Studies of the induction and maintenance of long-term graft acceptance by treatment with FK506 in heterotopic cardiac allotransplantation in rats

Immunosuppressive activities of the newly discovered FK506, isolated from Streptomyces tsukubaensis, were examined by using cardiac allotransplantation in the rat, and the mechanisms underlying induction and maintenance of FK506-induced long-term allograft survival were studied. Male rats of WKA (RT1k) and F344 (RT1lvl) strains were used as recipients and donors, respectively, and those of BN (RT1n) strain were used as third-party donors. Treatment with FK506, beginning from the day of allografting for 14, 10, or as few as 4 days, prolonged allograft survival significantly across the major histocompatibility barrier. The minimum doses for prolonging graft survival were 0.1 mg/kg/day by intramuscular treatment and 1.0 mg/kg/day by oral treatment. Treatment with FK506 at a dose of 0.32 mg/kg/day from day 4 until day 10 resulted in all the grafts surviving indefinitely and from days 5 to 10, half the grafts survived indefinitely, suggesting that the agent inhibited ongoing rejection. On the other hand, cyclosporine treatment at a dose of 20 mg/kg/day from day 2 did not prolong graft survival time statistically significantly. Induction of prolonged graft survival was not obtained by pretreatment of the prospective donor or recipient; prolonging effects were observed only when the agent was administered after allografting. Thus, the primary effect of the agent is exerted on responder lymphocytes reacting to the donor antigens in the induction phase of long-term graft acceptance. The mechanisms underlying the maintenance of long-term grafts were analyzed by testing the capacity of lymphocytes or serum of long-term graft-bearing rats to inhibit graft rejection in irradiated grafted hosts. Transfer of 2 x 10(8) lymphocytes from FK506-induced long-term F344 graft-bearing WKA rats resulted in indefinite survival of F344 heart allografts, but it did not prolong survival of third-party BN hearts. Transfer of 2.5 ml serum from long-term graft-bearing rats also prolonged graft survival of F344 hearts, but not BN hearts. These results suggest that donor strain-specific suppressor cells and humoral factor(s) are induced by treatment with FK506 in the presence of allografts, and that they play at least partial roles in the maintenance of long-term allograft acceptance.     

Extended total arch replacement for type B aortic dissection with ascending aneurysm following healed aortic dissection

We describe a case of type B aortic dissection with large ascending aortic aneurysm occurring 12.8 years after aortic root replacement (Cabrol procedure) in a non-Marfan patient with cystic medial necrosis of the aorta. We have successfully performed an extended total aortic arch replacement using a four-branched graft through the “L-indsion” approach (a combination of a left anterior thoracotomy and upper half median sternotomy). Of note, a histological specimen from the aneurysmal ascending aortic wall revealed “healed aortic dissection” with fibrous tissue replacing the media and intima in addition to multiple foci of cystic medial necrosis.     

The effect of FK506 on segmental pancreas allograft in mongrel dogs]

FK506 is a potent immunosuppressive agent on experimental and clinical organ transplantation. We studied the the effect of this agent on segmental pancreas allograft in mongrel dogs. Graft survival was prolonged significantly with continuous administration of FK506, 0.3mg/kg/day intramuscular and 1.0mg/kg/day orally. However such symptoms as loss of appetite, nausea and extreme emaciation were observed and caused death. While bolus therapy of FK506 (3 days administration with the dose of 1.0mg/kg i.m. from 4 to 6 day postoperatively) showed the same immunosuppressive effect as continuous therapy and less side effect. Furthermore it was suggested that FK506 plasma levels were concerned with the appearance of side effect. In conclusion, the administration of FK506 with plasma level monitoring was thought to be useful on pancreas transplantation.     

Differential sensitivity to halothane anesthesia of the genioglossus, intercostals, and diaphragm in kittens.

Recent studies in humans and animals have indicated that different inspiratory muscles have different sensitivities to respiratory depressants. The sensitivity of inspiratory muscles during early growth and development relative to that in adults of the same species, however, has not been studied. We therefore studied the activity of the diaphragm, the external intercostals, and the genioglossus by means of electromyography and its moving time average with different concentrations of halothane in seven 2-mo-old kittens. The kittens spontaneously breathed 1.0%-2.0% halothane in oxygen while PaCO2 was maintained at about 60 mm Hg by adding CO2 to the inspired gas as needed. Muscle activity was evaluated in terms of the peak height of the moving time average. Activity at 1% halothane was used as the control measurement because measurements at zero inspired concentrations of halothane could not be obtained without sedation, which is known to depress respiratory muscle activity. Halothane anesthesia significantly (P less than 0.01) decreased phasic inspiratory activity of the inspiratory muscles in a dose-dependent fashion. Genioglossal activity was completely abolished at 1.5% and 2.0% halothane. By contrast, in our previous study in adult cats under nearly identical experimental conditions, the phasic genioglossal activity was depressed but present even at 3.0% halothane. The degree of depression at 1.5% and 2.0% halothane was least in the crural diaphragm (71.8% +/- 5.8%, 66.6% +/- 4.5% of control, respectively), intermediate in the intercostals (68.9% +/- 9.6%, 35.4% +/- 8.8%), and greatest in the genioglossus (0.0%, 0.0%).(ABSTRACT TRUNCATED AT 250 WORDS)