Diannexin decreases inflammatory cell infiltration into the islet graft, reduces β-cell apoptosis, and improves early graft function.
BACKGROUND
A major unmet challenge is to reduce the islet mass needed for insulin independence in type 1 diabetic recipients after islet transplantation. The recombinant homodimer of human annexin V, diannexin, has completed a Phase II Clinical Trial in Kidney Transplantation (NCT00615966).


METHODS
We developed a marginal islet mass transplantation model (10-12 islets per gram of recipient body weight) and investigated whether diannexin prevents β-cell apoptosis and improves islet graft function. Diannexin was administered to islet cell donors shortly before pancreas harvest, added to isolation reagents, and infused into recipients at the time of transplantation and repeated daily until day 4.


RESULTS
In the syngeneic marginal islet mass transplantation model, the median time needed to achieve normoglycemia was reduced from 17.0 days among untreated controls to 3.5 days among diannexin-treated recipients (P=0.004). Histologic analysis of islet grafts harvested on day 3 posttransplantation revealed decreased macrophage (44.7%±9.8% vs. 19.2%±3.2%, P=0.007) and T-cell infiltration (25.9%±5.5% vs. 9.1%±1.1%, P=0.004), and a lower rate of islet cell apoptosis (20.5%±2.8% vs. 7.6%±2.3%, P=0.01) with diannexin treatment. Expression profiling of the islet grafts showed significantly lower levels of mRNA for the proapoptotic molecule Bid, but higher levels of interleukin-6, interferon-γ, and immunosuppressive cytokine interleukin-10.


CONCLUSIONS
Our findings demonstrate that diannexin improves the early function of marginal mass islet grafts, and its effects are associated with reductions in inflammatory cell infiltration and β-cell death by apoptosis after islet transplantation.
Cheng
Elaine Y
EY
Department of Surgery, New York Presbyterian-Weill Cornell Medical Center, New York, NY, USA.
Sharma
Vijay K
VK
Chang
Christina
C
Ding
Ruchuang
R
Allison
Anthony C
AC
Leeser
David B
DB
Suthanthiran
Manikkam
M
Yang
Hua
H
D000818:Animals; D017304:Annexin A5 / Q000502:physiology / Q000627:therapeutic use*; D017209:Apoptosis; D003920:Diabetes Mellitus / Q000601:surgery*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D006085:Graft Survival / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D016896:Treatment Outcome
D017304:Annexin A5; D012333:RNA, Messenger; C519264:diannexin, human; D051547:Heme Oxygenase-1