Article

DAB389IL-2 suppresses autoimmune inflammation in the CNS and inhibits T cell-mediated lysis of glial target cells.

Department of Radiology, Temple University School of Medicine, Philadelphia, PA 19140.
Experimental and Molecular Pathology (Impact Factor: 2.13). 07/2013; DOI: 10.1016/j.yexmp.2013.07.004
Source: PubMed

ABSTRACT 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 αβ(+) 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-α and IFN-γ 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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May 31, 2014