Immunosuppressive effects of defibrotide Journal Article

Authors: Ferraresso, M.; Rigotti, P.; Stepkowski, S. M.; Chou, T. C.; Kahan, B. D.
Article Title: Immunosuppressive effects of defibrotide
Abstract: The effect of defibrotide (DF) alone or in combination with CsA was examined using in vitro proliferation assays with human PBLs and in vivo heterotopic heart allografts in rate. DF alone (12.5-50 mg/ml) inhibited in vitro PBL proliferation more effectively after PHA (50-56%) or OKT3 (50-95%), than after alloantigenic (25-30%), stimulation. Furthermore, the combination of DF (1-4 mg/ml) with CsA (10-40 ng/ml) caused an 85.2-88.8% reduction in proliferative responses after OKT3 stimulation. Median-effect analysis documented that the combination index for DF and CsA was consistently lower than 0.3 at various concentration ratios of the 2 agents. Combination index values below 1.0 reflect drug synergism; those equal to 1.0 show additive, and above 1.0, antagonistic, interactions. Daily intraperitoneal injections of DF (150 mg/kg) failed to prolong the survival of Buffalo (RT-1b) heart allografts in Wistar-Furth (RT-1u) recipients, namely mean survival times of 7.0 +/- 0.7 days with, vs. 6.5 +/- 0.5 days without, DF treatment. Similarly, intravenous or intra-arterial infusion of DF (280 mg/kg) delivered directly into the heart allograft by a 7-day osmotic pump was ineffective. However, a course of local, but not systemic, DF (280 mg/kg) combined with a 14-day i.v. administration of a subtherapeutic dose of CsA (1 mg/kg) significantly prolonged heart allograft survival to 22.8 +/- 5.0 days (P < 0.001). Thus, in vitro DF is immunosuppressive alone at high concentrations, and in combination with CsA at low concentrations. Continuous infusion of DF into the graft combined with systemic administration of CsA prolonged transplant survival in vivo. These findings suggest that high tissue levels of DF potentiate the immunosuppressive effects of CsA.
Keywords: survival; proliferation; lymphocytes; cyclosporine; rejection; drugs; renal-transplantation; prostaglandin-e1; anti-thrombotic activity; allograft recipients
Journal Title: Transplantation
Volume: 56
Issue: 4
ISSN: 0041-1337
Publisher: Lippincott Williams & Wilkins  
Date Published: 1993-10-01
Start Page: 928
End Page: 933
Language: English
ACCESSION: WOS:A1993MD80500029
DOI: 10.1097/00007890-199310000-00029
PUBMED: 8212219
Notes: Article -- Source: Wos
Citation Impact
MSK Authors
  1. Ting-Chao Chou
    315 Chou