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Am J Neurodegener Dis 2013;2(2):129-139

Original Article
Tocilizumab infusion therapy normalizes inflammation in sporadic ALS
patients

Milan Fiala, Mathew T Mizwicki, Rachel Weitzman, Larry Magpantay, Norihiro Nishimoto

Department of Surgery, David Geffen School of Medicine at UCLA, 100 UCLA Medical Plaza, Suite 220, Los Angeles,
CA 90095-6970, USA; Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los
Angeles, 650 Charles E. Young Drive, Los Angeles, CA, 90095-1735, USA; Department of Molecular Regulation for
Intractable Diseases, Institute of Medical Sciences, Tokyo Medical University, Minamisenba, Chuo-ku, Osaka, 542-
0081, Japan

Received April 8 2013; Accepted May 19 2013; Epub June 21, 2013; Published July 1, 2013

Abstract: Patients with sporadic amyotrophic lateral sclerosis (sALS) show inflammation in the spinal cord and
peripheral blood. The inflammation is driven by stimulation of macrophages by aggregated superoxide dismutase 1
(SOD1) through caspase1, interleukin 1 (IL1), IL6 and chemokine signaling. Inflammatory gene activation is inhibited
in vitro by tocilizumab, a humanized antibody to IL6 receptor (IL6R). Tocilizumab inhibits global interleukin-6 (IL6)
signaling, a key mechanism in chronic rheumatoid disorders. Here we studied in vivo baseline inflammatory gene
transcription in peripheral blood mononuclear cells (PBMCs) of 10 sALS patients, and the effects of tocilizumab
(ActemraR) infusions. At baseline, one half of ALS subjects had strong inflammatory activation (Group 1) (8 genes up
regulated >4-fold, P<0.05 vs. controls) and the other half (Group 2) had weak activation. All patients showed greater
than four-fold up regulation of MMP1, CCL7, CCL13 and CCL24. Tocilizumab infusions in the Group 1 patients resulted
in down regulation of inflammatory genes (in particular IL1β), whereas in the Group 2 patients in up regulation of
inflammatory genes. Post-infusion serum and CSF concentrations of tocilizumab inhibited caspase1 activation in vitro.
Three of 5 patients receiving tocilizumab infusions showed time-limited attenuation of clinical progression. In
conclusion, inflammation of sALS patients at baseline is up- or down-regulated in comparison to controls, but is
partially normalized by tocilizumab infusions. (AJND1304002).

Keywords: Amyotrophic lateral sclerosis, tocilizumab, ActemraR, macrophage, superoxide dismutase1, caspase1,
interleukin1, interleukin6, CCL24, CCL20

Address correspondence to: Dr. Milan Fiala, 100 UCLA Medical Plaza, Suite 220, Los Angeles, CA 90095-6970.
Phone: 310-206-6392; Fax: 310- 246-1321; E-mail: Fiala@mednet.ucla.edu