A proteasome inhibitor effectively prevents mouse heart allograft rejection.
BACKGROUND
We have previously demonstrated in vitro that proteasome inhibitors could suppress proliferation and induce apoptosis of activated T cells. This finding suggests that such inhibitors could be used as a novel category of immunosuppressants in blocking allograft rejection.


METHODS
The proteasome inhibitor dipeptide boronic acid (DPBA) was tested in vitro for its inhibitory effect on mouse T-cell proliferation and lymphokine secretion. DPBA was also used in vivo to treat mouse heterotopic heart allograft rejection. Possible side effects of this compound were examined according to blood chemistry of mice treated with DPBA.


RESULTS
DPBA suppressed the T-cell proliferation and potently inhibited interleukin (IL)-2, IL-6, IL-10, IL-13, and IFN-gamma produced by anti-CD3-activated T cells. Given i.p. starting 1 day after transplantation at 0.66 mg/kg per day for 16 days, or at 1 mg/kg per day for 4 days followed by 0.5 mg/kg per day for 12 days, DPBA could prolong heart allograft survival to 35.5 days (mean survival time, MST) and to 36.2 days, respectively. The control group had MST of 7.3 days. When administrated 72 hr post operation at 1 mg/kg per day for 4 days, DPBA could prolong the graft survival to 19.8 days. During the course of these effective dosages, DPBA had no apparent toxicity in the liver, kidney, pancreas, or heart, according to analysis of blood chemistry.


CONCLUSIONS
The proteasome inhibitor could repress allograft rejection in mice without apparent side-effects at the effective dosages. This finding has opened a new dimension in development of novel immunosuppressants for organ transplantation.
Luo
H
H
The Research Center, CHUM, Notre-Dame Hospital, University of Montreal, Canada.
Wu
Y
Y
Qi
S
S
Wan
X
X
Chen
H
H
Wu
J
J
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004151:Dipeptides / Q000494:pharmacology*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008222:Lymphokines / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009097:Multienzyme Complexes / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors; D014184:Transplantation, Homologous
D001897:Boronic Acids; D017252:CD3 Complex; D004151:Dipeptides; D008222:Lymphokines; D009097:Multienzyme Complexes; C433028:Phe-Leu boronic acid; D011480:Protease Inhibitors; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex