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.
Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA.
Angaswamy
A
Nataraju
Deepti
D
Saini
Sabarinathan
S
Ramachandran
Nicholas
N
Benshoff
Wei
W
Liu
William
W
Chapman
Thalachallour
T
Mohanakumar
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000975:Antioxidants / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D007328:Insulin / Q000097:blood; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009828:Oleanolic Acid / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013370:Subrenal Capsule Assay; D014184:Transplantation, Homologous / Q000276:immunology / Q000502:physiology
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D007328:Insulin; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid