Interference with tissue factor prolongs intrahepatic islet allograft survival in a nonhuman primate marginal mass model.
BACKGROUND
Tissue factor (TF) expression on islets can result in an instant blood-mediated inflammatory reaction (IBMIR) that contributes to early islet loss. We tested whether peritransplant protection of islets from IBMIR with a monoclonal anti-TF antibody (CNTO859) would enhance engraftment in our nonhuman primate marginal mass model.


METHODS
Each of six pairs of cynomolgus monkeys (CM) with streptozotocin-induced diabetes was closely matched for metabolic control and was transplanted with 5,000 IEQ/kg allogeneic, ABO-compatible islets from the same donor under the cover of steroid-free immunosuppression. For each pair, experimental animals received islets cultured with 20 microg/mL anti-TF and were dosed with 6 mg/kg anti-TF intravenously, 10-25 min before islet infusion; control monkeys received an equal number of islets from the same preparation cultured without anti-TF and no in vivo treatment.


RESULTS
Early fasting C-peptide (CP) values were different between (P<0.01), but not within, pairs and correlated with in vitro functional capacity of islets as assessed by perifusion (r=0.60; P=0.022). Compared to their matched controls, experimental animals had decreased posttransplant markers of coagulation, higher fasting CP levels (1 month posttransplant and end of study) and prolonged graft function.


CONCLUSIONS
These data suggest that pretreatment of islets and the recipient with anti-TF may limit the effects of IBMIR, thereby enhancing islet engraftment and survival.
Berman
Dora M
DM
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. dberman2@med.miami.edu
Cabrera
Over
O
Kenyon
Norman M
NM
Miller
Joshua
J
Tam
Susan H
SH
Khandekar
Vrinda S
VS
Picha
Kristen M
KM
Soderman
Avery R
AR
Jordan
Robert E
RE
Bugelski
Peter J
PJ
Horninger
Denison
D
Lark
Michael
M
Davis
Janet E
JE
Alejandro
Rodolfo
R
Berggren
Per-Olof
PO
Zimmerman
Mark
M
O'Neil
John J
JJ
Ricordi
Camillo
C
Kenyon
Norma S
NS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D004305:Dose-Response Relationship, Drug; D005342:Fibrinolysis / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D008954:Models, Biological; D013311:Streptozocin; D013925:Thromboplastin / Q000187:drug effects / Q000502:physiology*; D023001:Transplantation Tolerance / Q000276:immunology*
D000911:Antibodies, Monoclonal; D013311:Streptozocin; D013925:Thromboplastin