TY - JOUR
T1 - Prevention of autoimmune diabetes and islet allograft rejection by beta cell expression of XIAP
T2 - Insight into possible mechanisms of local immunomodulation
AU - Obach, Mercè
AU - Hosseini-Tabatabaei, Azadeh
AU - Montane, Joel
AU - Wind, Katarina
AU - Soukhatcheva, Galina
AU - Dai, Derek
AU - Priatel, John J.
AU - Orban, Paul C.
AU - Verchere, C. Bruce
N1 - Funding Information:
This work was supported by grants to CBV from the JDRF ( 47-2013-521 ). MO was supported by a BC Children's Hospital Research Institute fellowship and the Canadian Institutes of Health Transplant Training Program . AHT and JM were supported by postdoctoral fellowships from the JDRF . CBV holds the Irving K Barber Chair in Diabetes Research and a BC Children's Hospital Research Institute Investigator award . The authors acknowledge core support from the Canucks for Kids Fund Childhood Diabetes Laboratories and Ms. Sigrid Alvarez for helpful suggestions.
Publisher Copyright:
© 2018
PY - 2018/12/5
Y1 - 2018/12/5
N2 - Overexpression of the X-linked inhibitor of apoptosis (XIAP) prevents islet allograft rejection. We constructed an adeno-associated virus expressing XIAP driven by the rat insulin promoter (dsAAV8-RIP-XIAP) for long-term beta-cell gene expression in vivo. Pancreatic delivery of dsAAV8-RIP-XIAP prevented autoimmune diabetes in 70% of non-obese diabetic (NOD) mice, associated with decreased insulitis. Islets from Balb/c mice transduced with dsAAV8-RIP-XIAP were protected following transplantation into streptozotocin (STZ)-diabetic Bl/6 recipients, associated with decreased graft infiltration. Interestingly, dsAAV8-RIP-XIAP transduction induced expression of lactate dehydrogenase (LDHA) and monocarboxylate transporter 1 (MCT1), two genes normally suppressed in beta cells and involved in production and release of lactate, a metabolite known to suppress local immune responses. Transduction of Balb/c islets with AAV8-RIP-LDHA-MCT1 tended to prolong allograft survival following transplant into STZ-diabetic Bl/6 recipients. These findings suggest that XIAP has therapeutic potential in autoimmune diabetes and raise the possibility that local lactate production may play a role in XIAP-mediated immunomodulation.
AB - Overexpression of the X-linked inhibitor of apoptosis (XIAP) prevents islet allograft rejection. We constructed an adeno-associated virus expressing XIAP driven by the rat insulin promoter (dsAAV8-RIP-XIAP) for long-term beta-cell gene expression in vivo. Pancreatic delivery of dsAAV8-RIP-XIAP prevented autoimmune diabetes in 70% of non-obese diabetic (NOD) mice, associated with decreased insulitis. Islets from Balb/c mice transduced with dsAAV8-RIP-XIAP were protected following transplantation into streptozotocin (STZ)-diabetic Bl/6 recipients, associated with decreased graft infiltration. Interestingly, dsAAV8-RIP-XIAP transduction induced expression of lactate dehydrogenase (LDHA) and monocarboxylate transporter 1 (MCT1), two genes normally suppressed in beta cells and involved in production and release of lactate, a metabolite known to suppress local immune responses. Transduction of Balb/c islets with AAV8-RIP-LDHA-MCT1 tended to prolong allograft survival following transplant into STZ-diabetic Bl/6 recipients. These findings suggest that XIAP has therapeutic potential in autoimmune diabetes and raise the possibility that local lactate production may play a role in XIAP-mediated immunomodulation.
KW - Apoptosis
KW - Autoimmunity
KW - Lactate
KW - Transplantation
KW - Type 1 diabetes
KW - XIAP
UR - http://www.scopus.com/inward/record.url?scp=85048829976&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000447987600005&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1016/j.mce.2018.05.015
DO - 10.1016/j.mce.2018.05.015
M3 - Article
C2 - 29883690
AN - SCOPUS:85048829976
SN - 0303-7207
VL - 477
SP - 48
EP - 56
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
ER -
