Protective effect of the type IV phosphodiesterase inhibitor rolipram in EAU: protection is independent of IL-10-inducing activity.
OBJECTIVE
Experimental autoimmune uveoretinitis (EAU) is a cell-mediated model of retinal autoimmunity that is negatively regulated by interleukin (IL)-10. The antidepressant drug rolipram, a type IV phosphodiesterase inhibitor, enhances IL-10 production by monocyte/macrophages. The effect of rolipram on induction of EAU and its associated immunologic responses was investigated.


METHODS
Mice were challenged for EAU induction by immunization with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP) or by adoptive transfer of uveitogenic T cells and were treated with rolipram. EAU severity and immunologic responses to IRBP were analyzed. In addition, the effect of rolipram added to the culture on antigen-driven responses of primed lymph node cells was tested.


RESULTS
Rolipram treatment from days -1 to 7 after immunization (afferent phase) was not protective, but severity of EAU was reduced to 50% by treatment from days 8 to 16 after immunization or when EAU was induced by adoptive transfer (efferent phase). Antigen-specific proliferation and interferon (IFN)-gamma production ex vivo by lymph node cells of protected mice were not reduced. However, the addition of rolipram directly to the culture suppressed IRBP-driven proliferation and IFN-gamma production by primed lymph node cells. Freshly explanted lymph node cells of treated mice showed inhibition of IFN-gamma mRNA but no parallel enhancement of IL-10 mRNA by quantitative polymerase chain reaction. Rolipram inhibited EAU in IL-10 knockout mice equally well compared with controls and suppressed their primed lymph node cells in culture.


CONCLUSIONS
Rolipram appears to inhibit the expansion and effector function of uveitogenic T cells, raising the possibility that it may be useful for treatment of established disease. Contrary to expectations based on in vitro studies, the protective effects in vivo appear to be independent of IL-10. The observation that suppression of antigen-specific responses is demonstrable only in the physical presence of the drug suggests that, in a clinical setting, continuous administration of rolipram might be needed to sustain its therapeutic effect.
Xu
H
H
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-1858, USA.
Strassmann
G
G
Chan
C C
CC
Rizzo
L V
LV
Silver
P B
PB
Wiggert
B
B
Caspi
R R
RR
D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D017931:DNA Primers / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005136:Eye Proteins; D005260:Female; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012173:Retinitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D012177:Retinol-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020889:Rolipram; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014605:Uveitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000099214:Retinol-Binding Proteins, Interstitial
D017931:DNA Primers; D005136:Eye Proteins; D007371:Interferon-gamma; D016753:Interleukin-10; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D012333:RNA, Messenger; D012177:Retinol-Binding Proteins; D020889:Rolipram; D000099214:Retinol-Binding Proteins, Interstitial