Use of low-dose cyclosporine A/methotrexate to prolong rat cardiac allograft survival.
Cyclosporine A (CSA) is the standard immunosuppressive agent used in human cardiac transplantation to prevent rejection; however, adverse side effects have been reported at therapeutic doses. Therefore, a need remains for the implementation of specific therapies designed to achieve transplant success with a minimum of undesirable side effects. The aims of the present study were: (1) to evaluate the efficacy of a low-dose CSA (1.0 mg/kg/day) / methotrexate (MTX) (450 micrograms/kg/week) combination therapy in prolonging rat cardiac allograft survival, and (2) to determine the effects of low-dose CSA/MTX on interleukin-2 (IL-2) gene expression in rat cardiac allografts. The average time to rejection of newborn donor Brown Norway (BN) rat hearts transplanted into the ear pinnae of CSA/MTX-treated adult Lewis recipients, measured by the absence of electrocardiographic (ECG) activity, more than doubled from day 8 post-transplantation (post-tx) to day 18 post-tx when compared to allografts in untreated control recipients (p < or = 0.01). Northern blot analysis demonstrated that IL-2 mRNA transcripts in cardiac allografts treated with low-dose CSA/MTX were detected as early as day 1 post-tx, and at increasing levels as rejection progressed post-tx. When IL-2 gene expression in allografts from CSA/MTX-treated recipients was compared to levels in allografts from untreated recipients, no significant difference in the pattern of IL-2 induction was observed. In contrast, IL-2 mRNA transcripts were not detected post-tx in allografts from recipients treated with high-dose (15 mg/kg/day) CSA or in cardiac isografts. The presence of IL-2 gene transcripts, therefore, appears to be allograft-specific.(ABSTRACT TRUNCATED AT 250 WORDS)
Pizarro
T T
TT
Department of Cell Biology, Neurobiology and Anatomy, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois 60153.
Malinowska
K
K
Kovacs
E J
EJ
Clancy
J
J
Robinson
J A
JA
Piccinini
L A
LA
D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage*; D004423:Ear; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D006339:Heart Rate; D016027:Heart Transplantation / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016042:Transplantation, Heterotopic
D007376:Interleukin-2; D016572:Cyclosporine; D008727:Methotrexate