Donor pretreatment with DHMEQ improves islet transplantation.
BACKGROUND
Currently, pancreatic islet transplantation to achieve normoglycemia in insulin-dependent diabetes mellitus (IDDM) requires two or more donors. This may be due to the inability to transplant functionally preserved and viable islets after isolation. Islets have already been subjected to various harmful stresses during the isolation process leading to apoptosis. One of the intracellular signaling pathways, the transcription factor nuclear factor-kappaB (NF-kappaB)-related pathway, is relevant to the mechanism of beta-cell apoptosis in isolated islets. We attempted to prevent islet apoptosis during isolation by a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ).


METHODS
DHMEQ was injected intraperitoneally into donor mice 2 h prior to isolation. NF-kappaB activation, the functioning of isolated islets, apoptosis after isolation, and cytokine- and apoptosis-related genes were analyzed. After 160 equivalents of islets were transplanted into diabetic mice, graft survival and function were evaluated.


RESULTS
Intra-islet NF-kappaB was activated immediately after isolation, and DHMEQ inhibited NF-kappaB activation without deterioration of islet function. DHMEQ significantly prevented apoptosis by inhibiting caspase 3/7 activities and down-regulated Bax, a pro-apoptotic gene. Donor pretreatment with DHMEQ significantly improved engraftment in syngeneic islet transplantation in mice, thus preserving insulin contents in the graft liver, as assessed by functional and histologic analyses.


CONCLUSIONS
DHMEQ is a promising agent in islet transplantation because it protects islets from apoptosis during isolation stress. Donor pretreatment with DHMEQ can significantly affect the success of islet engraftment.
Takahashi
Tohru
T
Department of General Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan. Ttohru616@aol.com
Matsumoto
Shuichiro
S
Matsushita
Michiaki
M
Kamachi
Hirofumi
H
Tsuruga
Yosuke
Y
Kasai
Hironori
H
Watanabe
Masaaki
M
Ozaki
Michitaka
M
Furukawa
Hiroyuki
H
Umezawa
Kazuo
K
Todo
Satoru
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D003512:Cyclohexanones / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D005947:Glucose; D005951:Glucose Tolerance Test; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D014019:Tissue Donors; D014185:Transplantation, Isogeneic; D019737:Transplants; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D001549:Benzamides; D003512:Cyclohexanones; D016207:Cytokines; D007328:Insulin; D016328:NF-kappa B; D051028:bcl-2-Associated X Protein; C464444:dehydroxymethylepoxyquinomicin; D053148:Caspase 3; D053179:Caspase 7; D005947:Glucose