Effects of tolerance induction on the actions of interferon-gamma on porcine cardiac allografts.

It is well known that interferon-gamma (IFN-gamma) not only plays a critical role in antigen-dependent but also in antigen-independent tissue injury; however, it is not clear how tolerance induction affects the actions of IFN-gamma in the transplant setting. To address this question, we compared the effects of IFN-gamma on porcine recipients of near-syngeneic, rejecting, and tolerant heart transplants. IFN-gamma was infused continuously into the left anterior descending artery of hearts transplanted into 3 groups of major histocompatibility complex (MHC) inbred miniature swine, each treated with a 12-day course of cyclosporine A (CyA). Group 1 recipients received a MHC class I disparate heart, group 2 recipients received a near-syngeneic heart, and group 3 recipients were cotransplanted with a MHC class I disparate heart and kidney, which uniformly induces tolerance to both grafts. An additional group of animals was not transplanted but received intracoronary IFN-gamma infusion into their native hearts. IFN-gamma perfusion not only accelerated the acute rejection of MHC class I disparate hearts (mean survival time = 19 +/- 7.21 vs 38 +/- 8.19 days, P = .025), but caused near-syngeneic heart transplants, which otherwise survive indefinitely, to reject within 35 days (n = 3). In contrast, IFN-gamma perfusion had no demonstrable effects on interstitial rejection, the development of vascular lesions, or graft survival in tolerant heart plus kidney allograft recipients (n = 4) or in autologous hearts (n = 2). These results suggest that tolerance induction mitigates the damaging effects of IFN-gamma itself and that the beneficial effects of tolerance induction on acute and chronic rejection may extend to antigen-independent factors like ischemia/reperfusion injury.

Long-term acceptance of porcine pulmonary allografts without chronic rejection.

OBJECTIVES: The mechanisms and treatment of chronic rejection in pulmonary allotransplantation remain elusive. Using a strategy to induce tolerance across strong allogeneic barriers, we have employed a brief, intensive course of immunosuppression to determine whether the induction of donor-specific hyporesponsiveness would prevent allograft rejection in a preclinical model of lung transplantation using MHC-inbred miniature swine. METHODS: Orthotopic left lung allografts were performed using MHC class I-disparate donors. The recipients received a 12-day postoperative course of cyclosporine (n = 6) or a 12-day postoperative course of high-dose tacrolimus (n = 3) as their only immunosuppression. Control animals received no immunosuppression (n = 3). RESULTS: Cyclosporine-treated recipients exhibited graft survival ranging from 67 to >605 days. All six animals developed acute cellular rejection between postoperative days (PODs) 27 and 108. Two animals lost their grafts on PODs 67 and 69, before developing obliterative bronchiolitis (OB). The other four recipients developed OB between PODs 119 and 238. In contrast, all tacrolimus-treated recipients maintained their grafts long term, without developing chronic rejection (>339, >308, and >231). These recipients also exhibited donor-specific hyporesponsiveness in assays of cell-mediated lymphocytotoxity. All untreated control animals lost their grafts to acute rejection by POD 11. CONCLUSIONS: This study demonstrates the ability of a brief course of high-dose tacrolimus to induce long-term graft acceptance with donor-specific hyporesponsiveness in a class I-disparate preclinical lung transplant model.

Hormonal variations influences learning - abstract

The study attempted to evaluate the influence of hormonal status (gender and oestrous cycle) on learning in male and female rats and to determine whether this difference was affected by dopamine agonists (cocaine and amphetamine). Rats were exposed to foot-shocks in a Y-maze. Exploratory and avoidance behaviours were tested on two trials, 24 hours following conditioning (Trial 1) and 2 weeks subsequently (Trial 2). Amphetamine (1mg/kg/ml) stimulated exploratory behaviour, whereas cocaine (1mg/kg/ml) had a depressant effect at Trial 1. Avoidance learning of a potentially dangerous environment was significantly less in oestrous than in diestrous and male rats. These results provide evidence that hormonal status influences learning. Cocaine and amphetamine given in a single low doses did not produce any significant effects on avoidance learning(AU)

Effects of hormone replacement therapy on mesolimbic extracellular dopamine stress: an in vivo microdialysis study

OBJECTIVE: To determine the effects of hormone replacement therapy on dopamine (DA) release in the nucleus accumbens septi (NAS) of rats following footshock stress and to correlate these effects with locomotory behaviour. DESIGN AND METHODS: Thirty-two Long Evans rats were ovariectomized and treated with oestradiol benzoate, progesterone or oil (control group). Rats were stereotaxically implanted with guide cannulae in the NAS and dialysis probes used to sample the extra-cellular fluid (ECF). Following baseline measurements, intermittent footshocks were delivered for 10 minutes, and dialysate DA levels and locomotor activity assessed over 20 minute intervals for 2 hours by high performance liquid chromatography and a photocell activity monitor, respectively. RESULTS: At baseline, hormone replacement significantly decreased DA levels in the NAS. Oestrogen treated rats had the lowest DA release at baseline (p<0.001). Following footshock, all groups exhibited significant increases in DA levels; oestrogen treated rats showed the most significant relative increase, but absolute levels remained lowest. Locomotor activity at baseline was highest in oestrogen treated rats and showed no change after footshock, remaining higher than in other groups. All other groups showed relative increase in activity after footshock (p=0.02). CONCLUSIONS: Oestrogen pre-treatment depresses baseline DA level in the NAS, but enhances relative levels after footshock, while suppressing changes in locomotor activity. There is a general reciprocal relationship between DA levels within ECF and locomotor activity in all groups. This finding may have implications for understanding of the processes regulated by NAS dopamine, e.g. addiction or associative learning.(Au)