Hematopoietic secretory granules as vehicles for the local delivery of cytokines and soluble cytokine receptors at sites of inflammation.
(2004) In European Cytokine Network 15(3). p.167-176- Abstract
- Cytokines play an important role in the regulation of homeostasis and inflammation. A de-regulated cytokine function can subsequently promote chronic inflammation. This is supported by clinical evidence showing the beneficial effect of inhibiting TNF-alpha through injection of antibodies and soluble receptor in disorders such as rheumatoid arthritis and Crohn's disease. Systemic anti-TNF-alpha therapy however is associated with infectious complications. We therefore suggest a concept for the local deposition of therapeutically active agents into areas of inflammation or malignancy, based on the use of hematopoietic storage and secretory granules as delivery vehicles. Hematopoietic cells are induced to express the therapeutically active... (More)
- Cytokines play an important role in the regulation of homeostasis and inflammation. A de-regulated cytokine function can subsequently promote chronic inflammation. This is supported by clinical evidence showing the beneficial effect of inhibiting TNF-alpha through injection of antibodies and soluble receptor in disorders such as rheumatoid arthritis and Crohn's disease. Systemic anti-TNF-alpha therapy however is associated with infectious complications. We therefore suggest a concept for the local deposition of therapeutically active agents into areas of inflammation or malignancy, based on the use of hematopoietic storage and secretory granules as delivery vehicles. Hematopoietic cells are induced to express the therapeutically active protein and to store it in the secretory lysosomes. The cells migrate into a tumour or site of inflammation, where the cells become activated and release the contents of their secretory lysosomes resulting in the local delivery of the therapeutically active protein. In support of this concept, gene transfer and granule loading can be achieved using the soluble TNF-alpha receptor (sTNFR1) after cDNA expression in hematopoietic cell lines. Endoplasmic reticulum (ER)-export can be facilitated by the addition of a transmembrane domain, and constitutive secretion can be prevented by incorporating a cytosol-sorting signal resulting in secretory lysosome targeting. The sTNFR1 is released from the transmembrane domain by proteolytic cleavage and finally, regulated sTNFR1-secretion can be triggered by a calcium signal. In vivo investigations are currently determining the feasibility of local protein delivery at sites of inflammation. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/130843
- author
- Hansson, Markus LU ; Gao, Ying LU ; Rosén, Hanna LU ; Tapper, Hans LU and Olsson, Inge LU
- organization
- publishing date
- 2004
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- tumor necrosis factor, inflammation, TNF-alpha, TNF-alpha soluble, sTNFR, receptor, secretory lysosome, NK-cell, granulocyte, mast cell, secretory lysosome targeting, local delivery
- in
- European Cytokine Network
- volume
- 15
- issue
- 3
- pages
- 167 - 176
- publisher
- John Libbey Eurotext
- external identifiers
-
- wos:000224649900001
- scopus:6344287118
- ISSN
- 1952-4005
- language
- English
- LU publication?
- yes
- id
- e7674425-e0aa-4e6e-8d71-42b5b86913f9 (old id 130843)
- alternative location
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15542440&dopt=Abstract
- date added to LUP
- 2016-04-01 12:07:36
- date last changed
- 2022-01-26 23:08:38
@article{e7674425-e0aa-4e6e-8d71-42b5b86913f9, abstract = {{Cytokines play an important role in the regulation of homeostasis and inflammation. A de-regulated cytokine function can subsequently promote chronic inflammation. This is supported by clinical evidence showing the beneficial effect of inhibiting TNF-alpha through injection of antibodies and soluble receptor in disorders such as rheumatoid arthritis and Crohn's disease. Systemic anti-TNF-alpha therapy however is associated with infectious complications. We therefore suggest a concept for the local deposition of therapeutically active agents into areas of inflammation or malignancy, based on the use of hematopoietic storage and secretory granules as delivery vehicles. Hematopoietic cells are induced to express the therapeutically active protein and to store it in the secretory lysosomes. The cells migrate into a tumour or site of inflammation, where the cells become activated and release the contents of their secretory lysosomes resulting in the local delivery of the therapeutically active protein. In support of this concept, gene transfer and granule loading can be achieved using the soluble TNF-alpha receptor (sTNFR1) after cDNA expression in hematopoietic cell lines. Endoplasmic reticulum (ER)-export can be facilitated by the addition of a transmembrane domain, and constitutive secretion can be prevented by incorporating a cytosol-sorting signal resulting in secretory lysosome targeting. The sTNFR1 is released from the transmembrane domain by proteolytic cleavage and finally, regulated sTNFR1-secretion can be triggered by a calcium signal. In vivo investigations are currently determining the feasibility of local protein delivery at sites of inflammation.}}, author = {{Hansson, Markus and Gao, Ying and Rosén, Hanna and Tapper, Hans and Olsson, Inge}}, issn = {{1952-4005}}, keywords = {{tumor necrosis factor; inflammation; TNF-alpha; TNF-alpha soluble; sTNFR; receptor; secretory lysosome; NK-cell; granulocyte; mast cell; secretory lysosome targeting; local delivery}}, language = {{eng}}, number = {{3}}, pages = {{167--176}}, publisher = {{John Libbey Eurotext}}, series = {{European Cytokine Network}}, title = {{Hematopoietic secretory granules as vehicles for the local delivery of cytokines and soluble cytokine receptors at sites of inflammation.}}, url = {{http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15542440&dopt=Abstract}}, volume = {{15}}, year = {{2004}}, }