PMID- 14528315
OWN - NLM
STAT- MEDLINE
DCOM- 20040624
LR  - 20071003
IS  - 1087-0156 (Print)
IS  - 1087-0156 (Linking)
VI  - 21
IP  - 11
DP  - 2003 Nov
TI  - Targeting cytokines to inflammation sites.
PG  - 1314-20
AB  - To increase the half-life of a cytokine and target its activation specifically to 
      disease sites, we have engineered a latent cytokine using the latency-associated 
      protein (LAP) of transforming growth factor-beta 1 (TGF-beta 1) fused via a 
      matrix metalloproteinase (MMP) cleavage site to interferon (IFN)-beta at either 
      its N or C terminus. The configuration LAP-MMP-IFN-beta resembles native TGF-beta 
      and lacks biological activity until cleaved by MMPs, whereas the configuration 
      IFN-beta-MMP-LAP is active. LAP provides for a disulfide-linked shell hindering 
      interaction of the cytokine with its cellular receptors, conferring a very long 
      half-life of 55 h in vivo. Mutations of the disulfide bonds in LAP abolish this 
      latency. Samples of cerebrospinal fluid (CSF) or synovial fluid from patients 
      with inflammatory diseases specifically activate the latent cytokine, whereas 
      serum samples do not. Intramuscular injection in arthritic mice of plasmid DNA 
      encoding these constructs demonstrated a greater therapeutic effect of the latent 
      as compared to the active forms.
FAU - Adams, Gill
AU  - Adams G
AD  - Bone and Joint Research Unit, William Harvey Research Institute, St. 
      Bartholomew's and Royal London School of Medicine and Dentistry, Queen Mary, 
      University of London, Charterhouse Square, London EC1M 6BQ, UK.
FAU - Vessillier, Sandrine
AU  - Vessillier S
FAU - Dreja, Hanna
AU  - Dreja H
FAU - Chernajovsky, Yuti
AU  - Chernajovsky Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20031005
PL  - United States
TA  - Nat Biotechnol
JT  - Nature biotechnology
JID - 9604648
RN  - 0 (Chemokines)
RN  - 0 (Receptors, Chemokine)
RN  - 0 (Recombinant Fusion Proteins)
SB  - IM
CIN - Nat Biotechnol. 2003 Nov;21(11):1293-4. PMID: 14595357
MH  - Animals
MH  - Cells, Cultured
MH  - Chemokines/administration & dosage/genetics/*immunology/*metabolism
MH  - Drug Delivery Systems/*methods
MH  - Endoplasmic Reticulum/immunology/metabolism
MH  - Gene Targeting/*methods
MH  - Humans
MH  - Mice
MH  - Osteitis/immunology/metabolism
MH  - Receptors, Chemokine/*immunology/*metabolism
MH  - Recombinant Fusion Proteins/administration & dosage/immunology/metabolism
EDAT- 2003/10/07 05:00
MHDA- 2004/06/25 05:00
CRDT- 2003/10/07 05:00
PHST- 2003/06/11 00:00 [received]
PHST- 2003/08/21 00:00 [accepted]
PHST- 2003/10/07 05:00 [pubmed]
PHST- 2004/06/25 05:00 [medline]
PHST- 2003/10/07 05:00 [entrez]
AID - nbt888 [pii]
AID - 10.1038/nbt888 [doi]
PST - ppublish
SO  - Nat Biotechnol. 2003 Nov;21(11):1314-20. doi: 10.1038/nbt888. Epub 2003 Oct 5.