STRATEGIES FOR THE THERAPEUTIC MANIPULATION OF CYTOKINES AND THEIR RECEPTORS IN INFLAMMATORY NEURODEGENERATIVE DISEASES

Although historically considered to be an ''immunopriviledged'' anatom ical site, a diversity of events can initiate an inflammatory cascade within the central nervous system (CNS). Inflammatory cascades are cha racterized by the migration of activated leukocytes from the circulati on into perivascular locations within CNS parenchyma and can be precip itated by events such as focal ischemia, viral infection, and demyelin ating autoimmune diseases. Activated leukocytes can directly or indire ctly disrupt tightly controlled CNS microenvironments, inducing the in jury of brain cells and the attendant symptoms of neurological disease . From the onset of leukocyte migration into the CNS parenchyma, to th e activation of indigenous CNS cells and subsequently infiltrating leu kocytes, to the downregulation and exit of activated leukocytes from t he CNS, each step in a CNS inflammatory cascade is exquisitely regulat ed by cytokines. The potentia I for blocking or down regulating cytoki nes or their receptors on specific types of cells at critical points d uring the course of an inflammatory cascade provides a promising appro ach to ameliorating the cellular pathology and diseases that result fr om unchecked inflammation in the CNS. Toward this end, numerous strate gies have been developed, with some success, to block the actions of p roinflammatory cytokines in the CNS. Such strategies include the syste mic or intrathecal injection of antibodies against cytokines or their receptors, of receptor fusion proteins, or of cytokine antisense oligo nucleotides. As techniques in molecular biology become increasingly so phisticated, a second generation of strategies has focused on manipula ting the expression of cytokines or their receptors in specific types of brain cells at specific times during an inflammatory cascade. A con ceptually related approach is to exploit the CNS sequestration of CNS- antigen-specific lymphocytes and use them as vehicles to deliver antii nflammatory cytokines into loci of CNS inflammation. Although technica lly challenging, the successful development of second-generation strat egies holds tremendous therapeutic potential for CNS diseases involvin g acute and chronic inflammation. (C) 1998 Wiley-Liss. Inc.