DABIL-2 suppresses autoimmune inflammation in the CNS and inhibits T cell-mediated lysis of glial target cells.

Authors: Bhopale, MK  Hilliard, B  Constantinescu, CS  Fujioka, T  Ventura, E  Phillips, SM  Rostami, A 
Citation: Bhopale MK, etal., Exp Mol Pathol. 2013 Jul 17. pii: S0014-4800(13)00090-7. doi: 10.1016/j.yexmp.2013.07.004.
Pubmed: (View Article at PubMed) PMID:23872438
DOI: Full-text: DOI:10.1016/j.yexmp.2013.07.004

In multiple sclerosis (MS) and its rodent model, experimental autoimmune encephalomyelitis (EAE), activated CD4+ T cells with upregulated IL-2R mediate inflammation and demyelination in the central nervous system (CNS). DAB389IL-2, a chimeric fusion protein of IL-2 and diphtheria toxin, inhibits human and rodent IL-2 activated T cells that express the high affinity interleukin-2 receptor. In the present study, DAB389IL-2 was used to treat rats with EAE. We wanted to investigate the possibility that DAB389IL-2 could prevent tissue destruction within the CNS. We used a suboptimal dose of DAB389IL-2 that allowed substantial transmigration of inflammatory cells across the blood-brain barrier. DAB389IL-2 inhibited infiltration of CD4+, CD8+, CD25+ and TCR alphabeta+ associated mononuclear cells and inflammatory macrophages in the spinal cord on day 13 post-immunization, at the peak of disease. Gene expression study showed that DAB389IL-2 treatment suppressed TNF-alpha and IFN-gamma as well as IL-10 cytokine gene expression in the spinal cord of rats with EAE on day 13. DAB389IL-2 in vitro treatment suppressed cytotoxicity of MBP-activated T cells from rats with EAE against oligodendrocytes in culture by 66%. Astrocytes were less targeted by MBP activated T cells in vitro. This study suggests that DAB389IL-2 directly targets CD4+ and CD25+ (IL-2R) T cells and effector T cell function and also indirectly suppresses the activation of macrophage CD169+ (ED3+) and microglia CD11b/c (OX42+) populations in the CNS.


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CRRD Object Information
CRRD ID: 7364993
Created: 2013-10-15
Species: All species
Last Modified: 2013-10-15
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.