Prolongation of Allograft Survival in Rat Heterotopic Heart Transplantation by Tlck, a Serine Protease Inhibitor

Morrissey, Paul; Gollin, Gerald; Brusett, Kent; Marks, William H.

doi:10.1097/00007890-199402000-00027

Cited by 6 publications

(1 citation statement)

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“…Body weight and clinical behavior were monitored each morning; transplanted grafts function was assessed by palpation for the ventricular impulse and graded daily for rejection using a previously validated heart beat scoring system ranging from 4 (normal) to 0 (rejection). 13 These assessments were made in reference to a cohort of syngeneic heart transplants observed over an extended period. Hearts possessing a barely palpable impulse or complete cessation of ventricular motion were considered rejected.…”

Section: Postoperative Assessment and Endpointsmentioning

confidence: 99%

Immunosuppressive effect of combination schedules of brequinar with leflunomide or tacrolimus on rat cardiac allotransplantation

et al. 1999

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Drug toxicity is one of the major problems in clinical immunosuppression. Combining two immunosuppressants in low or ineffective doses is an attractive strategy if it helps to reduce drug-related toxicity. We examined the immunosuppressive efficacy of brequinar (BQR) in combination with leflunomide (Lef) or tacrolimus (FK) in a heterotopic rat cardiac allotransplantation model. Abdominal heterotopic heart grafts (DA × LEW) were immunosuppressed from the time of transplantation and continued until the ninth posttransplant day (POD) in experiments examining prophylaxis of rejection treatment (PRT). In a separate series of experiments designed to test rescue treatment (RT), immunosuppression was begun on POD 4 and continued for 10 days; transplanted rats were sacrificed the following day intentionally. Cardiac rejection was monitored by palpation and documented by light microscopy. Immunosuppressive drugs (BQR 3 mg/kg and 12 mg/kg; BQR 3 mg/kg + Lef 5 mg/kg; BQR 3 mg/kg + FK 0.5 mg/kg) were given orally by gavage; thrice weekly according to the monotherapy or dual-therapy dosing protocol. Median survival time of the cardiac graft for controls (no treatment) was 5 days. BQR monotherapy 3 mg/kg (low dose) improved graft survival (P = 0.003); graft histology showed moderate acute rejection. BQR monotherapy 12 mg/kg (therapeutic dose) application in the PRT or RT treatment arms of the study design resulted in aorticgraft ruptures and clinical toxicity in each treatment arm due to overimmunosuppression; normal graft morphology was maintained. Successful rescue of rejecting grafts was histologically documented. Combining BQR with Lef or FK in the PRT protocol showed prolonged graft survival in both drug combination groups (median survival time, 14 days; P = 0.009 and 0.014, respectively). Using an identical combination protocol for RT, all grafts achieved a 14-day graft survival; cardiac histology showed reversible moderate acute rejection. BQR given in the presence of Lef or FK not only prevented acute rejection but intercepted it so long as it was administered; grafts were rejected within 4 days of stopping immunosuppression in the PRT study. These combinations using low or subtherapeutic doses may be important for controlling transplant rejection and rescuing ongoing graft rejection. The need for continuing treatment in this strongly allogeneic model is highlighted.

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Section: Postoperative Assessment and Endpointsmentioning

confidence: 99%

Immunosuppressive effect of combination schedules of brequinar with leflunomide or tacrolimus on rat cardiac allotransplantation

et al. 1999

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Effect of peritransplant FTY720 alone or in combination with post-transplant tacrolimus in a rat model of cardiac allotransplantation

Pirenne

Antoniou

et al. 1998

Transplant International

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FTY720 is a recently discovered compound that is derived from the fungus Isaria sinclairii. Using a DA donor-to-LEW recipient rat combination, we assessed the efficacy of peritransplant FTY720 alone or in combination with post-transplant tacrolimus on the survival of cardiac allografts. Peritransplant FTY720 given orally at a dose of 5 mg/kg on days-1 and 0 prolonged graft survival from 5 to 13 days (P < 0.05). Combining peritransplant FTY720 with post-transplant tacrolimus resulted in a further prolongation of allograft survival. The lymphocyte count in transplanted rats decreased within 24 h to 46.6%. Analysis of lymphocyte subsets by FACS revealed that FTY720 affected the total population of CD3-bearing T cells while the ratio of CD4 to CD8 cells remained unchanged. Kidney and liver biochemistry remained elevated for 2 weeks. In conclusion, FTY720 is a powerful immunosuppressive agent when used as induction therapy and may have an additive effect--perhaps a synergistic one--with post-transplant tacrolimus.

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Combination treatment effectively intercepts advanced acute cardiac rejection

Antoniou

Xu²,

Howie

et al. 1997

Transplantation Proceedings

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Prolongation of Allograft Survival in Rat Heterotopic Heart Transplantation by Tlck, a Serine Protease Inhibitor

Cited by 6 publications

References 0 publications

Immunosuppressive effect of combination schedules of brequinar with leflunomide or tacrolimus on rat cardiac allotransplantation

Immunosuppressive effect of combination schedules of brequinar with leflunomide or tacrolimus on rat cardiac allotransplantation

Effect of peritransplant FTY720 alone or in combination with post-transplant tacrolimus in a rat model of cardiac allotransplantation

Combination treatment effectively intercepts advanced acute cardiac rejection

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