Modulation of the IL-10/IL-12 cytokine circuit by interferon-beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis.
IFN-beta has been shown to be effective in the treatment of multiple sclerosis (MS). However, the primary mechanism by which IFN-beta mediates its therapeutic effect remains unclear. Recent studies indicate that under defined conditions, IFN-beta may downregulate DC expression of IL-12. We and others have shown that IFN-beta may also downregulate IL-10. In light of the recently proposed paradigm that an IL-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease, we examined the effect of IFN-beta on the development and behavior of the autoreactive T cell repertoire during experimental autoimmune encephalomyelitis (EAE), an animal model sharing many features with MS. SWXJ mice were immunized with the immunodominant p139-151 determinant of myelin proteolipid protein (PLP), and at onset of EAE were treated every other day with IFN-beta. After eight weeks of treatment, we assessed autoreactivity and observed no significant IFN-beta effect on splenocyte proliferation or splenocyte production of IFN-gamma, IL-2, IL-4, or IL-5 in response to the priming determinant used to initiate disease. However, in IFN-beta treated mice, the cytokine profile in response to the priming immunogen was significantly skewed toward an increased production of IL-10 and a concurrent decreased production of IL-12. Moreover, the in vivo modulation of the IL-10/IL-12 immunoregulatory circuit in response to the priming immunogen was accompanied by an aborted development of epitope spreading. Our results indicate that IFN-beta induces a reciprocal modulation of the IL-10/IL-12 cytokine circuit in vivo. This skewed autoreactivity establishes an inflammatory microenvironment that effectively prevents endogenous self-priming thereby inhibiting the progression of disease associated with epitope spreading.
Tuohy
V K
VK
Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, 44195, Cleveland, OH, USA. tuohyv@ccf.org
Yu
M
M
Yin
L
L
Mathisen
P M
PM
Johnson
J M
JM
Kawczak
J A
JA
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007114:Immunization; D016899:Interferon-beta / Q000494:pharmacology*; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018991:Myelin Proteolipid Protein / Q000276:immunology / Q000494:pharmacology; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D018984:Epitopes, T-Lymphocyte; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151); D016753:Interleukin-10; D018664:Interleukin-12; D016899:Interferon-beta