Jm. Dopp et J. Devellis, STRATEGIES FOR THE THERAPEUTIC MANIPULATION OF CYTOKINES AND THEIR RECEPTORS IN INFLAMMATORY NEURODEGENERATIVE DISEASES, Mental retardation and developmental disabilities research reviews, 4(3), 1998, pp. 200-211
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.