EVIDENCE THAT LS-2616 (LINOMIDE) CAUSES ACUTE REJECTION OF RAT ALLOGRAFTS PROTECTED BY CYCLOSPORINE BUT NOT OF LONG-TERM SURVIVING ALLOGRAFTS

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Abstract
The immunomodulator LS-2616 (Linomide) induces rejection of cyclosporine-protected rat cardiac allografts. The aim of this study was to characterize this rejection in the presence of CsA and to test LS-2616 in other models of permanent graft acceptance in the rat. PVG rat hearts were transplanted heterotopically to Wistar/Kyoto (Wi/Ky) rat recipients on day 0. The recipients were treated orally on days 0–9 with CsA (10–40 mg/kg) and/or with LS-2616 (2.5–160 mg/kg) starting at different times (day −7-+5) until the day of complete rejection. The addition of LS-2616 (day −1-stop) to CsA (10 mg/kg) resulted in a dose-dependent antagonism of the immunosuppressive effect of CsA with daily doses of 2.5–160 mg/kg. Furthermore, the results were similar, irrespective of whether LS-2616 treatment (160 mg/kg) was started on day −7, −1, +1, +3, or +5. LS-2616 (160 mg/kg) pretreatment of the recipient for 7 days before transplantation was considerably less effective. CsA (20 mg/kg) for 14 days after a PVG to DA transplantation resulted in permanent graft survival. This was not abrogated by LS-2616. Neither was rejection induced in long-term surviving grafts of RT1.C incompatible Lewis recipients. Our data suggest that LS-2616 activates already stimulated and sensitized T cells that are otherwise controlled by CsA.

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