C5a-inhibitory peptide combined with gabexate mesilate prevents the instant blood-mediated inflammatory reaction in a rat model of islet transplantation.
BACKGROUND
The instant blood-mediated inflammatory reaction (IBMIR), in which the activation of both the coagulation and the complement cascades plays a key role, is one of the main obstacles to successful islet transplantation. At present, however, no useful protocol is clinically available. Therefore the aim of this study was to examine whether complementary peptides against an active region of C5a were safe to suppress IBMIR, owing to their extremely low molecular mass, when combined with a clinically available anticoagulant.


METHODS
Complement receptors on pancreatic tissues and isolated islets were analyzed by immunohistochemical staining and flow cytometry. Two-and-a-half islet equivalents per gram of syngeneic rat islet grafts were transplanted intraportally into 4 groups of 10-13 animals each after streptozotocin induction of diabetes: control, gabexate (Gab), C5a-inhibitory peptide (C5aINH), and C5aINH plus Gab. Recipients injected with equivalent amounts of saline solution served as control subjects. Plasma samples were collected at 0, 0.5, 1, 3, 6, and 24 h after transplantation for analysis. We also evaluated the curative rate, intravenous glucose tolerance test, and insulin amounts in the liver of the recipients.


RESULTS
C3a receptor (C3aR) was scarcely expressed on the isolated islets with relatively strong expression of C5a receptor (C5aR): C3aR: 0.44 +/- 0.38%; C5aR: 7.91 +/- 2.83%). However, C5aR was not expressed on pancreatic tissues before the isolation procedures. Thrombin-antithrombin complex was significantly suppressed in the 3 treated groups (P = .0015). The curative rate was also significantly improved (0% vs 33% vs 67% vs 100%, respectively; P = .03). Glucose tolerance was significantly improved among the 3 treated groups (P < .0005). Insulin amounts in the liver were considerably higher among treated versus control hosts. Notably, the treatment did not affect the increased body weight of the recipient.


CONCLUSIONS
This study suggested that C5a-inhibitory peptide combined with gabexate mesilate may be a useful approach to control the IBMIR induced in clinical islet transplantation and one that is free of side effects.
Tokodai
K
K
Division of Advanced Surgical Science and Technology, Tohoku University, Sendai, Japan. tsu7ka5so8mi@yahoo.co.jp
Goto
M
M
Inagaki
A
A
Nakanishi
W
W
Okada
N
N
Okada
H
H
Satomi
S
S
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism*; D015936:Complement C5a / Q000494:pharmacology*; D016670:Gabexate / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology; D007249:Inflammation / Q000517:prevention & control*; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D011183:Postoperative Complications / Q000517:prevention & control; D051381:Rats; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics; D014185:Transplantation, Isogeneic
D000925:Anticoagulants; D001786:Blood Glucose; D007155:Immunologic Factors; D044087:Receptor, Anaphylatoxin C5a; D016670:Gabexate; D015936:Complement C5a