Image-guided intrathymic injection of multipotent stem cells supports lifelong T-cell immunity and facilitates targeted immunotherapy Journal Article

Authors: Tuckett, A. Z.; Thornton, R. H.; Shono, Y.; Smith, O. M.; Levy, E. R.; Kreines, F. M.; van den Brink, M. R. M.; Zakrzewski, J. L.
Article Title: Image-guided intrathymic injection of multipotent stem cells supports lifelong T-cell immunity and facilitates targeted immunotherapy
Abstract: T-cell deficiency related to disease, medical treatment, or aging represents a major clinical challenge and is associated with significant morbidity and mortality in cancer and bone marrow transplantation recipients. This study describes several innovative and clinically relevant strategies to manipulate thymic function based on an interventional radiology technique for intrathymic injection of cells or drugs. We show that intrathymic injection of multipotent hematopoietic stem/progenitor cells into irradiated syngeneic or allogeneic young or aged recipients resulted in efficient and long-lasting generation of functional donor T cells. Persistence of intrathymic donor cells was associated with intrathymic presence of cells resembling long-term hematopoietic stem cells, suggesting a self-renewal capacity of the intrathymically injected cells. Furthermore, our approach enabled the induction of long-term antigen-specific T-cell-mediated antitumor immunity following intrathymic injection of progenitor cells harboring a transgenic T-cell receptor gene. The intrathymic injection of interleukin-7 prior to irradiation conferred radioprotection. In addition, thymopoiesis of aged mice improved with a single intrathymic administration of low-dose keratinocyte growth factor, an effect that was sustained even in the setting of radiation-induced injury. Taken together, we established a preclinical framework for the development of novel clinical protocols to establish lifelong antigen-specific T-cell immunity. © 2014 by The American Society of Hematology.
Keywords: controlled study; mortality; nonhuman; cancer patient; flow cytometry; neoplasms; cd8+ t lymphocyte; t-lymphocytes; mouse; phenotype; animals; mice; cancer immunotherapy; low drug dose; morbidity; animal experiment; animal model; stem cell transplantation; cell renewal; age factors; radiation injury; whole body radiation; cellular immunity; immunotherapy; antigens; receptors, antigen, t-cell; thymus gland; cd4+ t lymphocyte; hematopoietic stem cells; single drug dose; immunophenotyping; upregulation; hematopoietic stem cell; disease models, animal; bone marrow transplantation; lymphopoiesis; multipotent stem cell; multipotent stem cells; recombinant interleukin 7; drug administration route; cell selection; whole-body irradiation; radiation protection; immunity, cellular; male; female; priority journal; article; recombinant keratinocyte growth factor; intrathymic administration
Journal Title: Blood
Volume: 123
Issue: 18
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2014-05-01
Start Page: 2797
End Page: 2805
Language: English
DOI: 10.1182/blood-2013-10-535401
PUBMED: 24652996
PROVIDER: scopus
PMCID: PMC4007607
Notes: Export Date: 1 August 2014 -- CODEN: BLOOA -- Source: Scopus
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MSK Authors
  1. Andrea Tuckett
    15 Tuckett
  2. Yusuke Shono
    33 Shono
  3. Odette Marsinay Smith
    95 Smith
  4. Emily Rose Levy
    9 Levy
  5. Fabiana Maria Kreines
    14 Kreines