Treatment of autoimmune uveoretinitis in the rat with rapamycin, an inhibitor of lymphocyte growth factor signal transduction.
Rapamycin (RAPA) is a macrolide antibiotic with unique immunosuppressive properties. RAPA inhibits T-cell function by interfering with IL-2 and IL-4 signal transduction. It does not prevent IL-2 production or IL-2R expression. The efficacy of RAPA in the treatment of autoimmune diseases was evaluated using the experimental autoimmune uveoretinitis (EAU) model. EAU was actively induced in Lewis rats by immunization with S-antigen in Hunter's adjuvant. RAPA and control vehicle were administered by continuous intravenous infusion over a 14 day period by miniosmotic pump. RAPA treatment initiated on the day of immunization or 7 days later was found to efficiently inhibit EAU induction. The minimal effective dose was 0.1 mg/kg/d. EAU inhibition was correlated with reduced number of cells in the immunization site draining lymph nodes, as well as with a shift and lowering of the peak of the lymphocyte proliferative response curve. The anti-S-antigen antibody response was delayed by 3 days under RAPA treatment and the serum levels lowered in a dose dependent manner. An initial body weight loss was observed during the first week of drug administration, but there was a normal weight gain afterward.
Roberge
F G
FG
Laboratory of Immunology, National Eye Institute, Bethesda, MD.
Xu
D
D
Chan
C C
CC
de Smet
M D
MD
Nussenblatt
R B
RB
Chen
H
H
D000818:Animals; D000941:Antigens / Q000032:analysis; D019393:Arrestin; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000032:analysis; D007074:Immunoglobulin G / Q000032:analysis; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D011090:Polyenes / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D012173:Retinitis / Q000188:drug therapy* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus; D013601:T-Lymphocytes / Q000276:immunology; D014605:Uveitis / Q000188:drug therapy* / Q000276:immunology
D000941:Antigens; D019393:Arrestin; D005136:Eye Proteins; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D011090:Polyenes; D020123:Sirolimus