NFkB activation promotes immune activation in HTLV-I-associated myelopathy/tropical spastic paraparesis

Citation:

Oh U, McCormick M, Datta D, Turner R, Bobb K, Monie D, Sliskovic RD, Zhang J, Meshulam J, Jacobson S. NFkB activation promotes immune activation in HTLV-I-associated myelopathy/tropical spastic paraparesis. J Neurovirol. 2010;16 (Suppl 1) :63–64.

Abstract:

Background: Human T lymphotropic virus type I (HTLV-I) is the etiologic agent of HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic inflammatory disorder of the central nervous system. Evidence suggests that viral-induced immune activation plays a key role in the pathogenesis of HAM/TSP. The HTLV-I-encoded transactivating protein Tax is known to activate nuclear factor kappa B (NFkB), a key host signaling pathway regulating immune response, but the contribution of the NFkB pathway to the immune activation associated with HAM/TSP has yet to be fully defined. To further delineate the role of NFkB activation in HAM/TSP, we examined NFkB activation in peripheral-blood mononuclear cells (PBMC) from subjects with HAM/TSP, and tested the effect of NFkB inhibition on key ex vivo correlates of immune activation in HAM/TSP.

Materials and Methods: We examined the role of NFkB activation during immune activation associated with HAM/TSP by using small molecule NFkB inhibitors, including a newly developed selective inhibitor of NFkB, PBS-1086. NFkB activation was measured by a DNA-binding ELISA on nuclear extracts from PBMC of subjects with HAM/TSP and healthy donors to detect nuclear translocation of NFkB subunits. Immune activation in HAM/TSP PBMC was measured by tritiated thymidine incorporation, a marker for spontaneous proliferation, and by FACS analysis of the lymphocyte activation markers CD25 and CD69 and the pro-inflammatory cytokine STAT5. Proviral loads in untreated and inhibitor-treated HAM/TSP samples were measured by real time PCR.

Results: NFkB activation was assessed in peripheral-blood mononuclear cells (PBMC) from subjects with HAM/TSP and in healthy donors (HD). Nuclear translocation of the NFkB RelA was significantly higher in PBMC from subjects with HAM/TSP compared to HD (p = 0.032) following short-term (20 h) culture, indicating increased activation of the NFkB pathway in HAM/TSP. Treatment with the small molecule inhibitor PBS-1086 reduced NFkB activation (p < 0.01). PBS-1086 reduced expression of CD25 and CD69 in HAM/TSP PBMC as well as phosphorylation of STAT5 in a dose-dependent manner (p < 0.01 for all). PBS-1086 also inhibited spontaneous lymphoproliferation of HAM/TSP PBMC in a dose-dependent manner. PBS-1086treatment resulted in a mean proviral load reduction of 20% compared to untreated PBMC in a 72 h culture.

Discussion: These results indicate that NFkB activation plays a critical upstream role in the immune activation associated with HAM/TSP, and identify the NFkB pathway as a potential therapeutic target for immune modulation in HAM/TSP.

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Last updated on 06/26/2020