unique 61-protein signature of GVT without GVHD. Finally, the single-cell profiling in activated T cells found 43 of the 61 genes. Novel markers, such as RPL23, ILF2, CD58, and CRTAM, were identified and could be extended to other antitumoral responses. CONCLUSION: Our multiomic analysis provides, to our knowledge, the first human plasma signature for GVT without GVHD. Risk stratification on the basis of this signature would allow for customized treatment plans.
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    Impact of cytogenetic abnormalities on outcomes of adult Philadelphia-negative acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: a study by the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research
    (Ferrata Storti Foundation, 2019-09-26) Lazaryan, Aleksandr; Dolan, Michelle; Zhang, Mei-Jie; Wang, Hai-Lin; Kharfan-Dabaja, Mohamed A.; Marks, David I.; Bejanyan, Nelli; Copelan, Edward; Majhail, Navneet S.; Waller, Edmund K.; Chao, Nelson; Prestidge, Tim; Nishihori, Taiga; Kebriaei, Partow; Inamoto, Yoshihiro; Hamilton, Betty; Hashmi, Shahrukh K.; Kamble, Rammurti T.; Bacher, Ulrike; Hildebrandt, Gerhard C.; Stiff, Patrick J.; McGuirk, Joseph; Aldoss, Ibrahim; Beitinjaneh, Amer M.; Muffly, Lori; Vij, Ravi; Olsson, Richard F.; Byrne, Michael; Schultz, Kirk R.; Aljurf, Mahmoud; Seftel, Matthew; Savoie, Mary Lynn; Savani, Bipin N.; Verdonck, Leo F.; Cairo, Mitchell S.; Hossain, Nasheed; Bhatt, Vijaya Raj; Frangoul, Haydar A.; Abdel-Azim, Hisham; Al Malki, Monzr; Munker, Reinhold; Rizzieri, David; Khera, Nandita; Nakamura, Ryotaro; Ringdén, Olle; van der Poel, Marjolein; Murthy, Hemant S.; Liu, Hongtao; Mori, Shahram; De Oliveira, Satiro; Bolaños-Meade, Javier; Elsawy, Mahmoud; Barba, Pere; Nathan, Sunita; George, Biju; Pawarode, Attaphol; Grunwald, Michael; Agrawal, Vaibhav; Wang, Youjin; Assal, Amer; Castillo Caro, Paul; Kuwatsuka, Yachiyo; Seo, Sachiko; Ustun, Celalettin; Politikos, Ioannis; Lazarus, Hillard M.; Saber, Wael; Sandmaier, Brenda M.; De Lima, Marcos; Litzow, Mark; Bachanova, Veronika; Weisdorf, Daniel; Acute Leukemia Committee of the CIBMTR; Medicine, School of Medicine
    Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia (ALL). To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative ALL in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to the Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. The leukemia-free survival and overall survival rates at 5 years after transplantation in patients with abnormal cytogenetics were 40% and 42%, respectively, which were similar to those in patients with a normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (P=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse [hazard ratio (HR)=2.11; 95% confidence interval (95% CI): 1.04-4.27] and treatment failure (HR=1.97; 95% CI: 1.20-3.24). Complex karyotype was prognostic for relapse (HR=1.69; 95% CI: 1.06-2.69), whereas t(8;14) predicted treatment failure (HR=2.85; 95% CI: 1.35-6.02) and overall mortality (HR=3.03; 95% CI: 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse [monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy], intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (P=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities in ALL can be overcome by transplantation, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.
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    Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease
    (American Society for Clinical Investigation, 2016-05-05) Li, Wei; Liu, Liangyi; Gomez, Aurelie; Zhang, Jilu; Ramadan, Abdulraouf; Zhang, Qing; Choi, Sung W.; Zhang, Peng; Greenson, Joel K.; Liu, Chen; Jiang, Di; Virts, Elizabeth; Kelich, Stephanie L.; Chu, Hong Wei; Flynn, Ryan; Blazar, Bruce R.; Hanenberg, Helmut; Hanash, Samir; Paczesny, Sophie; Department of Microbiology & Immunology, IU School of Medicine
    Gastrointestinal graft-versus-host-disease (GI-GVHD) is a life-threatening complication occurring after allogeneic hematopoietic cell transplantation (HCT), and a blood biomarker that permits stratification of HCT patients according to their risk of developing GI-GVHD would greatly aid treatment planning. Through in-depth, large-scale proteomic profiling of presymptomatic samples, we identified a T cell population expressing both CD146, a cell adhesion molecule, and CCR5, a chemokine receptor that is upregulated as early as 14 days after transplantation in patients who develop GI-GVHD. The CD4+CD146+CCR5+ T cell population is Th17 prone and increased by ICOS stimulation. shRNA knockdown of CD146 in T cells reduced their transmigration through endothelial cells, and maraviroc, a CCR5 inhibitor, reduced chemotaxis of the CD4+CD146+CCR5+ T cell population toward CCL14. Mice that received CD146 shRNA-transduced human T cells did not lose weight, showed better survival, and had fewer CD4+CD146+CCR5+ T cells and less pathogenic Th17 infiltration in the intestine, even compared with mice receiving maraviroc with control shRNA- transduced human T cells. Furthermore, the frequency of CD4+CD146+CCR5+ Tregs was increased in GI-GVHD patients, and these cells showed increased plasticity toward Th17 upon ICOS stimulation. Our findings can be applied to early risk stratification, as well as specific preventative therapeutic strategies following HCT.