Prolongation of rat skin and cardiac allograft survival by low molecular weight heparin.
BACKGROUND
We have previously reported that very low doses of low molecular weight heparin compounds (LMWH) inhibit a variety of T-cell-mediated reactions by down-regulation of TNF-alpha production. This study tested the efficacy of LMWH in organ transplantation.


METHODS
Skin and heterotopic heart transplantations were performed between recipient Wistar rats and donor BN rats. Two doses of LMWH were given sc, 1 and 20 micrograms, each in three protocols, with day of grafting as Day 0: (A) Daily: -1, 0, 1 ellipsis, (B) Late Weekly: -1, 6, 13 ellipsis, and (C) Early Weekly: -7, 0, 7 ellipsis. Doses and schedules were selected based on efficacy in autoimmune models. Skin graft rejection was defined by complete separation of the graft, and heart transplant rejection was defined as cessation of heartbeat.


RESULTS
Treatment with 1 microgram (26.8 +/- 2.0 days) and 20 micrograms (24.5 +/- 2.3 days) of LMWH using the Early Weekly protocol significantly prolonged skin allograft survival compared to controls (17.8 +/- 4.4 days), P < 0.001 for both, whereas other protocols did not. Compared to controls (8.3 +/- 1.4 days), treatment with both 1 and 20 micrograms of LMWH using all three protocols significantly prolonged cardiac allograft survival. The efficacy, however, varied considerably. Increase in graft survival ranged from 18% (1 microgram, Daily, 9.8 +/- 0.7 days, P = 0.02) to more than twofold (20 micrograms, Early Weekly, 20.8 +/- 5.5 days, P < 0.001) according to the dose and schedule of LMWH.


CONCLUSIONS
Treatment with very low doses of nonanticoagulant LMWH preparations having anti-TNF-alpha activity significantly prolongs rat skin and cardiac allograft survival in a dose- and schedule-dependent manner.
Shapira
O M
OM
Department of Cardiothoracic Surgery, Boston University School of Medicine, Boston, Massachusetts, 02118, USA. oshapira@bu.edu
Rene
H
H
Lider
O
O
Pfeffermann
R A
RA
Shemin
R J
RJ
Cohen
I R
IR
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016038:Skin Transplantation; D013997:Time Factors; D014184:Transplantation, Homologous
D006495:Heparin, Low-Molecular-Weight