title: Evidence that LS-2616 (linomide) causes acute rejection of rat allografts protected by cyclosporine but not of long-term surviving allografts.
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.
authors.affiliation: Department of Surgery, University of Uppsala, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Wanders
authors.forename: P
authors.initials: P
authors.lastname: Vogt
authors.forename: A
authors.initials: A
authors.lastname: Karlsson-Parra
authors.forename: K
authors.initials: K
authors.lastname: Wonigkeit
authors.forename: B
authors.initials: B
authors.lastname: Gerdin
authors.forename: G
authors.initials: G
authors.lastname: Tufveson
mesh_terms: D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006084:Graft Rejection / Q000187:drug effects*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000502:physiology; D006912:Hydroxyquinolines / Q000009:adverse effects*; D007150:Immunohistochemistry; D016030:Kidney Transplantation / Q000502:physiology; D008297:Male; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY; D013997:Time Factors; D014184:Transplantation, Homologous / Q000502:physiology
chemical_list: D003524:Cyclosporins; D006912:Hydroxyquinolines; C045282:roquinimex