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Paulo F. Torres, Tanja P. A. M. Slegers, Ron Peek, Nico van Rooijen, Ruth van der Gaag, Aize Kijlstra, Alex F. de Vos; Changes in Cytokine mRNA Levels in Experimental Corneal Allografts after Local Clodronate–Liposome Treatment. Invest. Ophthalmol. Vis. Sci. 1999;40(13):3194-3201.
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purpose. Corneal allograft rejection in rats can be prevented by subconjunctival
injections of liposomes containing dichloromethylene diphosphonate
(clodronate–LIP), which selectively eliminate macrophages. In this
study, the effect of clodronate–LIP treatment on cytokine mRNA levels
in corneal allografts was examined.
methods. AO rats received corneal grafts of PVG rats. Rats were either
not treated or injected subconjunctivally with clodronate–LIP on the
day of transplantation and on postoperative days (PODs) 2, 4, 6, and 8.
RNA was isolated from the graft and rim of corneas at different times
after transplantation and from normal controls. Interleukin (IL)-1β,
IL-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-6, IL-10, IL-12p40,
tumor necrosis factor (TNF)-α, TNF-β/lymphotoxin (LT), interferon
(IFN)-γ, monocyte chemotactic protein 1 (MCP-1), and macrophage
inflammatory protein 2 (MIP-2) mRNA levels were analyzed by
semiquantitative reverse transcription–polymerase chain reaction
results. Corneal rejection, observed in all untreated rats by POD 12, was
associated with increased mRNA levels of all cytokines investigated in
grafts and rims. Clodronate–LIP treatment prevented allograft
rejection and strongly decreased the levels of IL-1β, IL-1RA, IL-2,
IL-4, IL-6, IL-10, IFN-γ, TNF-β/LT, MCP-1, and MIP-2 mRNA in grafts
and IL-1 β, IL-2, IL-4, IL-6, and IFN-γ mRNA in rims.
Interleukin-12p40 mRNA levels were unaltered in clodronate-treated
rats, except for a transient increase in grafts at POD 3. TNF-α mRNA
levels were increased by clodronate–LIP in grafts and rims early after
transplantation (PODs 3 and 7). Despite a normal appearance, long-term
accepted corneal grafts (POD 100) contained mRNA for IL-10, IL-12p40,
TNF-α, MCP-1, and MIP-2.
conclusions. Clodronate-liposome treatment markedly altered the mRNA levels of all
cytokines investigated in corneal allografts. These results may explain
in part the mechanism by which clodronate–LIP treatment prevents
corneal allograft rejection.
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