Compromised kidney graft rejection response in Vervet monkeys after withdrawal of immunosuppressants tacrolimus and sirolimus.

BACKGROUND: In nonprimates, organ allografts are often not rejected after withdrawal of immunosuppression. In this study, we examined whether such a phenomenon also occurs in primates. METHODS: Vervet monkeys were transplanted with renal allografts and treated for 60 days with tacrolimus, or tacrolimus plus sirolimus. The drugs were totally withdrawn on day 61. The survival of the monkeys was monitored, and their response to donor- or third party-derived alloantigens was examined in vivo and in vitro. RESULTS: The majority (80-100%) of the grafts survived for at least additional 30 days with no signs of acute rejection. The compromised rejection is donor-specific, because recipient monkeys failed to reject a donor-derived skin graft, but a third-party skin graft was rejected. In vitro mixed lymphocyte reaction and interleukin-2 production in the mixed lymphocyte reaction between the recipients and their donors or between the recipients and a third party had no discernable patterns, and thus did not reflect the in vivo status of the immune system. Although the recipients could not reject the graft acutely after drug withdrawal, the kidney grafts and the donor-derived skin grafts had pathological findings of chronic rejection. CONCLUSIONS: The rejection response of the monkeys to an established graft after withdrawal of immunosuppression is compromised. The compromised rejection is specific and is not due to a permanent alteration of the immune system by the initial drug treatment. The allografts are not inert but have low levels of interaction with the recipient immune system.

Effect of tacrolimus (FK506) and sirolimus (rapamycin) mono- and combination therapy in prolongation of renal allograft survival in the monkey.

BACKGROUND: Our previous studies confirmed that tacrolimus (FK506) and sirolimus [rapamycin (RAPA)], in combination, are not antagonistic but are synergistic in the prolongation of heart and small bowel grafts in the rodent. The aim of this study was to confirm further the synergistic effect of combined FK506 and RAPA in the more clinically relevant model, kidney transplantation in monkeys. METHODS: A total of 60 male Vervet monkeys were randomly assigned to 10 groups (n> or =5). Monkeys with renal allografts were treated with different doses of FK506 and/or RAPA orally for 60 days. Graft survival, body weight, clinical biochemistry determinations, oral glucose tolerance test, trough levels of the two drugs, and histopathology were investigated. RESULTS: Low doses of FK506 (1 or 4 mg/kg) combined with RAPA (0.5 mg/kg) produced synergistic effect in the prolongation of renal graft survival [combination index (CI) = 0.292, 0.565]. There were no additive or synergistic drug-associated toxicities such as hyperglycemia, nephrotoxicity, and hyperlipidemia. There also was no pharmacological antagonism. CONCLUSION: Concomitant therapy of low-dose (drug-optimal) FK506 and RAPA produced a synergistic effect in the prolongation of kidney allograft survival in Vervet monkeys without additive drug-associated toxicities.

Studies in suppression of nocifensive reflexes measured with tail flick electromyograms and using intrathecal drugs in barbiturate anesthetized rats.

We report on the effects of somatic conditioning stimuli on the reflexive nocifensive tail flick electromyograms (TFEMGs) in the rat anesthetized with continuous pentobarbital infusions. Rather than using a reflexive tail movement as a measure of noxious responses, TFEMGs were recorded from the base of the rat's tail as this gave more reliable results in the anesthetized state. In order to demonstrate the compatibility of this model with previous tail flick studies, we demonstrated an inhibition of TFEMGs by intrathecal morphine which was reversed by intravenous naloxone. The TFEMG latencies were then shown to be increased by electroacupuncture. This effect was antagonized by intrathecal naltrexone pretreatment. All of these results under barbiturate anesthesia resembled those observed previously in awake rats. The constant pentobarbital infusion maintained a stable baseline state, as reflected by TFEMG latencies and blood pressure recordings during the prolonged time-course of each experiment (approximately 1 h). We feel that this method of studying electroacupuncture suppression of nocifensive reflexes is valuable for its relative simplicity and reliability. It also has the virtue of avoiding the pitfalls of such studies in awake animals.

Long latency spinal cord dorsum potential; suppression by intrathecal morphine and enkephalin analog.

We have developed a new method which combines intrathecal recordings of spinal cord dorsum potentials (CDPs) with application of drugs to the spinal cord via an intrathecal catheter. With this technique we have discovered a late component (LC) in the CDP which has not been previously described. The LC is evoked by high intensity electrical stimulation of the rat tail. Whereas previous reports describe early components in the CDP evoked by low intensity A-fiber stimulation, ours is the first to describe a late evoked potential implicating C-fiber activation of the cord. Moreover, we show that the LC is blocked by intrathecal application of morphine sulphate or D-Ala-Met-enkephalinamide in a naloxone reversible manner. We postulate that this LC represents, at least in part, the spinal cord evoked response to C-polymodal nociceptive afferent inputs.