In order to analyze a putative immunomodulatory effect of NGF in experimental autoimmune encephalomyelitis (EAE) of the Lewis rat, we transduced myelin basic protein (MBP)-specific CD4(+) T cells with a recombinant retrovirus encoding NGF. These T(MBP)NGF cells secreted high levels of NGF, along with an unaltered Th1-like cytokine pattern. Transfer studies showed that T(MBP)NGF cells were unable to mediate clinical EAE, when transferred alone, and, more important, they efficiently suppressed induction of clinical EAE by non-transduced MBP-specific T cells (T(MBP )cells). In contrast, NGF transduced ovalbumin-specific T cells, which secreted high NGF levels, did not affect EAE induction. Suppression of clinical EAE by T(MBP)NGF cells was associated with a general reduction of inflammatory CNS infiltrates, with a most pronounced decrease of the monocyte/macrophage component. Using a culture model of the endothelial blood-brain barrier (BBB), we found that NGF directly acts on blood-derived monocytes via the p75 NGF receptor, thus interfering with monocyte migration through the activated BBB endothelium. Our data establish NGF as an anti-inflammatory mediator interfering with T cell mediated autoimmune disease in the CNS. They further point to monocyte migration through blood vascular endothelium as one possible mechanism of NGF action.