The role of macrophage migration inhibitory factor in mouse islet transplantation.
BACKGROUND
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced by many tissues including pancreatic beta-cells.


METHODS
This study investigates the impact of MIF on islet transplantation using MIF knock-out (MIFko) mice.


RESULTS
Early islet function, assessed with a syngeneic marginal islet mass transplant model, was enhanced when using MIFko islets (P<0.05 compared with wild-type [WT] controls). This result was supported by increased in vitro resistance of MIFko islets to apoptosis (terminal deoxynucleotide tranferase-mediated dUTP nick-end labeling assay), and by improved glucose metabolism (lower blood glucose levels, reduced glucose areas under curve and higher insulin release during intraperitoneal glucose challenges, and in vitro in the absence of MIF, P<0.01). The beneficial impact of MIFko islets was insufficient to delay allogeneic islet rejection. However, the rejection of WT islet allografts was marginally delayed in MIFko recipients by 6 days when compared with WT recipient (P<0.05). This effect is supported by the lower activity of MIF-deficient macrophages, assessed in vitro and in vivo by cotransplantation of islet/macrophages. Leukocyte infiltration of the graft and donor-specific lymphocyte activity (mixed lymphocyte reaction, interferon gamma ELISPOT) were similar in both groups.


CONCLUSIONS
These data indicate that targeting MIF has the potential to improve early function after syngeneic islet transplantation, but has only a marginal impact on allogeneic rejection.
Toso
Christian
C
Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton AB, Canada. Christian.toso@hcuge.ch
Serre-Beinier
Véronique
V
Emamaullee
Juliet
J
Merani
Shaheed
S
Armanet
Mathieu
M
Wojtusciszyn
Anne
A
Bosco
Domenico
D
Calandra
Thierry
T
Roger
Thierry
T
Morel
Philippe
P
Shapiro
A M James
AM
Berney
Thierry
T
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000601:surgery; D006084:Graft Rejection / Q000235:genetics; D006085:Graft Survival / Q000235:genetics; D007249:Inflammation; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D008262:Macrophage Activation; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016896:Treatment Outcome
D001786:Blood Glucose; D008263:Macrophage Migration-Inhibitory Factors; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse