Protective effect of the type IV phosphodiesterase inhibitor rolipram in EAU: Protection is independent of IL-10-inducing activity

PURPOSE. Experimental autoimmune uveoretinitis (EAU) is a cell-mediated mod el of retinal autoimmunity that is negatively regulated by interleukin (IL) -10. The antidepressant drug rolipram, a type IV phosphodiesterase inhibito r, enhances IL-10 production by monocyte/macrophages. The effect of rolipra m on induction of EAU and its associated immunologic responses was investig ated. METHODS. Mice were challenged for EAU induction by immunization with the re tinal antigen interphotoreceptor retinoid-binding protein (IRBP) or by adop tive transfer of uveitogenic T cells and were treated with rolipram. EAU se verity and immunologic responses to IRBP were analyzed. In addition, the ef fect 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 treatm ent from days 8 to 16 after immunization or when EAU was induced by adoptiv e transfer (efferent phase). Antigen-specific proliferation and interferon (IFN)-gamma production ex vivo by lymph node cells of protected mice were n ot reduced. However, the addition of rolipram directly to the culture suppr essed IRBP-driven proliferation and IFN-gamma production by primed lymph no de cells. Freshly explanted lymph node cells of treated mice showed inhibit ion of IFN-gamma mRNA but no parallel enhancement of IL-LO mRNA by quantita tive polymerase chain reaction. Rolipram inhibited EAU in IL-10 knockout mi ce equally well compared with controls and suppressed their primed lymph no de cells in culture. CONCLUSIONS. Rolipram appears to inhibit the expansion and effector functio n of uveitogenic T cells, raising the possibility that it may be useful for treatment of established disease. Contrary to expectations based on in vit ro studies, the protective effects in vivo appear to be independent of IL-1 0. The observation that suppression of antigen-specific responses is demons trable only in the physical presence of the drug suggests that, in a clinic al setting, continuous administration of rolipram might be needed to sustai n its therapeutic effect.