Regulation of the inflammatory response in animal models of multiple sclerosis by interleukin-12.
Interleukin 12 (IL-12), a novel heterodimeric protein produced primarily by antigen-presenting cells, serves as a key regulator of innate and adaptive immune responses. In addition to being a potent inducer of IFN-gamma, IL-12 is widely considered to be the principal cytokine that regulates the generation of Th1 type effector cells. As the successful induction of experimental autoimmune encephalomyelitis (EAE) is associated with a strong Th1 type cellular response, we have evaluated the role of IL-12 in regulating the pathogenesis of EAE in SJL/J mice and Lewis rats. In both settings, treatment with IL-12 was found to accelerate the onset and increase the severity and duration of clinical disease. More importantly, administration of IL-12 to Lewis rats that had recovered from primary disease was found to trigger clinical relapse. In all instances, IL-12-induced exacerbation was associated with a profound increase in iNOS positive macrophages within the perivascular lesions. Although IL-12-induced IFN-gamma does not appear to be required for exacerbation of disease, neutralizing antibodies against murine IL-12 delay the onset and reduce the severity of adoptively transferred EAE, indicating a role for endogenous IL-12 as regulator of disease. Based on the above findings, effective inhibition of IL-12 in vivo may have great therapeutic value in the treatment of MS and other Th1-associated inflammatory disorders.
Leonard
J P
JP
Genetics Institute, Andover, MA 01810, USA.
Waldburger
K E
KE
Schaub
R G
RG
Smith
T
T
Hewson
A K
AK
Cuzner
M L
ML
Goldman
S J
SJ
D019264:Adoptive Transfer; D000818:Animals; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology* / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology* / Q000517:prevention & control; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D018664:Interleukin-12