Prolonged survival of hamster-to-rat pulmonary xenografts by tacrolimus (FK506) and cyclophosphamide.
BACKGROUND
Severe shortage of donor organs in clinical lung transplantation prompted us to investigate the potential use of pulmonary xenografts. The purpose of this study was to determine whether an immunosuppressive regimen of tacrolimus (FK506) and cyclophosphamide would prolong the survival of hamster-to-rat pulmonary xenografts.


METHODS
Left lung transplantation was done with male Golden Syrian hamsters used as donors and inbred male Lewis rats as recipients. Control animals (n = 10) received no immunosuppressive drugs whereas experimental animals (n = 6) were treated with tacrolimus and cyclophosphamide. Tacrolimus was administered intramuscularly at a dosage of 2 mg/kg per day on postoperative days 0 to 4, followed by 1 mg/kg per day on days 5 to 29 and 0.5 mg/kg per day on days 30 to 99. Cyclophosphamide (8 mg/kg per day) was administered orally from the day before transplantation to day 8. After transplantation the animals were monitored by chest radiography. Recipient animals were killed at timed intervals (days 60 and 100) and when the chest radiograph showed complete opacification of the transplanted lung. At necropsy, pulmonary xenografts were examined histologically for evidence of rejection, which was graded on a scale of 0 (no rejection) to 4 (severe rejection). Antihamster lymphocytotoxic antibody titer was also measured in recipient animals after transplantation.


RESULTS
Pulmonary xenografts in the control animals had a median [correction of medium] survival time of 3 days, whereas the median survival in treated animals was more than 74 days. All pulmonary xenografts in control animals had severe rejection on day 3 after transplantation, whereas those in the treated animals had no rejection on days 60 and 100. The lymphocytotoxic antibody titers in control animals increased from 1:16 before operation to 1:4096 on day 3 (p < 0.01). In the treated animals, the lymphocytotoxic antibody titer on day 21 was 1: 8, which was not different from the preoperative value (1:16).


CONCLUSIONS
These results indicate that a combination of tacrolimus and a short course of cyclophosphamide prolongs the survival of pulmonary xenografts in a hamster-to-rat model.
Komatsu
K
K
Department of Surgery, University of Pittsburgh, School of Medicine, Pa., USA.
Youm
W
W
Konishi
H
H
Kawaharada
N
N
Yousem
S A
SA
Murase
N
N
Griffith
B P
BP
Pham
S M
SM
D000818:Animals; D000961:Antilymphocyte Serum / Q000097:blood / Q000187:drug effects; D006224:Cricetinae; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016040:Lung Transplantation / Q000276:immunology* / Q000379:methods; D008647:Mesocricetus; D051381:Rats; D011917:Rats, Inbred Lew; D013047:Specific Pathogen-Free Organisms; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors; D014183:Transplantation, Heterologous
D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D016559:Tacrolimus