Suppression of collagen-induced arthritis by natural killer T cell activation with OCH, a sphingosine-truncated analog of alpha-galactosylceramide.
OBJECTIVE
OCH, a synthetic analog of alpha-galactosylceramide with a truncated sphingosine chain, stimulates natural killer T (NKT) cells to produce predominantly Th2 cytokines. Thus, OCH may be a potential agent for the treatment of Th1-mediated autoimmune diseases. This study was designed to evaluate the protective effects of OCH on collagen-induced arthritis (CIA) in mice.


METHODS
Mice were immunized with type II collagen (CII) and injected intraperitoneally twice per week with OCH, before or after the onset of CIA. They were monitored to assess the effect of OCH treatment on the severity of disease. Anti-CII antibodies and cytokine production were measured by enzyme-linked immunosorbent assay. Expression of cytokine genes was determined by quantitative reverse transcriptase-polymerase chain reaction.


RESULTS
OCH inhibited CIA in wild-type C57BL/6 (B6) mice but not in NKT-deficient mice. OCH suppressed CIA in SJL mice, which are prone to autoimmune diseases and have a deficiency in the number and function of NKT cells which is similar to that in patients with autoimmune diseases, even after disease has already developed. Disease protection conferred by OCH correlated with its ability to selectively induce Th2 cytokine production mediated by NKT cells and to promote collagen-specific Th2 responses. Neutralization of interleukin-4 (IL-4) or IL-10 with monoclonal antibodies abolished disease protection by OCH, indicating a critical role for these cytokines.


CONCLUSIONS
Taken together, our findings suggest that OCH holds possibilities as a therapeutic agent for autoimmune diseases such as rheumatoid arthritis.
Chiba
Asako
A
National Institute of Neuroscience, NCNP and Juntendo University School of Medicine, Tokyo, Japan. miyake@ncnp.go.jp
Oki
Shinji
S
Miyamoto
Katsuichi
K
Hashimoto
Hiroshi
H
Yamamura
Takashi
T
Miyake
Sachiko
S
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D005699:Galactosylceramides / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013110:Sphingosine; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D005699:Galactosylceramides; D016753:Interleukin-10; D015847:Interleukin-4; D013110:Sphingosine