STAT-1 decoy oligonucleotide improves microcirculation and reduces acute rejection in allogeneic rat small bowel transplants.
During acute rejection leukocyte-endothelial cell interaction fuelled by costimulatory molecules such as the CD40/CD154 receptor/ligand dyad disrupts microcirculation of the small bowel. Downregulating endothelial CD40 expression by employing a decoy oligonucleotide (dODN) neutralizing the transcription factor signal transducer and activator of transcription-1 (STAT-1) may protect the graft. Therefore allogenic small bowel transplantation was performed in the Brown Norway to Lewis rat model. Graft vessels were pretreated with STAT-1 dODN, mutant control ODN (20 microM) or vehicle (n=8). CD40 antisense ODN and scrambled control ODN-treated transplants served as target control (n=3 each). Intravital microscopy, histology, immunohistochemistry and Western blot analyses were performed 7 days later. Functional capillary density, red blood cell velocity and perfusion index in STAT-1 dODN and CD40 antisense ODN-treated transplants were improved whereas stasis index was reduced. Leukocyte-endothelial cell interaction showed no difference. Histological parameters of rejection, infiltrating CD3-positive cells and apoptotic bodies were also reduced in STAT-1 dODN and CD40 antisense ODN-treated transplants 7 days post-transplantation. CD40 protein abundance was reduced to less than 10% of control in STAT-1 dODN-treated grafts. STAT-1 dODN blockade of CD40 expression improves mucosal perfusion, reduces graft rejection, T-cell infiltration and apoptosis in rat small bowel allografts during acute rejection.
Stojanovic
T
T
Department of Heart, Thoracic and Vascular Surgery, University Hospital Göttingen, Germany. tstojan@gwdg.de
Scheele
L
L
Wagner
A H
AH
Middel
P
P
Bedke
J
J
Lautenschläger
I
I
Leister
I
I
Panzner
S
S
Hecker
M
M
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D001783:Blood Flow Velocity; D015153:Blotting, Western; D019013:CD40 Antigens / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000276:immunology; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D006084:Graft Rejection / Q000517:prevention & control; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000098:blood supply / Q000276:immunology; D007421:Intestine, Small / Q000098:blood supply / Q000276:immunology* / Q000637:transplantation*; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D008833:Microcirculation; D023421:Models, Animal; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D050794:STAT1 Transcription Factor / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D014184:Transplantation, Homologous
D019013:CD40 Antigens; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D050794:STAT1 Transcription Factor