Oleanolic Acid, a Plant Triterpenoid, Significantly Improves Survival and Function of Islet Allograft

Background. Oleanolic acid (OA) is a ubiquitous triterpenoid, with potent antioxidant and anti-inflammatory properties. Here, we tested whether these combined properties of OA can prevent nonimmunologic primary nonfunctioning and immunologic phenomena ascribed to graft rejection hence prolong islet allograft survival. Methods. Islet transplants were performed under kidney capsule of streptozotocin-induced diabetic C57BL/6 mice with BALB/c islets. Recipients were treated with 0.5 mg/day of OA intraperitoneally, and serum samples were collected once in 2 days and used for luminex, ELISA, and donor-specific antibody screening. Transplanted mice were killed at different time intervals to obtain splenocytes and kidney samples for ELISPOT, mixed leukocyte reaction, and immunohistochemical studies. Results. After transplantation, the decrement of blood glucose was significantly faster in mice receiving OA less than 2 +/- 1 days compared with untreated (4 +/- 2 days). OA prolonged survival of transplanted islets up to 23 +/- 3 days and reversed diabetes even with 250 islets. Treatment group showed increased serum interleukin (IL)-10 (twofold) and decreased inducible protein-10 and IL-4 (threefold) in luminex. Significantly reduced frequency of interferon-gamma (4.5-fold), IL-4 (3.5-fold), IL-2 (2.3-fold), and IL-17 (fourfold) producing T-cell populations were found in ELISPOT. OA-treated grafts had significant reduced and delayed infiltration of CD4+ and CD8+ T cells. OA also delayed donor-specific antibody generation up to 19 days after transplantation. Combined treatment with cyclosporine A, OA further prolonged the islet allograft survival to 34 +/- 3 days. Conclusions. In conclusion, OA is an attractive, dietary nontoxic plant triterpenoid, which suppresses the production of proinflammatory cytokines and delays graft-specific immune responses to prolong islet allograft survival.