Successful treatment of acute, ongoing rat lung allograft rejection with the novel immunosuppressant SDZ-RAD.
BACKGROUND
Recent experimental data have shown that coadministration of microemulsion cyclosporine and the novel immunosuppressant SDZ-RAD potentiates the immunosuppressive efficacies of both drugs to suppress allograft rejection. Our study was designed to assess the potential of delayed SDZ-RAD administration, in addition to cyclosporine maintenance therapy, to reverse acute rejection in an allogeneic rat lung transplant model.


METHODS
Unilateral left lung transplantation was performed using Brown-Norway donors implanted into Lewis recipients. An untreated control group and a cyclosporine monotherapy group (7.5 mg/kg) were followed for 7 days. An additional cyclosporine monotherapy group (7.5 mg/kg), and a combined therapy group treated with cyclosporine (7.5 mg/kg) plus SDZ-RAD (2.5 mg/kg), were followed for 21 days. For treatment of ongoing rejection, 7.5 mg/kg cyclosporine was given as maintenance therapy, and SDZ-RAD (2.5 mg/kg) was added on postoperative day 7. Drugs were given orally, and in the combined therapy regimens, administered 6 hours apart. Outcome variables included daily weight, radiographs, and histology.


RESULTS
Radiographs on postoperative day 7 showed mild and moderate opacification of the left chest in the cyclosporine monotherapy groups and the untreated control group. Addition of SDZ-RAD to cyclosporine treatment on postoperative day 7 reversed opacification by postoperative days 14 and 21. Monotherapy with microemulsion CsA resulted in mild histological rejection by day 7, which progressed to moderate rejection by day 21. Addition of SDZ-RAD on postoperative day 7 reversed acute rejection, resulting in none or minimal rejection at day 21.


CONCLUSIONS
SDZ RAD reverses acute rejection under cyclosporine maintenance therapy in a stringent lung allotransplant model.
Hausen
B
B
Transplantation Immunology, Department of Cardiothoracic Surgery, Stanford University, Palo Alto, California 94305-5407, USA. hausen@leland.stanford.edu
Boeke
K
K
Berry
G J
GJ
Christians
U
U
Schüler
W
W
Morris
R E
RE
D000208:Acute Disease; D000818:Animals; D001835:Body Weight; D000068338:Everolimus; D006084:Graft Rejection / Q000188:drug therapy*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016040:Lung Transplantation / Q000000981:diagnostic imaging / Q000473:pathology; D008297:Male; D011859:Radiography; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D012074:Remission Induction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus