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T-cell immune responses to Wilms tumor 1 protein in myelodysplasia responsive to immunosuppressive therapy

Sloand, Elaine M., Melenhorst, J. Joseph, Tucker, Zachary C. G., Pfannes, Loretta, Brenchley, Jason M., Yong, Agnes, Visconte, Valeria, Wu, Colin, Gostick, Emma, Scheinberg, Phillip, Olnes, Matthew J., Douek, Daniel C., Price, David, Barrett, A. John and Young, Neal S. 2011. T-cell immune responses to Wilms tumor 1 protein in myelodysplasia responsive to immunosuppressive therapy. Blood 117 (9) , pp. 2691-2699. 10.1182/blood-2010-04-277921

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Abstract

Clinical observations and laboratory evidence link bone marrow failure in myelodysplastic syndrome (MDS) to a T cell–mediated immune process that is responsive to immunosuppressive treatment (IST) in some patients. Previously, we showed that trisomy 8 MDS patients had clonally expanded CD8+ T-cell populations that recognized aneuploid hematopoietic progenitor cells (HPC). Furthermore, microarray analyses showed that Wilms tumor 1 (WT1) gene was overexpressed by trisomy 8 hematopoietic progenitor (CD34+) cells compared with CD34+ cells from healthy donors. Here, we show that WT1 mRNA expression is up-regulated in the bone marrow mononuclear cells of MDS patients with trisomy 8 relative to healthy controls and non–trisomy 8 MDS; WT1 protein levels were also significantly elevated. In addition, using a combination of physical and functional assays to detect the presence and reactivity of specific T cells, respectively, we demonstrate that IST-responsive MDS patients exhibit significant CD4+ and CD8+ T-cell responses directed against WT1. Finally, WT1-specific CD8+ T cells were present within expanded T-cell receptor Vβ subfamilies and inhibited hematopoiesis when added to autologous patient bone marrow cells in culture. Thus, our results suggest that WT1 is one of the antigens that triggers T cell–mediated myelosuppression in MDS.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: American Society of Hematology
ISSN: 0006-4971
Last Modified: 08 Aug 2019 20:38
URI: http://orca.cf.ac.uk/id/eprint/28354

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