RAD, a new immunosuppressive macrolide in murine corneal transplantation.
BACKGROUND
RAD is a novel macrolide immunosuppressant with effects on growth factor signalling. We investigated the potency of RAD in inhibiting allograft rejection in the rat model of orthotopic allogeneic penetrating keratoplasty.


METHODS
Fifty-four allogeneic orthotopic penetrating keratoplasties were performed using Fisher rats as donors and Lewis rats as recipients. The animals were divided into five groups: syngeneic control, allogeneic control, RAD 1.5 mg/kg bw per day, RAD 2.5 mg/kg bw per day, cyclosporin A (CSA) 10 mg/kg bw per day. Medication started on the day of operation and continued daily for the duration of 18 days. Each animal was examined by slit-lamp microscopy every 3rd day. For immunohistological evaluation rats were killed on day 14. Immunohistology was performed using monoclonal mouse anti-rat antibodies against CD4, CD8, CD25, CD45 and CD54.


RESULTS
The average transplant survival time in the allogeneic combination was 12.3 days (+/- 0.3). Therapy with RAD 1.5 mg/kg and 2.5 mg/kg led to a statistically significant prolongation of transplant survival to 32.3 days (+/- 11.3, P<0.05) and 37.7 days (+/- 12.5), respectively. This efficacy was similar to that of CSA 10 mg/kg (39.7 +/- 12.5 days). There was a statistically significant reduction in the number of CD4+, CD8+ as well as CD45+ cells in both the RAD- and the CSA-treated animals compared with the allogeneic control.


CONCLUSIONS
The results show that oral immunosuppression with RAD significantly prolongs corneal allograft survival. Further investigation of RAD in preclinical and clinical high-risk keratoplasty is warranted.
Reis
A
A
Eye Clinic, Heinrich-Heine University, Düsseldorf, Germany. reis@uni-duesseldorf.de
Megahed
M
M
Reinhard
T
T
Braunstein
C
C
Godehardt
E
E
Sundmacher
R
R
D000284:Administration, Oral; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D003315:Cornea / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015948:Keratoplasty, Penetrating; D018942:Macrolides / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
D015703:Antigens, CD; D007166:Immunosuppressive Agents; D018942:Macrolides; C416483:RAD macrolide