Assessment of new immunosuppressive drugs in a rat cardiac allograft heterotopic model.
We assessed FK506 (FK) and rapamycin (RPM) in a heterotopic abdominal rat heart transplant model using a major histocompatibility mismatch (DA to LEW). The end point of our study was histologic grading of rejection (Billingham and working formulation) at 1 week. Two doses of FK (2.0 and 8.0 mg/kg p.o., q.d.) and RPM (1.5 and 6.0 mg/kg i.p., q.d.) were compared to allografts without and with ciclosporin (12.5 mg/kg p.o., q.d.) treatment. Results show: (1) weak heartbeat and full rejection on day 5 in all untreated allografts; (2) weak heartbeat and high degree of rejection in groups receiving low doses of FK and RPM; (3) strong heartbeat and mild rejection in both high FK and RPM dose groups comparable to the results of the hearts treated with ciclosporin; (4) 1 animal in each high FK and RPM dose group showed possible signs of toxicity, and (5) the strength of the heartbeat was not a reliable indicator of the efficacy of an immunosuppressive drug. We conclude that even in a major histocompatibility mismatch model at the time of the strongest immune response (1 week), all three tested drugs can reduce the degree of rejection from severe (untreated allografts) to mild if given in an adequate dosage.
Walpoth
B
B
Department of Thoracic and Cardiovascular Surgery, University of Berne, Switzerland.
Galdikas
J
J
Vorburger
T
T
Altermatt
H J
HJ
Schaffner
T
T
Althaus
U
U
Billingham
M
M
Morris
R
R
D000818:Animals; D003524:Cyclosporins / Q000627:therapeutic use; D006084:Graft Rejection / Q000187:drug effects; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D011090:Polyenes / Q000009:adverse effects / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D020123:Sirolimus; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D003524:Cyclosporins; D007166:Immunosuppressive Agents; D011090:Polyenes; D020123:Sirolimus; D016559:Tacrolimus