The role of interleukin-12 in immune responses in the nervous system

Many organ-specific autoimmune diseases are mediated by T lymphocytes of the Th1 subset, i.e., producing the proinflammatory cytokines interleukin (IL)-2, interferon (IFN)-γ, and tumor necrosis factor. On the other hand, Th2 cytokines, IL-4, IL-10, IL-13 may have a protective effect. Experimental autoimmune encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune attack against the myelin of the central nervous system, characterized by neurological deficits such as paralysis, thus representing a useful model for the human inflammatory demyelinating disease multiple sclerosis. IL-12, a product of antigen-presenting cells and phagocyte cells, is a heterodimeric cytokine which is essential for the development of Th1 immune responses. Neutralization of IL-12 can suppress monophasic EAE. Investigating immunologic mechanisms in a relapsing model of EAE which closely resembles relapsing-remitting multiple sclerosis, we demonstrate here a crucial role for IL-12 in the pathogenesis of spontaneous relapses. Because in this model bacterial superantigens such as staphylococcal enterotoxins A or B can precipitate relapses, we demonstrate that IL-12 neutralization can block superantigen-induced relapses. Blocking the interaction between the CD40 Ligand (CD154) on activated T cells and the costimulatory molecule CD40 on antigen-presenting cells suppresses EAE. Here we show that IL-12 reverses suppression of experimental autoimmune encephalomyelitis achieved through the blockade of the CD40 ligand-CD40 interaction. Cells of the central nervous system such as astrocytes and the resident macrophages, microglia, can have immune functions and can present antigen to T cells. Here we also demonstrate that IL-12 is expressed in the nervous system during T cell-mediated autoimmunity and that astrocyte and microglia antigen presentation is IL-12 dependent. Moreover, we show that these cells can produce IL-12. We investigate whether the Th1/Th2-dichotomy dictates susceptibility to EAE, and show that, after immunization with neuroantigen, resistant mice produce IL-4 while susceptible mice produce IFN-γ. Neutralization of IL-4 yielded resistant mice susceptible. Preliminary analysis of the IL-12 receptor expression in splenic T cells of these mice did not show any differential upregulation. Expression of the IL-12 receptor in this experimental system will be subject to further investigation. These experiments show an essential role for IL-12 at multiple levels in EAE and suggest that therapeutical approaches targeting this important proinflammatory cytokine may be useful for the treatment of multiple sclerosis