Lipopolysaccharide Pretreatment of Cyclosporine-Treated Rats Enhances Cardiac Allograft Survival

Abstract

Lipopolysaccharide (LPS), the endotoxin in gram-negative bacterial cell walls, is a major factor in septic shock. Tumor necrosis factor (TNF) appears immediately after LPS release or LPS injection in rats, but when these animals have LPS reinjected for up to 7 days, TNF production is inhibited. Because inhibiting TNF with anti-TNF antibodies prolongs cardiac allograft survival and is synergistic with cyclosporine (CsA), enhanced graft survival could result from inhibiting TNF via LPS pretreatment. Accordingly, heterotopic rat heart transplants were performed in: I, untreated controls: II, LPS pretransplant treatment: III, LPS post-transplant treatment; IV, low-dose CsA posttransplant treatment; V, CsA post-transplant treatment and PBS (LPS vehicle); or VI, LPS pretransplant treatment and low-dose CsA post-transplant treatment, using Brown Norway (BN) donors and Lewis (LEW) recipients. Rejection was defined by a lack of contractions. Results showed that while LPS pre- or post-treatment alone had little allograft survival effect, LPS pretreatment combined with CsA significantly prolonged survival vs control or CsA alone (22.0 +/- 1.6 days vs 6.8 +/- 0.6 days or 13.4 +/- 1.1 days; P 3H]thymidine incorporation than untreated LEW splenocytes (3671 +/- 349 vs 7828 +/- 14 cpm). TNF assays of untreated and PBS-treated LEW spleen cells cocultured with irradiated BN spleen cells had 1.3 and 1.1 pg of TNF/106 cells, respectively, in 2 hr, but no TNF from LPS-pretreated LEW cells was detected. These results suggest that LPS-enhanced allograft survival may be due to TNF inhibition and lymphocyte suppression, providing insight into immunosuppressive mechanisms.