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Changes in Cytokine mRNA Levels in Experimental Corneal Allografts after Local Clodronate–Liposome Treatment

¹ From the Department of Ophthalmology, Cornea and Immunology Unit, Hospital Geral de Santo António, Porto, Portugal; the ² Department of Ophthalmology, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Portugal; the ³ Department of Ophthalmo-Immunology, Netherlands Ophthalmic Research Institute, Amsterdam, the Netherlands; the ⁴ Department of Cell Biology, Free University, Amsterdam, the Netherlands; and the ⁵ Department of Ophthalmology, University of Amsterdam.

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)-1ß, IL-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-6, IL-10, IL-12p40, tumor necrosis factor (TNF)-, TNF-ß/lymphotoxin (LT), interferon (IFN)-, monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein 2 (MIP-2) mRNA levels were analyzed by semiquantitative reverse transcription–polymerase chain reaction (RT–PCR).

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-1ß, IL-1RA, IL-2, IL-4, IL-6, IL-10, IFN-, TNF-ß/LT, MCP-1, and MIP-2 mRNA in grafts and IL-1 ß, IL-2, IL-4, IL-6, and IFN- mRNA in rims. Interleukin-12p40 mRNA levels were unaltered in clodronate-treated rats, except for a transient increase in grafts at POD 3. TNF- 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-, 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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