Survival of mitomycin C-treated pancreatic islet xenografts is mediated by increased expression of transforming growth factor-beta.
BACKGROUND
Mitomycin C (MMC) can trigger various intracellular signals. The authors previously showed that pretreatment of highly immunogenic crude pancreatic islets with MMC improved their survival in a rat-to-mouse transplantation model. The aim of this study was to investigate the role of transforming growth factor (TGF)-beta in mediating MMC-induced survival of islet xenografts.


METHODS
: Collagenase-digested islets obtained from WS rats (RT1k) were incubated for 30 min with 10 microg/mL MMC and then transplanted into streptozotocin-induced diabetic C57BL/6 (H-2b) mice after 20 hr of culture at 37 degrees C.


RESULTS
Survival of xenografts was enhanced by pretreatment of islets with MMC. MMC-treated xenografts showed a mild inflammatory cell response and significantly minimal infiltration of macrophages, CD4 T cells, and CD8 T cells compared with untreated grafts. TGF-beta mRNA was increased at 20 hr after MMC treatment, and TGF-beta protein expression was also increased compared with untreated islet xenografts. TGF-beta concentration in blebs formed around the xenografts (but not in the serum) was higher in animals that underwent transplantation with MMC-treated islets than with untreated islets. Simultaneous transplantation of MMC-treated and untreated islets separately in each kidney of recipient mice showed that protection was only found in MMC-treated islets. Treatment of islets before transplantation by neutralizing anti-TGF-beta antibody suppressed the MMC-protective effects on graft survival, whereas no such effect was noted with isotype-matched immunoglobulin.


CONCLUSIONS
: The authors' results indicate that MMC treatment effectively reduces local inflammatory response and that such effects are mediated by increase of TGF-beta during the early period of islet transplantation.
Ise
Kazuya
K
Department of Surgery 1, Fukushima Medical University, Hikarigaoka, Fukushima, Japan.
Kanazawa
Yukio
Y
Sato
Yoshihiro
Y
Matsuyama
Shinichi
S
Gunji
Takashi
T
Endo
Yuichi
Y
Hojo
Hiroshi
H
Abe
Masafumi
M
Gotoh
Mitsukazu
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D006085:Graft Survival / Q000187:drug effects*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016685:Mitomycin / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014183:Transplantation, Heterologous / Q000276:immunology*
D000903:Antibiotics, Antineoplastic; D016212:Transforming Growth Factor beta; D016685:Mitomycin