Simultaneous blockade of the CD40/CD40L and NF-κB pathways prolonged islet allograft survival.
Activation of NF-κB pathway and co-stimulatory system CD40/CD40L promotes the inflammation, which plays a key role in the failure of islet graft. Therefore, the purpose of this study was to determine if simultaneous blockade of CD40/CD40L and IκB/NF-κB pathways could protect islet graft. Streptozocin-induced diabetic Wistar rats were transplanted intraportally with 2000 IEQ islets isolated from Sprague-Dawley rats. The rats were divided into five groups: nontreatment group, AdGFP-treated group, Ad-IκBα-treated group, Ad-sCD40LIg-treated group, and Ad-IκBα-IRES(2) -sCD40L-treated group. The islet graft mean survival time (MST), insulin expression of islet grafts, and the levels of cytokines in peripheral blood, were measured for the animals in each group. Our study confirmed that islet cells transfected with low doses of adenovirus could achieve high transfection efficiency, and would not affect the function of islet cells (P > 0.05). Splenocytes cultured with Ad-IκBα-IRES2-CD40L-transfected islets resulted in homospecific hyporesponsiveness. The islet graft MST (>100 d) in the Ad-IκBα-IRES2-sCD40L-treated group was dramatically prolonged compared with that in the nontreatment group (7.1 ± 1.16 d). In addition, TNF-α, IL-1β, and IFN-γ were diminished in the Ad-IκBα-IRES2-sCD40L-treated group, which was commensurate with the reduced cellular infiltration (P < 0.01). Simultaneous blockade of the CD40/CD40L and IκB/NF-κB pathways could effectively extend the survival of islet grafts.
Department of Renal Transplant, Center of Nephropathy, The First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an, Shanxi Province, China.
Xiao-Hong
XH
Wang
Xiao-Ming
XM
Ding
Yang
Y
Li
Hong-Bao
HB
Liu
Wu-Jun
WJ
Xue
Xiao-Hui
XH
Tian
Xin-Shun
XS
Feng
Feng-Mei
FM
Jiao
Jin
J
Zheng
D000818:Animals; D019013:CD40 Antigens / Q000096:biosynthesis*; D023201:CD40 Ligand / Q000096:biosynthesis*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental; D006085:Graft Survival; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology; D013311:Streptozocin / Q000494:pharmacology; D013997:Time Factors
D019013:CD40 Antigens; D016207:Cytokines; D016328:NF-kappa B; D023201:CD40 Ligand; D013311:Streptozocin