Administration of neutralizing antibodies to interleukin-6 (IL-6) reduces experimental autoimmune encephalomyelitis and is associated with elevated levels of IL-6 bioactivity in central nervous system and circulation.
BACKGROUND
We previously demonstrated the local production of the pleiotropic cytokine interleukin-6 (IL-6) in the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis.


METHODS
To assess the role of IL-6 in autoimmune CNS inflammation, we administered neutralizing antibodies to IL-6 in the EAE model. Their effect was examined at the clinical and histopathological level. Levels of administered antibody and IL-6 bioactivity were followed in serum and cerebrospinal fluid (CSF).


RESULTS
Systemically administered antibodies penetrated into the fluid CSF in animals in which EAE was induced. Administration of anti-IL-6 reduced the development of actively induced as well as adoptively transferred EAE and was associated with increased levels of IL-6 activity in the CSF and to a lesser extent in the serum. Anti-IL-6 was still effective when given 1 day before the onset of disease signs in adoptively transferred EAE. The disease-reducing effect of anti-IL-6 was also reflected at the pathological level by the absence of inflammatory infiltrates in the CNS.


CONCLUSIONS
Our study indicates that IL-6 plays an important role in autoimmune CNS inflammation. However, due to the complex nature of the in vivo interactions of administered antibodies, the disease-reducing effect of the anti-IL-6 antibodies could be caused by neutralization of IL-6 activity or by enhancement of IL-6 activity via induction of higher IL-6 levels in the CNS.
Gijbels
K
K
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, CA 94305-5429, USA.
Brocke
S
S
Abrams
J S
JS
Steinman
L
L
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D001681:Biological Assay; D017690:Cell Transplantation; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000209:etiology*; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D015850:Interleukin-6 / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000209:etiology; D051381:Rats
D000906:Antibodies; D015850:Interleukin-6