C5a inhibitory peptide combined with gabexate mesilate is a clinically available candidate for preventing the instant blood-mediated inflammatory reaction.
BACKGROUND
The instant blood-mediated inflammatory reaction, characterized by activation of both the coagulation and complement cascades, is a serious obstacle to successful islet engraftment. No attractive protocol is clinically available as yet. The objective of the present study was to examine whether complementary peptide against an active region of C5a in combination with a clinically available anticoagulant could provide an effective protocol for suppression of the instant blood-mediated inflammatory reaction.


METHODS
Three islet equivalents per gram of syngeneic rat grafts were transplanted intraportally into 6 pairs of rats with streptozotocin-induced diabetes. Islets from the same donor were transplanted into each pair. In each pair, one rat was treated with C5a inhibitory peptide in addition to continuous intravenous infusion of gabexate mesilate and the other rat, injected with equivalent amount of saline solution, served as the control. In addition, 6 rats that received transplants from irrelevant donors were treated with the same dose of gabexate mesilate. We evaluated the cure rate, time to normoglycemia, liver insulin concentration in recipients, and results of in vivo glucose tolerance tests.


RESULTS
The cure rate was remarkably improved and the time to normoglycemia in cured animals was significantly shortened with C5a inhibitor plus gabexate treatment. In six rats that received only gabexate mesilate, normoglycemia was not restored during the study.


CONCLUSIONS
These data suggest that C5a inhibitory peptide combined with gabexate mesilate could be an attractive drug candidate without adverse effects to control the detrimental innate immune responses induced in clinical islet transplantation.
Tokodai
K
K
Division of Advanced Surgical Science and Technology, Tohoku University, Miyaga, Japan. tsu7ka5so8mi@yahoo.co.jp
Goto
M
M
Imura
T
T
Ogawa
N
N
Fujimori
K
K
Kurokawa
Y
Y
Okada
H
H
Satomi
S
S
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015936:Complement C5a / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery*; D004195:Disease Models, Animal; D016670:Gabexate / Q000627:therapeutic use*; D006085:Graft Survival / Q000187:drug effects*; D007249:Inflammation / Q000097:blood / Q000517:prevention & control*; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use
D001786:Blood Glucose; D015842:Serine Proteinase Inhibitors; D016670:Gabexate; D015936:Complement C5a