Regulation of the inflammatory response in animal models of multiple sclerosis by interleukin-12

Crit Rev Immunol. 1997;17(5-6):545-53.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Adoptive Transfer
  • Animals
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control
  • Humans
  • Inflammation / immunology*
  • Interleukin-12 / immunology*
  • Interleukin-12 / pharmacology
  • Lymphocyte Activation
  • Mice
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / prevention & control
  • Rats
  • Rats, Inbred Lew
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*

Substances

  • Interleukin-12