Prevention of primary non-function of islet xenografts in autoimmune diabetic NOD mice by anti-inflammatory agents.
OBJECTIVE
High levels of inflammation locally in the graft during the initial days after transplantation can cause primary non-function (PNF) of grafted xenogeneic islets in NOD mice. The aim of this study was to explore in a model of spontaneous diabetes, the NOD mouse, the potential of anti-inflammatory agents in the prevention of PNF after xenogeneic islet transplantation.


METHODS
Spontaneously diabetic NOD mice were transplanted with 300 rat islets. Animals were treated with acetylsalicylic acid (AsA), rofecoxib, TGF-beta or IL-1 receptor antagonist (IL-1ra). Intra-graft expression of inflammation-related molecules was measured by real time PCR 8 h post-transplantation. At the same time point, plasma nitrite levels were measured.


RESULTS
Xenogeneic islets transplanted in control spontaneously diabetic mice resulted in PNF in 16 out of 38 mice (42%). Initial graft loss was not altered by administration of rofecoxib (30%) or TGF-beta (25%). AsA reduced the rate of rapid graft loss to 8% ( p<0.05 vs controls) and administration of IL-1ra even totally prevented PNF (0%, p<0.05 vs controls). Furthermore, all therapies prolonged the mean survival time of xenogeneic islet grafts. The inhibition of PNF by AsA was associated with decreased intra-islet levels of inflammation-related molecules (IL-1, TNF-alpha, iNOS, COX-2) and chemokines (MCP-1 and MIP-3alpha). Finally, also a diminished production of systemic nitrite levels was observed in AsA- and IL-1ra-treated islet recipients.


CONCLUSIONS
These data show that treatment with AsA or IL-1ra prevents PNF after islet transplantation in spontaneously diabetic NOD mice. Moreover, the involvement of non-specific inflammation is recognized in xenogeneic islet PNF in spontaneously diabetic NOD mice.
Gysemans
C
C
LEGENDO, UZ Gasthuisberg O and N, Herestraat 49, 3000 Leuven, Belgium.
Stoffels
K
K
Giulietti
A
A
Overbergh
L
L
Waer
M
M
Lannoo
M
M
Feige
U
U
Mathieu
C
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000601:surgery*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007783:Lactones / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D013450:Sulfones; D014183:Transplantation, Heterologous / Q000276:immunology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D001241:Aspirin