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Secretory lysosome targeting and induced secretion of human soluble TNF-alpha receptor in murine hematopoietic cells in vivo as a principle for immunoregulation in inflammation and malignancy.

Johansson, Åsa LU ; Kutty Selva, Nandakumar LU ; Persson, Ann-Maj LU ; Olsson, Inge LU and Hansson, Markus LU (2009) In Experimental Hematology 37. p.969-978
Abstract
OBJECTIVE: Systemic administration of immunotherapeutics often gives rise to severe side effects. A local deposition, using secretory lysosomes of hematopoietic cells as vehicles for delivery, can overcome this problem. In the present study, the validity of this concept was investigated using retroviral transduction of the human soluble tumor necrosis factor-alpha receptor 1 (hsTNFR1) into murine bone marrow cells, followed by transfer of the genetically modified cells into irradiated mice. MATERIALS AND METHODS: Bone marrow cells from donor mice were transduced with retroviral vector containing cDNA for hsTNFR1, together with a transmembrane domain and a tyrosine-sorting signal in order to facilitate the endoplasmic reticulum export and... (More)
OBJECTIVE: Systemic administration of immunotherapeutics often gives rise to severe side effects. A local deposition, using secretory lysosomes of hematopoietic cells as vehicles for delivery, can overcome this problem. In the present study, the validity of this concept was investigated using retroviral transduction of the human soluble tumor necrosis factor-alpha receptor 1 (hsTNFR1) into murine bone marrow cells, followed by transfer of the genetically modified cells into irradiated mice. MATERIALS AND METHODS: Bone marrow cells from donor mice were transduced with retroviral vector containing cDNA for hsTNFR1, together with a transmembrane domain and a tyrosine-sorting signal in order to facilitate the endoplasmic reticulum export and to achieve secretory lysosome loading. Expression of hsTNFR1 in recipient mice was investigated using flow cytometry and Western blot. Enzyme-linked immunosorbent assay was used to measure levels of tumor necrosis factor-alpha, hsTNFR1, and murine TNFR1. RESULTS: Stable long-term expression of hsTNFR1 was achieved in transplanted mice. Hematopoietic cells, such as natural killer, T and B cells, and neutrophils contained hsTNFR1. Exposure of lipopolysaccaride (in vivo) or phorbole-myristrate esterase (in vitro) induced significant secretion of hsTNFR1. Release of endogeneous murine sTNFR1 did not differ between cells transduced with hsTNFR1 or an "empty" vector. CONCLUSION: Long-term expression in vivo and inducible secretion of hsTNFR1 in murine hematopoietic cells support the potential use of storage organelles in hematopoietic cells as vehicles for targeting inflamed/malignant sites with therapeutically active agents. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Hematology
volume
37
pages
969 - 978
publisher
Elsevier
external identifiers
  • wos:000268373400010
  • pmid:19486922
  • scopus:67650032902
ISSN
1873-2399
DOI
10.1016/j.exphem.2009.05.009
language
English
LU publication?
yes
id
9317d016-1367-47ce-9c4e-0c9d260fd9c3 (old id 1434659)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19486922?dopt=Abstract
date added to LUP
2009-07-02 12:53:54
date last changed
2017-01-01 07:38:29
@article{9317d016-1367-47ce-9c4e-0c9d260fd9c3,
  abstract     = {OBJECTIVE: Systemic administration of immunotherapeutics often gives rise to severe side effects. A local deposition, using secretory lysosomes of hematopoietic cells as vehicles for delivery, can overcome this problem. In the present study, the validity of this concept was investigated using retroviral transduction of the human soluble tumor necrosis factor-alpha receptor 1 (hsTNFR1) into murine bone marrow cells, followed by transfer of the genetically modified cells into irradiated mice. MATERIALS AND METHODS: Bone marrow cells from donor mice were transduced with retroviral vector containing cDNA for hsTNFR1, together with a transmembrane domain and a tyrosine-sorting signal in order to facilitate the endoplasmic reticulum export and to achieve secretory lysosome loading. Expression of hsTNFR1 in recipient mice was investigated using flow cytometry and Western blot. Enzyme-linked immunosorbent assay was used to measure levels of tumor necrosis factor-alpha, hsTNFR1, and murine TNFR1. RESULTS: Stable long-term expression of hsTNFR1 was achieved in transplanted mice. Hematopoietic cells, such as natural killer, T and B cells, and neutrophils contained hsTNFR1. Exposure of lipopolysaccaride (in vivo) or phorbole-myristrate esterase (in vitro) induced significant secretion of hsTNFR1. Release of endogeneous murine sTNFR1 did not differ between cells transduced with hsTNFR1 or an "empty" vector. CONCLUSION: Long-term expression in vivo and inducible secretion of hsTNFR1 in murine hematopoietic cells support the potential use of storage organelles in hematopoietic cells as vehicles for targeting inflamed/malignant sites with therapeutically active agents.},
  author       = {Johansson, Åsa and Kutty Selva, Nandakumar and Persson, Ann-Maj and Olsson, Inge and Hansson, Markus},
  issn         = {1873-2399},
  language     = {eng},
  pages        = {969--978},
  publisher    = {Elsevier},
  series       = {Experimental Hematology},
  title        = {Secretory lysosome targeting and induced secretion of human soluble TNF-alpha receptor in murine hematopoietic cells in vivo as a principle for immunoregulation in inflammation and malignancy.},
  url          = {http://dx.doi.org/10.1016/j.exphem.2009.05.009},
  volume       = {37},
  year         = {2009},
}