C5a Inhibitory Peptide Combined With Gabexate Mesilate Is a Clinically Available Candidate for Preventing the Instant Blood-Mediated Inflammatory Reaction

• Published in: Transplantation proceedings 2009, Vol.41 (1), p.67-68
• Main Authors: Tokodai, K, Goto, M, Imura, T, Ogawa, N, Fujimori, K, Kurokawa, Y, Okada, H, Satomi, S
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Glucose - drug effects; Blood Glucose - metabolism; Complement C5a - therapeutic use; Diabetes Mellitus, Experimental - surgery; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gabexate - therapeutic use; Graft Survival - drug effects; Inflammation - blood; Inflammation - prevention & control; Islets of Langerhans Transplantation - adverse effects; Medical sciences; Prevention and actions; Public health. Hygiene; Public health. Hygiene-occupational medicine; Rats; Serine Proteinase Inhibitors - therapeutic use; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tissue, organ and graft immunology
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/j.transproceed.2008.10.029

Abstract 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.