Role of interleukin-1beta in acute inflammation and graft death after cell transplantation to the heart.
BACKGROUND
Poor survival of grafted cells is a major factor hindering the therapeutic effect of cell transplantation; however, the causes of cell death remain unclear. We hypothesized that interleukin-1beta (IL-1beta) might play a role in the acute inflammatory response and graft death after cell transplantation and that inhibition of IL-1beta might improve graft survival.


RESULTS
14C-labeled male skeletal muscle precursor cells were implanted into female mouse hearts by direct intramuscular injection. The amount of 14C-label provides an estimate of the surviving cell number, whereas the amount of male-specific Smcy gene measured by polymerase chain reaction indicates the total (surviving+proliferated) number of donor-derived cells. At 10 minutes after implantation, 44.8+/-2.4% of the grafted cells survived and this steadily decreased to 14.6+/-1.1% by 24 hours, and to 7.9+/-0.6% by 72 hours (n=6 in each point). Proliferation of the surviving cells, which began after 24 hours, resulted in an increase in the total cell number from 15.5+/-0.8% at 24 hours to 24.4+/-1.6% at 72 hours. Acute inflammation was prominent at 24 hours and was reduced by 72 hours, in parallel with IL-1beta expression. Administration of anti-IL-1beta antibody improved graft survival at both 24 (25.6+/-1.6%) and 72 hours (14.8+/-1.1%) and resulted in a 2-fold increase in the total cell number at 72 hours (45.8+/-2.4%). The effects of IL-1beta inhibition corresponded with a reduced inflammatory response.


CONCLUSIONS
IL-1beta is involved in acute inflammation and graft death after direct intramyocardial cell transplantation. Targeted inhibition of IL-1beta may be a useful strategy to improve graft survival.
Suzuki
Ken
K
Cell and Gene Therapy Group, Harefield Heart Science Centre, National Heart and Lung Institute, Imperial College London, Harefield, Middlesex, United Kingdom. k.suzuki@ic.ac.uk
Murtuza
Bari
B
Beauchamp
Jonathan R
JR
Brand
Nigel J
NJ
Barton
Paul J R
PJ
Varela-Carver
Anabel
A
Fukushima
Satsuki
S
Coppen
Steven R
SR
Partridge
Terence A
TA
Yacoub
Magdi H
MH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers; D002454:Cell Differentiation; D002455:Cell Division; D002461:Cell Line, Transformed / Q000637:transplantation; D002470:Cell Survival / Q000187:drug effects; D017690:Cell Transplantation / Q000009:adverse effects; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D056466:Histone Demethylases; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D032446:Myoblasts / Q000473:pathology / Q000637:transplantation*; D009205:Myocarditis / Q000188:drug therapy / Q000209:etiology* / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism; D009195:Peroxidase / Q000032:analysis; D011506:Proteins / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015778:Minor Histocompatibility Antigens
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D056466:Histone Demethylases; D007074:Immunoglobulin G; D007375:Interleukin-1; D009195:Peroxidase; D011506:Proteins; C490659:Kdm5d protein, mouse; D015778:Minor Histocompatibility Antigens