02 May 2003
PARP inhibition is therapeutic in CNS inflammation through immunomodulationD. Hooper, R. Kean, T. Mikheeva, J. Mabley, C. Szabo, G. Scott
Med Sci Monit 2003; 9(1): 28- :: ID: 15080
We have used a novel phenathridinone PARP inhibitor, PJ-34, to probe the contribution of PARP to the pathogenesis of the multiple sclerosis model, experimental allergic encephalomyelitis (EAE). PJ-34 administration to mice immunized with myelin basic protein (MBP) significantly reduced the incidence of the disease as well as delayed the onset and reduced the severity of clinical signs of EAE in the treated mice that became sick. The loss of blood-brain barrier (BBB) integrity that facilitates immune/inflammatory cell invasion into central nervous system (CNS) tissues in EAE was inhibited by PJ-34, as was T cell infiltration into the CNS. On the other hand, the accumulation of activated monocytes in the CNS was only partly inhibited in PJ-34-treated mice that remained healthy and similar to that of diseased controls in mice where treatment was less effective. Similar patterns were seen for the expression of TNF-a, ICAM-1, IFN-g, and iNOS in CNS tissues in that PJ-34-treated mice with EAE resembled sick controls and treated mice that remained healthy were comparable to normal mice. While PJ-34 did not affect MBP-specific T cell proliferation in vitro, the proliferative response of T cells from PJ-34-treated mice immunized with MBP was reduced. The isotype profile of the antigen-specific antibodies elicited by MBP immunization was also altered, from predominantly IgG2a to IgG1 and IgG2b, by PJ-34 treatment. These results indicate that PARP inhibition is therapeutic in EAE by changing the bias of the response to MBP from pathogenic Th1-associated CNS inflammation to a Th-2 dependent humoral response.
Keywords: CNS, MS/EAE, T cells
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