Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal 
neurodegenerative disorder characterized by the selective death of motor neurons 
(MN) in the spinal cord, and is associated with local neuroinflammation. 
Circulating CD4(+) T cells are required for controlling the local detrimental 
inflammation in neurodegenerative diseases, and for supporting neuronal 
survival, including that of MN. T-cell deficiency increases neuronal loss, while 
boosting T cell levels reduces it. Here, we show that in the mutant superoxide 
dismutase 1 G93A (mSOD1) mouse model of ALS, the levels of natural killer T 
(NKT) cells increased dramatically, and T-cell distribution was altered both in 
lymphoid organs and in the spinal cord relative to wild-type mice. The most 
significant elevation of NKT cells was observed in the liver, concomitant with 
organ atrophy. Hepatic expression levels of insulin-like growth factor (IGF)-1 
decreased, while the expression of IGF binding protein (IGFBP)-1 was augmented 
by more than 20-fold in mSOD1 mice relative to wild-type animals. Moreover, 
hepatic lymphocytes of pre-symptomatic mSOD1 mice were found to secrete 
significantly higher levels of cytokines when stimulated with an NKT ligand, 
ex-vivo. Immunomodulation of NKT cells using an analogue of α-galactosyl 
ceramide (α-GalCer), in a specific regimen, diminished the number of these cells 
in the periphery, and induced recruitment of T cells into the affected spinal 
cord, leading to a modest but significant prolongation of life span of mSOD1 
mice. These results identify NKT cells as potential players in ALS, and the 
liver as an additional site of major pathology in this disease, thereby 
emphasizing that ALS is not only a non-cell autonomous, but a non-tissue 
autonomous disease, as well. Moreover, the results suggest potential new 
therapeutic targets such as the liver for immunomodulatory intervention for 
modifying the disease, in addition to MN-based neuroprotection and systemic 
treatments aimed at reducing oxidative stress.