Dipeptide boronic acid, a novel proteasome inhibitor, prevents islet-allograft rejection.
BACKGROUND
We have demonstrated previously in vitro that proteasome inhibitors suppress the proliferation, and induce the apoptosis, of activated T cells. This implies that they could be used as a novel category of immunosuppressants to block allograft rejection. Therefore, in this study, dipeptide boronic acid (DPBA) was tested for its effect on mouse islet transplantation.


METHODS
First, DPBA was investigated in vitro for its effect on mouse mixed lymphocyte reaction (MLR) and cytotoxic T-lymphocyte (CTL) activity. DPBA was then used in vivo to treat mouse islet-allograft rejection.


RESULTS
Both MLR and CTL were dose dependently suppressed by the proteasome inhibitor. A 17-day DPBA regimen resulted in islet-allograft survival in 50% of the recipients for a duration of up to 60 days, whereas the control group without immunosuppressants rejected the islet graft in 7 days. DPBA showed moderate side effects according to blood biochemistry; the function of endogenous islets after treatment appeared normal on glucose challenge.


CONCLUSIONS
The proteasome inhibitor could inhibit islet-allograft rejection in mice without serious side effects at therapeutic dose levels. This has opened a new dimension in the development of better immunosuppression regimens for islet transplantation.
Wu
Yulian
Y
Laboratory of Immunology, Centre hospitalier de l'Universite de Montreal (CHUM)-Notre Dame Hospital, Montreal, Quebec, Canada.
Han
Bing
B
Luo
Hongyu
H
Shi
Guixiu
G
Wu
Jiangping
J
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D002469:Cell Separation / Q000379:methods; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D007515:Islets of Langerhans / Q000166:cytology; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods; D007519:Isoantigens / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology*
D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D007519:Isoantigens; D009097:Multienzyme Complexes; C433028:Phe-Leu boronic acid; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex