Strategies for the therapeutic manipulation of cytokines and their receptors in inflammatory neurodegenerative diseases

Abstract

Although historically considered to be an “immunopriviledged” anatomical site, a diversity of events can initiate an inflammatory cascade within the central nervous system (CNS). Inflammatory cascades are characterized by the migration of activated leukocytes from the circulation into perivascular locations within CNS parenchyma and can be precipitated by events such as focal ischemia, viral infection, and demyelinating autoimmune diseases. Activated leukocytes can directly or indirectly disrupt tightly controlled CNS microenvironments, inducing the injury of brain cells and the attendant symptoms of neurological disease. From the onset of leukocyte migration into the CNS parenchyma, to the activation of indigenous CNS cells and subsequently infiltrating leukocytes, to the downregulation and exit of activated leukocytes from the CNS, each step in a CNS inflammatory cascade is exquisitely regulated by cytokines. The potential for blocking or downregulating cytokines or their receptors on specific types of cells at critical points during the course of an inflammatory cascade provides a promising approach to ameliorating the cellular pathology and diseases that result from unchecked inflammation in the CNS. Toward this end, numerous strategies have been developed, with some success, to block the actions of proinflammatory cytokines in the CNS. Such strategies include the systemic or intrathecal injection of antibodies against cytokines or their receptors, of receptor fusion proteins, or of cytokine antisense oligonucleotides. As techniques in molecular biology become increasingly sophisticated, a second generation of strategies has focused on manipulating the expression of cytokines or their receptors in specific types of brain cells at specific times during an inflammatory cascade. A conceptually related approach is to exploit the CNS sequestration of CNS-antigen–specific lymphocytes and use them as vehicles to deliver antiinflammatory cytokines into loci of CNS inflammation. Although technically challenging, the successful development of second-generation strategies holds tremendous therapeutic potential for CNS diseases involving acute and chronic inflammation. MRDD Research Reviews 1998;4:200–211. © 1998 Wiley-Liss, Inc.