Redox modulation protects islets from transplant-related injury.
OBJECTIVE
Because of reduced antioxidant defenses, beta-cells are especially vulnerable to free radical and inflammatory damage. Commonly used antirejection drugs are excellent at inhibiting the adaptive immune response; however, most are harmful to islets and do not protect well from reactive oxygen species and inflammation resulting from islet isolation and ischemia-reperfusion injury. The aim of this study was to determine whether redox modulation, using the catalytic antioxidant (CA), FBC-007, can improve in vivo islet function post-transplant.


METHODS
The abilities of redox modulation to preserve islet function were analyzed using three models of ischemia-reperfusion injury: 1) streptozotocin (STZ) treatment of human islets, 2) STZ-induced murine model of diabetes, and 3) models of syngeneic, allogeneic, and xenogeneic transplantation.


RESULTS
Incubating human islets with catalytic antioxidant during STZ treatment protects from STZ-induced islet damage, and systemic delivery of catalytic antioxidant ablates STZ-induced diabetes in mice. Islets treated with catalytic antioxidant before syngeneic, suboptimal syngeneic, or xenogeneic transplant exhibited superior function compared with untreated controls. Diabetic murine recipients of catalytic antioxidant-treated allogeneic islets exhibited improved glycemic control post-transplant and demonstrated a delay in allograft rejection. Treating recipients systemically with catalytic antioxidant further extended the delay in allograft rejection.


CONCLUSIONS
Pretreating donor islets with catalytic antioxidant protects from antigen-independent ischemia-reperfusion injury in multiple transplant settings. Treating systemically with catalytic antioxidant protects islets from antigen-independent ischemia-reperfusion injury and hinders the antigen-dependent alloimmune response. These results suggest that the addition of a redox modulation strategy would be a beneficial clinical approach for islet preservation in syngeneic, allogeneic, and xenogeneic transplantation.
Sklavos
Martha M
MM
Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Rangos Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Bertera
Suzanne
S
Tse
Hubert M
HM
Bottino
Rita
R
He
Jing
J
Beilke
Joshua N
JN
Coulombe
Marilyne G
MG
Gill
Ronald G
RG
Crapo
James D
JD
Trucco
Massimo
M
Piganelli
Jon D
JD
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000601:surgery*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000379:methods*; D008297:Male; D008665:Metalloporphyrins / Q000627:therapeutic use*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D014183:Transplantation, Heterologous / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
D000975:Antioxidants; D008665:Metalloporphyrins; C520506:manganese tetrakis-(N-ethyl-2 pyridyl) porphyrin