Prolonged survival of rat cardiac allografts by donor pretreatment with methotrexate. Enhancement by combined immunosuppressant treatment of the recipient.
Using an intraabdominal heterotopic cardiac transplant procedure, we determined that the Fischer 344 rat (donor)/Long Evans rat (recipient) combination provides a suitable model for studying acute rejection of cardiac allografts. Rejection time was 9.7 +/- 0.2 days. With this model we investigated the effect of donor pretreatment with methotrexate on allograft survival. Methotrexate injection at a single optimum dose of 100-200 mg/kg, i.p., resulted in a 55-60% increase in allograft survival with indefinite survival of some allografts. The optimum time for methotrexate administration was found to be 3-24 hr before transplant, indicating the clinical feasibility of this approach. Combining methotrexate with different recipient treatments (cyclosporine, methylprednisolone, or methylprednisolone plus azathioprine) resulted in significantly longer allograft survival than with any treatment alone. We have demonstrated a novel and clinically feasible approach to the treatment or prevention of acute allograft rejection. Such a treatment could allow reduction in the dose of immunosuppressant drugs to the recipient and thus lessen the toxicity of immunosuppressant therapy.
Kahn
D R
DR
Princeton Heart Institute, Baptist Medical Center, Alabama 35211.
Forrest
D E
DE
Otto
D A
DA
D000818:Animals; D001379:Azathioprine / Q000627:therapeutic use; D003524:Cyclosporins / Q000627:therapeutic use; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008775:Methylprednisolone / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D003524:Cyclosporins; D001379:Azathioprine; D008775:Methylprednisolone; D008727:Methotrexate